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If they do a reverse split it may benefit longs, but it depends on timing and whether or not it will be followed by a capital raise. If have to raise after they split, then that will hurt big time. But if they raise before they reverse split -- assuming they do need to raise before study news -- then even if it drops it would recover above reverse split price with positive endpoint news. It would reduce stock price manipulation, and any initial fear drop can recover. Yet if they reverse split, and the stock drops, and then raise they do before news breaks would be done at that further depressed price. That could be a significant dilution. I doubt they would do it that way. If they do, it would mean they are desperate for funding. I suspect given yesterday's news that they will only do a verse split at a point where it's clear that they don't need to raise anytime soon, should they opt to do one.
No, I do not mean to imply that, at all. It is impossible for me to determine -- without specific enrollment and progression study data— that if OS endpoint were to to trigger in May/June" timeframe it somehow means a OS median bad news. It’s a lot easier to determine whether the study is going well, verses badly based on when endpoints are reached and how much time has passed since then. But that said, I still think it’s unlikely that we reach the OS threshold anytime soon.
Now why do I see it the way I do? The company gave us an estimated timing of when we could expect the 233 OS event to come in, below:
“There are 331 patients enrolled in the Trial. The Trial endpoints involve thresholds of 248 “events” for PFS and 233 “events” for OS. PFS events are primarily tumor progression (i.e., recurrence), although they can occasionally be patient deaths which occur without prior evidence of tumor recurrence. OS events are patient deaths. The PFS and OS events are continuing to accumulate as the Trial continues. The PFS events have surpassed the 248-event threshold, but the OS events have not yet reached the 233-event threshold. Based upon the pace of OS events during the last six to eight months, the Company’s current anticipation is that it will be several months until the Trial reaches 233 OS events.” — NW Bio Feb 2017
https://www.nwbio.com/nw-bio-announces-lifting-clinical-hold-dcvax-l-phase-iii-trial-fda-progression-free-survival-events-reached-overall-survival-events-not-yet-reached/
They told us they anticipated it would take “several months” to cross the OS endpoint. But they used the progression-to-death conversion pace average starting from either August 2016 (6 months) or June 2016 - (8 months). Think about that 6-to-8 month period that the company referenced for a second. Most of the death events that comprised that period would be coming from patients who possibly had first progression events that came in at least a few months earlier, which dates back progression to Early 2016/Late 2015. And that would mean the pace events would contain a fair amount of patients who may have been screened during the height of enrollment ramp-up period (Fall 2014 - Fall 2015).
What do we know about screening in that period? Germany opened enrollment and had begun screening to a lower White Blood Count inclusion criteria. And so it’s reasonable for me to assume that the death events that came during the June 2016 - February 2017 timeframe contained a fair amount of German patients whose immune systems may have been compromised. These immune comprised patients, particularly if on placebo only, would be more likely to be unable to tolerate cytotoxic drugs, which would result in lower PFS, and that subsequently converts to an earlier death. These are the patients that they include in their event pace. They are not apples to apples to the progression that convert to death patients that we should expect to see now if you ask me.
Said another way, we are waiting for the patients with progression events that triggered in late 2016/early 2017 to convert to a death event. We don't know how many patients we are specifically waiting for. But the patient pool that remains alive -- both with and without a of progression event -- are not the same as those who have died during the company "death pace" estimation period -- regardless that all the patients may have come from similar enrollment periods. Understand there are patients who recur before progression medians. And these patients would be more likely to convert into death events that triggered before the OS median. Then there are patients who recur at or after progression medians. And these later recurrences patients would be more likely to convert into death events that trigger after the OS Median. PFS events correlate to OS events. But, the earlier on a patient progresses, the more likely the time between progression to death be brief. The longer progression is delayed, the MEAN time between progression to death begins to rises. But means are averages. Healthier patients at progression, leads to a health delay in death, particularly if the patients have time to mount an immune response. And so we possibly have to wait for the events of the above average patients to come in.
Neither the MEAN pace or the MEDIAN pace accurately captures the distance it could take for "late progression" patient on average to die. The reality is that the company under enrolled. And because they did, there is a smaller group of patients that death events can convert from progression than originally anticipated. Those patients that contributed to progression event that occurred after the 248 patient progression event was reached are least likely to contribute to death events here and now. The longer the patient goes without a first progression event, the more likely they are able to move onto subsequent therapies. The patients tumor MGMT status doesn't change even if it does take on a Mesenchymal signature. And so if they were responsive to TMZ before progression, the odds are they will be again. Those odds go up the greater the distance to their last TMZ adjuvant treatment. The late progression patients may be eligible for repeat surgery and possibly even targeted radiation therapy -- therapies that are synergistic with the vaccine, particularly for the crossover patients. Prior trials did not have patients continue on vaccine therapy after progression. This one does. And there has been no DCVax-L study that treated recurrent patients at the first confirmed sign of progression. This study allows for that, supply permitting. Then there is the fact that the crossover patients do not have to wait for the vaccine to be made for them. And so hopefully for the healthier immune patient the vaccine extends the distance between progression and death. While we may not know how many months out from progression the patients may be, we do know that it could take a long time for patients who are responding to salvage therapy to die. The event pace of deaths that converted from early last year's progression patients shouldn't be the pace that is used to ballpark how long we have to wait now. And so I was simply was pointing out that I think we may have a way to go to reach OS.
It's a combination of not wanting to argue when we are all just waiting for the final results, plus being very short on time; also been reading all the AACR abstracts. Better use of the time I do have. :)
Yes, you did eventually see that there was a possibility that they wouldn't unblind at progression. That's true. I brought it up, not to point out my accuracy, but instead to say that it wasn't as we didn't understand it was a possibility. The longs on this iHub did discuss it.
I think it's nuts that folks have used the fact that trial was not unblinded at the progression endpoint against the company, as if it reveals something negative. Reality is that treating PFS as an interim always existed as an option within the protocol. I didn't uncover anything that anyone else with a protocol copy couldn't find. But yes, I did suspect it before I received my copy. That 2014 Annual shareholder meeting led me to believe they wouldn't unblind progression before recording enough OS events. And it doesn't spell trouble to me that they opted to keep progression blinded. And I agree with you that it may have been somewhat of a evolving decision to keep it blinded for now. It could even be based on the fact that they didn't meet their enrollment expectations. We don't know. Since they are waiting on OS, it certainly makes sense to me that the Company would want to capture the longer tail events for the PFS KM Curve. That's a smart decision in terms of regulatory review -- assuming there is a long tail advantage for vaccine and vaccine crossover patients, as far as I'm concerned -- though we may have to suffer through some stock volatility.
Folks who are not invested are entitled to vocalize their negative and skeptical opinions. It's rinse and repeat post in my opinion. I'm tired of rinsing and repeating the counter arguments so I mostly stopped -- at least for now. They are welcome to have the stage. It certainly has no bearings on my shareholder position. I haven't been adding or reducing risk. The stock has certainly been volatile though. Just because the stock is suffering from lack of support after capital raises, it has no bearing on the study outcome. Shareholder support is lighter due to the relentless attacks, no doubt. I don't think the overall share count is out of control were if/when study news comes in it won't come back. If they do need to raise again before the results are in, then that obviously could change the risk/reward picture. We all get the risks. The company has always been able to raise, and so I believe should they need to, they will continue to. I'm expecting that they will do what they need to do to get to the end of the study. And just like you, I'll be very happy if this study OS endpoint comes in later, as believe if it does it will result in a positive outcome. :)
Flip,
Most PsPD are MGMT methylation. But that does not mean that most MGMT methylation presents PsPD. Radiation causes a blood barrier disruption to allow the drugs to get through better. But many tumors will not respond due to hypoxia. The rates of PsPD went up once TMZ was brought up front. But that doesn't mean all PsPD (mimic progression -- inflammation swelling) will show up at the 2 weeks post radiation. Many will show up later. It's the patients that have residual disease at BASELINE scan that were more likely to have shown signs of psPDs that early on IMHO. And you know my viewpoint afterwards -- there will be PsPD who show up in both arms as not all PsPD show up at the two week post window.
RANO effectively allows for a pseudo decision tree, and this trial will benefit from it. And RANO also captures progression of disease earlier than MacDonald as the non-enhancing disease component of using T-2/FLAIR means that PFS can be caught earlier in patients, before it shows up as enhancement disease in patients. In fact when RANO was used the medians PFS is about 1.3 months sooner than MacDonald. OS didn't change. There has to be something said about capturing progression before neurological signs show in a patient. Had RANO, with the FLAIR non enhancement disease component, been used when my nephew was a patient, then his progression would have been caught before his seizure event. They may have been able to start Bevacizamub and TMZ again or salvage therapy sooner. And he would have been eligible for his vaccine at crossover. And so the way I see it is that the patients who progress in this study will be able to be treated at a time that all therapies can help and be synergistic with the vaccine.
You and I debated long ago whether the trial would remain blinded at PFS endpoint. I was adamant that it would. You were convinced it would not. Now that it has and I was correct, the shorts are having a field day. But the protocol always had the option to treat the 100% PFS events as an interim to OS and they are in fact doing that.
I don't have much time lately to read/post. When I do, it's the same nonsense of allegations and "trial failure" hogwash. Rinse and repeat as they do. Once enrollment closed, the company had no control over PFS or OS. They are waiting just as we are.
I will say that I see that the death event rate at this point in the study will be slower than what most of this iHub expects. I will not be surprised one but if we are still waiting in the Fall. While the study has reached over 248 progression events by now, I suspect it will take a bit of time for those progression events to convert to death. While the median time from progression to death may be 7-9 months (depending on the image assessment -- using RANO is results in a 9 month median) even the event rate should have a long tail, similar to PFS and OS. Therefore in my opinion it isn't a simple 5-7 months after progression endpoint that the OS endpoint will hit. The fact is that the study under enrolled by 17 patients, so there is less of a patient pool to which to derive OS events. It is also fact that the event rate is not a stagnant occurrence. The one the company witnessed may have been based on the median. And I perceive the event rate is now at the longer tail. Patients who evented shortly after enrollment will be patients who were not as responsive to one or more of the standard of care therapies (i.e, Radiation, TMZ or a bit of both). But the patients who reached progression later in the study were responsive to standard of care therapy. And there reason to believe they will be responsive again. Typically the longer the patients go without recurrence, the more likely they will qualify for another surgery. MGMT status does not change at progression. The more time the patient is off TMZ, the more likely they will be responsive once again. I'm long as the next person, but let me be clear, I know we reached 248 progression events. I just honestly believe we still have a way to go to OS endpoint. I was correct on the my assumption that the company wouldn't unblind the trial at progression. I sense I'll be accurate about this too. Time will tell.
Excellent news.
I'm here for the long hall. An investor not a trader. I realize that a bunch of the volume is trading volume. Share count is low. And they have plenty of capital for prior raise. Any short swings means I can sell out my highest share costs and rebuy if they continue to discount. It's great news today. This company will have a successful pipeline. This is the start.
Institutional owners undoubtedly added today. SNGX captured the market's attention today. Volume spoke volumes. It's only the start IMHO. But expect a possible dip given the jump today.
Someday MUST be hurting. Happy with my holdings. :)
Interesting. My guess is that it may be due to Novocure. That device was approved in 2015. If memory serves me, I believe it was official approved in October 2015. With that device approval it may have been deemed unreasonable to limit newly diagnosed GBM patients care to less than the "new standard" before and after a progression event. I can imagine how the FDA may have wanted to put the company on notice and new screening on hold.
If the Company were to screen additional patients after that device approval it would likely require a new set of consent forms due to a new accepted standard of care. Consent would need to include use of that device at newly diagnosed GBM and would require IRB review. And so, who knows, maybe the Company initially considered screening but then the process was drawn out and they became concerned about screening under a new standard. If they were to screen now, the use of that device potential adds a PFS confounding variable, if the patients adhere to a new SoC before progression event. Perhaps that's why they stopped screening outside the US as well. And perhaps they didn't want to mention it -- other than they did in SEC statements-- as that device adds another possible confounding element to OS. And while the truth may be that device use might not be widespread adoption factor during the dates of this trial or at least it wasn't in late 2015-mid 2016. But, I can see why they would want to avoid the "confounding" of survival topic, particularly as it isn't uncommon for skeptics to use any gray news, to try an twist news to make it appear worse than it is.
The likelihood is that there are a few patients opted to try the device at recurrence, and as this trial gets closer to the end that likelihood goes up. Patients who progressed before 2016 wouldn't of had the option. Anyway, just a thought over that bit of new info.
Believe it was 306 patients enrolled by the time the halt went into effect. Forget how we know that. But, yes, now you're following the pipeline. :)
Sorry, it's really hard for me to chat today. But I wanted to at least respond to the bulk of your message.
First consent equals screening eligible. It isn't as B states where patients were turned away from the trial if they were not at the pre-leuk point. The Company only stopped accepting new consent in mid-August. Anyone who signed just before the halt was eligible to see if they qualified to met all inclusion criteria. And that means a possible few straggler enrolled patients in November 2015. Hope that helps. :)
Anyone who signed the first consent form entered the screening process; but they weren't officially "eligible" to complete the other screening steps until they had surgery. The FDA could have made the Company turn away those patients who were not quite at surgery point. That's possible. But I doubt they did that, the same as you. We were told that just stopped them from pursuing new recruitment. And so in theory there may have been a few patients who literally signed their consent forms the day before the halt went into effect. In practice, I think it is highly improbable that all the 25 patients (beyond the 306 that were already randomized by the time of the halt) signed their first consent form on the day before the "no more consent" forms allowed for "new" screening halt passed. Doing so would have meant their were no patients in the pipeline, and since they were recruiting heavily back then it's more likely that patients were at various points on route to randomization.
We also know the halt occurred days before that PR -- Tasty discovered it over at IV. By time we "officially" learned of the halt I would imagine all the last signed consent to lysate surgeries were scheduled, if not done on most of the last screened in patients. With GBM, due to its infiltrate nature surgery is pretty much shortly after a patient learns they have the disease. Usually these are not the type of surgeries that are delayed, even if the consent form was requested back signed in advance. But yes, I agree it definitely is possible that a few nGBM patients who signed initial consent were awaiting a surgery date, given the possible summer holidays to schedule around. Don't think that the assumptions that all 331 surgeries being completed by August 2015 is wrong or that it will have made much of a difference if it's ends up being that a couple of patients surgery dates landed in early September.
Back to waiting patiently. :)
They describe recruitment of new patient, basically as the protocol did, as in before first consent is signed.
Here's the releases:
"NW Bio Confirms Phase III Trial of DCVax®-L for GBM Brain Cancer Is Ongoing
Patients In Trial Continuing To Be Treated Per Protocol, Including In Germany
BETHESDA, MD, August 21, 2015 – Northwest Biotherapeutics (NASDAQ: NWBO) (“NW Bio”), a U.S. biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, confirmed today that its Phase III trial of DCVax®-L for newly diagnosed glioblastoma multiforme (GBM) is ongoing and the patients enrolled in the trial are continuing to be treated per the protocol.
Over 300 patients have been recruited for the trial. The total anticipated enrollment is 348 patients.
The only change in status of the trial is that new screening of patient candidates for the trial has been temporarily suspended while the Company submits certain information from the trial for regulatory review.
Such screening involves the initial evaluation of patient candidates to determine whether they meet eligibility criteria for the trial (e.g., whether they are within the eligible age range, do not have certain viral diseases, etc.)
Some blogs and social media comments have noted that the EudraCT trials database in Europe states that there is a “Temporary Halt” of the trial in Germany. In actuality, the trial status in Germany is that the trial is ongoing as noted above, and the Company has only undertaken a temporary suspension of new screening.
The Company has sought to have the EudraCT listing corrected, but the database includes only certain pre-specified categories and there is no category that corresponds to a temporary suspension of new screening only, while a trial is ongoing.
The Company is in the process of preparing the trial information for regulatory review and anticipates submission within the next couple of weeks."
**
Dear Regina,
Last Friday, we issued an announcement confirming that our Phase III clinical trial of DCVax®-L remains ongoing and that all patients in the trial continue to be treated in accordance with the protocol, including in Germany. We mentioned in that announcement that some 300 patients out of the anticipated total 348 patients have been enrolled in the trial.
Following our announcement, certain bloggers tried to introduce "confusion" about the enrollment number, and we received some questions from shareholders about whether the 300 were actually enrolled in the trial and being treated, or were just screened.
We addressed those questions today, and incorporated the answers in an 8-K filed with the SEC, so that all shareholders and the public can have the benefit of those answers.
The answer is that the 300 patients are actually enrolled in the trial and being treated. And, none of these 300 patients are in the Information Arm or the Pseudo-Progression Arm outside the trial.
For your convenience, you will find the relevant sections of the 8-K filing, including the questions and answers, by clicking HERE. You can access the complete filing by going to our website at www.nwbio.com and clicking on "SEC Filings" under the "INVESTORS AND MEDIA" menu tab.
Thanks for your continuing attention and support.
Sincerely,
Item 8.01 Other Events.
On Friday, August 21, 2015, the Company issued a press release confirming that the Company’s Phase III clinical trial of DCVax®-L for newly diagnosed Glioblastoma multiforme is ongoing and all patients in the trial are continuing to be treated in accordance with the protocol. The Company reported that over 300 patients have been recruited for the trial. The Company reported that the only change in the status of the trial is that new screening of patient candidates has been suspended while the Company prepares and submits certain information from the trial for regulatory review. A copy of the press release is attached as
Exhibit 99.1.
The Company received various shareholder inquiries, asking whether the 300 patients are actually enrolled and being treated in the trial, or were just screened for the trial. On Monday, August 24, the Company responded by confirming that the 300 patients are actually enrolled and being treated in the trial. The Company also noted that being in the trial means not being in the Information Arm, and not being in the pseudo-progression arm, each of which are parallel with the trial but outside the trial.
A shareholder inquiry also asked what information the Company is submitting to regulators. The Company’s response noted that such submissions would not normally be discussed in the middle of a regulatory process or dialog, and that the Company plans to report when the process has been completed.
A copy of the shareholder reply is attached as Exhibit 99.2.
Shareholder Question:
Exhibit 99.2
There is a lot of confusion about your trial on the message boards. Are the 300 patients actually in the trial and being treated or are they just being screened? Also, what information are you submitting for regulatory review?
Company Answer: Yes, the 300 patients are actually enrolled and being treated in the trial.
Also, being in the trial means that the patients are not in the Information Arm, and not in the pseudo-progression arm, each of which are parallel with the trial but outside the trial.
The supposed “confusion” about our enrollment is, once again, certain bloggers and commentators trying to turn good news into bad news about NW Bio and its trial. People familiar with clinical trials are generally aware that screening of patient candidates for eligibility is different than recruitment or enrollment of patients for treatment.
Regarding the information we are submitting for regulatory review: companies do not normally discuss such information when they are in the middle of a regulatory process or dialog, and we do not plan to do so either. We will provide an update when the process is finished and there is something to report. "
Next SEC
Northwest Bio - SEC statement on 10-8-15:
Shareholder inquiry: What is going on with the change in completion date of the Phase 3 trial on clinicaltrials.gov? Is there a new change or delay in the trial?
Company answer: No, there is no new change or delay in the Phase 3 trial. In all of our public presentations all year long, we have stated that we anticipated finishing the recruitment this fall, and reaching the primary endpoint around approximately the end of summer or September of next year [September 2016].
The clinicaltrials.gov profile was very out of date, and the change of date in that profile from September of this year [2015] to October of next year [October 2016] simply conforms the clinicaltrials.gov profile to the information we have provided publicly all year long, plus about a month of cushion to take account of the temporary hold on new screening for the trial as we announced in August [2015].
We are also updating the profile to correct the number of patients. As stated in all of our presentations for over a year, the total enrollment will be 348. The clinicaltrials.gov profile was very out of date in listing 300. We will simply be conforming the number in the profile to the number we have long presented publicly." -- end of SEC statement.
Recruitment would mean no more acceptance of new first consent forms. The screening process started on the basis of consent to collect lysate at surgery. No new forms would be accepted as of screening halt. But since randomization was not closed, the screening pipeline patients were enrolled. Any patient that signed that form and they collected sufficient lysate would not be turned away from randomization provided they met all "inclusion" eligibility criteria.
"8.2. SCREENING PROCESS
Pre-Screening: The following parameters should be established prior to entering the screening process: age (must be in range), absence of prior malignancies (within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer) and no known unresolved autoimmune disease, HIV-1,2 or Hepatitis infection, no known genetic cancer-susceptibility syndromes, or known pregnancy. If these conditions are satisfied, patients are entered into the screening process by signing the first consent form.
Visits 1-3 (see Appendix A) are used to screen patients for initial eligibility for the trial. The following tests and assays determine eligibility:
Visit 1 (Surgery): All patients (or their LAR) will sign an informed consent form to allow collection of the tumor and perform study activities required for screening. The surgical intent should be a total or near total resection. Collection of tumor tissue: all available tumor tissue should be collected to maintain maximal chances for eligibility. Determination of eligibility is based on the amount of tumor lysate protein recovered rather than on the amount of tumor tissue submitted.
All patients must have newly diagnosed, unilateral GBM without metastases. All pathologic diagnoses of GBM will be reviewed by independent pathology review.
As soon as possible following surgery, slides for independent pathology confirmation of the GBM diagnosis as well as slides for determination of MGMT methylation status should be sent in. In some cases, the status will already be determined as part of standard care at the institution. If it is confirmed that the MGMT methylation status was evaluated at a laboratory approved by the study sponsor, a redacted lab report may be sent with the requisition. Refer to the study laboratory manual for additional information. MGMT methylation status is a predictive factor for Temodar
responsiveness3, and is used for stratification of the randomization.
Visit 2 (Post-surgery MRI): MRI scans pre- and post-surgery need to document extent of resection beyond biopsy only. Patients must have a surgically accessible tumor for which surgical resection, with intent to perform a gross total or near gross total resection, is indicated. Biopsy only does not satisfy eligibility rules. MRI scan (post-surgical) must demonstrate that a resection was performed beyond biopsy only. All MRI scans will be reviewed by independent radiology review.
The post-surgery MRI will be used to quantitatively determine the extent of resection for purposes of the statistical analyses in section 13.2.3 and 13.3.3. Extent of resection will be defined as the amount of residual tumor volume measured in mm3.
The amount of tumor lysate protein is determined as soon as possible after surgery by the contract manufacturer. Determination that sufficient tumor lysate protein was generated is required for a patient to remain eligible and to undergo leukapheresis.
Patients may have received steroid therapy as part of their primary treatment. Steroid treatment should preferably be stopped or if continued steroid use is clinically indicated, be tapered down to 2-4 mg dexamethasone qd approximately 7 days prior to leukapheresis to secure the highest possible quality of the cells used for DCVax-L
manufacturing.
• Visit 3 (Pre-leukapheresis): Just prior to proceeding to leukapheresis, patients are assessed for viral status and bone marrow and liver function. The following tests are done at the pre-leukapheresis visit:
• Sign study consent form (second informed consent)
• History
• Pregnancy test
• Hematology: CBC, differential, platelets
• Virology testing: HIV-1, 2, HTLV-1,2, Hepatitis B, C
• Serum Chemistries: calcium, SGOT, SGPT, alkaline phosphatase, LDH, total bilirubin, BUN, creatinine, electrolytes, magnesium and glucose
• Urinalysis: normal routine urinalysis
Collection of AE and concomitant medications begins at Visit 3.
Visit 4 (Leukapheresis): Patients proceed to leukapheresis as soon as they are sufficiently recovered from surgery, the second consent form is signed and after continued eligibility has been determined (GBM diagnosis confirmed, sufficient tumor lysate generated, negative viral status, adequate bone marrow and liver function). It is recommended that patients complete leukapheresis no later than within 1 week of
starting chemotherapy and radiation. An absolute minimum of 45 days is required from the date of leukapheresis and the Baseline Visit.
Visit 5 (Baseline/Baseline 2): Visit 5 takes place 2 weeks (± 2 days) after the last day of radiation therapy with concurrent temozolomide chemotherapy. A minimum of
5 immunizations must be available for treatment as determined by the contracted manufacturer. At the Baseline Visit, the patient undergoes an MRI to assess disease
progression and blood draws to assess eligibility.
Patients who have clear evidence of objective disease progression (measured by MRI, compared with post-surgery MRI and verified by independent review), are not
eligible for this study. Patients who do not have progressive disease at baseline are enrolled in the study, and will be randomized to receive DCVax-L or placebo at a 2:1 ratio. All remaining inclusion and exclusion criteria must be met for all patients to be enrolled.
In the event that the scan and or clinical signs cannot unambiguously determine progression or stability (inflammatory artifact, necrosis, other post operative/radiation changes) then perfusion MRI or other imaging modalities (conforming to local regulation) can be performed at institutional discretion. If tumor status is still equivocal, the patient will be scheduled to return at 10 weeks after the last day of radiation therapy with concurrent temozolomide for a repeat baseline visit: Baseline 2. Baseline 2 Visit is a repeat of the first baseline visit. The patient’s study schedule, timelines and windows, will shift accordingly (by ~8 weeks). A patient who has a Baseline 2 Visit MRI which confirms that the patient does not have disease progression is eligible for enrollment. All decisions regarding tumor progression status are made through independent radiology review.
The following tests and examinations are to be performed at Baseline (Visit 5) and Baseline 2 (Visit 5a):
• MRI with and without contrast of the brain to confirm absence of disease progression (verified by independent radiology review)
• Physical Examination
• Neurological Exam
• Vitals
• KPS
• CBC and differential, Blood chemistry.
• Pregnancy test: Serum hCG pregnancy test is performed on female subjects of child bearing potential
• Anti-DNA antibodies as a marker of autoimmune disease. Results from this test are not required prior to immunizations
• Optional tumor burden tests: Other imaging modalities, conforming to local regulation, may be performed at the investigator’s discretion, or if necessary to determine if recurrence has occurred.
Eligibility to be enrolled in the study will be determined on the basis of the outcome of these tests, which are to be evaluated within the shortest possible time after the
Baseline (or Baseline 2) Visit (target <1 week) to ensure earliest administration of DCVax-L.
8.3. ENROLLMENT AND RANDOMIZATION
In order for a patient to be enrolled in the main study arm, they must meet all eligibility criteria above, including absence of disease progression following radiation with concurrent temozolomide chemotherapy. Absence of disease progression must be confirmed by central independent review of the post radiation MRI performed at the Baseline Visit (Visit 5), compared to the post-surgery MRI.
The patients meeting these criteria are enrolled, and immediately randomized into the treatment cohort or the placebo cohort of the main arm of the study (enrollment
and randomization happen concurrently). Final review prior to enrolling and randomizing a patient into the trial will be made by the Sponsor and the outcome will be communicated to the clinical site via email.
In order for a patient to be enrolled in the pseudoprogression study arm, they must meet all eligibility criteria above, except the unequivocal absence of disease progression following radiation with concurrent temozolomide chemotherapy.
Absence of disease progression must be confirmed by central independent review of the Baseline Visit 2 MRI performed at 10 weeks post completion of radiation therapy
compared to the Baseline Visit (Visit 5), MRI. The patients meeting these criteria are enrolled, and immediately randomized into the treatment cohort or the placebo cohort of the pseudoprogression study arm
(enrollment and randomization happen concurrently)..
Randomisation of patients will be performed by an interactive voice-/web-response system (IXRS). Upon receipt of Sponsor confirmation of a patient’s eligibility, the site
will call or log onto the IXRS to randomize the patient." Protocol.
I still don't think you're following properly. It doesn't matter when the exclusion testing begins. You're getting hung up on exclusion criteria. It start with inclusion criteria. The MOMENT the patients cleared surgery, the weeks leading up to pre-leukapheresis do not mean a patient hasn't begun the screening process. It's an "intend to treat" gross total resection patient population, and patients who have had surgery, signed first consent and volunteered to enter the study are AUTOMATICALLY part of the screening process. Provided they survived surgery and have had their tumor tissue collected, the weeks leading up to pre-leukapheresis would still be considered part of the screening timeline, as those patients are guaranteed their post surgery screening step, assuming randomization was not closed.
"Patients 18 to 70 years old with newly diagnosed GBM (Grade 4 astrocytoma), who have undergone surgery, are eligible to enter into screening." -- protocol
They didn't stop enrollment or randomization. And that means they had a pipeline of patients who were somewhere through the "evaluation Phase" who were eligible to complete screening, who had undergone surgery. The company stopped screening of new patients, and by that they they meant they had to STOP accepting new CONSENTS for randomization eligibility. Only patients who started the CONSENT process continued to be eligible for possible randomization. And so obviously the patients who already underwent surgery had collected tissue already volunteered for the study. Anyone who didn't undergo surgery they could turn away. But the patients that did have surgery were already some where in the 3 months "time to treatment" process, between surgery and randomization. Some would be further along, perhaps maybe a week out before randomization; while others would be recovering from surgery and not quite begun their pre-leukapheresis evaluation step prior to concurrent chemoradiation. Again, the screen process pipeline would include any patient that had already started the screening consent process. All those that did would have been allowed to continue to see if they met eligibility for enrollment, as only screening of "new" patients was stopped. Again the evaluation Phase starts with "intend to treat" surgery qualifying step of seeking out the "inclusion" criteria patients. And so you're thing to cut and dry about what constitutes exclusion screening, and forgetting to include the patients who were already cleared for screening. You're thinking of when patients who officially are at graduation points to next points. But it starts at first consent, tumor tissue collected. Anyone who signed first consent AUTOMATICALLY to collect lysate comes back -- health permitting -- to see if they meet the Dendritic Cell qualification screening step and then if they pass that; they come back at baseline to see if they have no evidence of tumor.
Anyway, here's the protocol portion that proves my interpretation is correct. Notice it states patients enter the screening process by signing first consent form.
"8.2. SCREENING PROCESS
Pre-Screening: The following parameters should be established prior to entering the
screening process: age (must be in range), absence of prior malignancies (within the
last 5 years, except for adequately treated basal cell or squamous cell skin cancer or
in situ cervical cancer) and no known unresolved autoimmune disease, HIV-1,2 or
Hepatitis infection, no known genetic cancer-susceptibility syndromes, or known
pregnancy. If these conditions are satisfied, patients are entered into the screening
process by signing the first consent form.
Visits 1-3 (see Appendix A) are used to screen patients for initial eligibility for the
trial. The following tests and assays determine eligibility:
Visit 1 (Surgery): All patients (or their LAR) will sign an informed consent form to
allow collection of the tumor and perform study activities required for screening. The
surgical intent should be a total or near total resection.
Collection of tumor tissue: all available tumor tissue should be collected to maintain
maximal chances for eligibility. Determination of eligibility is based on the amount of
tumor lysate protein recovered rather than on the amount of tumor tissue submitted.
All patients must have newly diagnosed, unilateral GBM without metastases. All
pathologic diagnoses of GBM will be reviewed by independent pathology review.
As soon as possible following surgery, slides for independent pathology confirmation
of the GBM diagnosis as well as slides for determination of MGMT methylation status
should be sent in. In some cases, the status will already be determined as part of
standard care at the institution. If it is confirmed that the MGMT methylation status
was evaluated at a laboratory approved by the study sponsor, a redacted lab report
may be sent with the requisition. Refer to the study laboratory manual for additional
information. MGMT methylation status is a predictive factor for Temodar
responsiveness3, and is used for stratification of the randomization.
Visit 2 (Post-surgery MRI): MRI scans pre- and post-surgery need to document
extent of resection beyond biopsy only. Patients must have a surgically accessible
tumor for which surgical resection, with intent to perform a gross total or near gross
total resection, is indicated. Biopsy only does not satisfy eligibility rules. MRI scan
(post-surgical) must demonstrate that a resection was performed beyond biopsy
only. All MRI scans will be reviewed by independent radiology review.
The post-surgery MRI will be used to quantitatively determine the extent of resection
for purposes of the statistical analyses in section 13.2.3 and 13.3.3. Extent of
resection will be defined as the amount of residual tumor volume measured in mm3.
The amount of tumor lysate protein is determined as soon as possible after surgery
by the contract manufacturer. Determination that sufficient tumor lysate protein was
generated is required for a patient to remain eligible and to undergo leukapheresis.
Patients may have received steroid therapy as part of their primary treatment.
Steroid treatment should preferably be stopped or if continued steroid use is clinically
3 Hegi, ME et al. 2005. N Engl J Med. 2005 Mar 10;352(10):997-1003.
indicated, be tapered down to 2-4 mg dexamethasone qd approximately 7 days prior
to leukapheresis to secure the highest possible quality of the cells used for DCVax-L
manufacturing.
• Visit 3 (Pre-leukapheresis): Just prior to proceeding to leukapheresis, patients
are assessed for viral status and bone marrow and liver function. The following
tests are done at the pre-leukapheresis visit:
• Sign study consent form (second informed consent)
• History
• Pregnancy test
• Hematology: CBC, differential, platelets
• Virology testing: HIV-1, 2, HTLV-1,2, Hepatitis B, C
• Serum Chemistries: calcium, SGOT, SGPT, alkaline phosphatase, LDH, total
bilirubin, BUN, creatinine, electrolytes, magnesium and glucose
• Urinalysis: normal routine urinalysis
Collection of AE and concomitant medications begins at Visit 3.
Visit 4 (Leukapheresis): Patients proceed to leukapheresis as soon as they are
sufficiently recovered from surgery, the second consent form is signed and after
continued eligibility has been determined (GBM diagnosis confirmed, sufficient tumor
lysate generated, negative viral status, adequate bone marrow and liver function). It
is recommended that patients complete leukapheresis no later than within 1 week of
starting chemotherapy and radiation. An absolute minimum of 45 days is required
from the date of leukapheresis and the Baseline Visit.
Visit 5 (Baseline/Baseline 2): Visit 5 takes place 2 weeks (± 2 days) after the last
day of radiation therapy with concurrent temozolomide chemotherapy. A minimum of
5 immunizations must be available for treatment as determined by the contracted
manufacturer. At the Baseline Visit, the patient undergoes an MRI to assess disease
progression and blood draws to assess eligibility.
Patients who have clear evidence of objective disease progression (measured by
MRI, compared with post-surgery MRI and verified by independent review), are not
eligible for this study. Patients who do not have progressive disease at baseline are
enrolled in the study, and will be randomized to receive DCVax-L or placebo at a 2:1
ratio. All remaining inclusion and exclusion criteria must be met for all patients to be
enrolled.
In the event that the scan and or clinical signs cannot unambiguously determine progression or stability (inflammatory artifact, necrosis, other post operative/radiation changes) then perfusion MRI or other imaging modalities (conforming to local regulation) can be performed at institutional discretion. If tumor status is still equivocal, the patient will be scheduled to return at 10 weeks after the last day of radiation therapy with concurrent temozolomide for a repeat baseline visit: Baseline 2. Baseline 2 Visit is a repeat of the first baseline visit. The patient’s study schedule, timelines and windows, will shift accordingly (by ~8 weeks). A patient who has a
Baseline 2 Visit MRI which confirms that the patient does not have disease progression is eligible for enrollment. All decisions regarding tumor progression status are made through independent radiology review.
The following tests and examinations are to be performed at Baseline (Visit 5) and
Baseline 2 (Visit 5a):
• MRI with and without contrast of the brain to confirm absence of disease progression (verified by independent radiology review)
• Physical Examination
• Neurological Exam
• Vitals
• KPS
• CBC and differential, Blood chemistry.
• Pregnancy test: Serum hCG pregnancy test is performed on female subjects of child bearing potential
• Anti-DNA antibodies as a marker of autoimmune disease. Results from this test are not required prior to immunizations
• Optional tumor burden tests: Other imaging modalities, conforming to local regulation, may be performed at the investigator’s discretion, or if necessary to determine if recurrence has occurred.
Eligibility to be enrolled in the study will be determined on the basis of the outcome of these tests, which are to be evaluated within the shortest possible time after the
Baseline (or Baseline 2) Visit (target <1 week) to ensure earliest administration of DCVax-L.
8.3. ENROLLMENT AND RANDOMIZATION
In order for a patient to be enrolled in the main study arm, they must meet all eligibility criteria above, including absence of disease progression following radiation with concurrent temozolomide chemotherapy. Absence of disease progression must be confirmed by central independent review of the post radiation MRI performed at the Baseline Visit (Visit 5), compared to the post-surgery MRI.
The patients meeting these criteria are enrolled, and immediately randomized into
the treatment cohort or the placebo cohort of the main arm of the study (enrollment
and randomization happen concurrently). Final review prior to enrolling and randomizing a patient into the trial will be made by the Sponsor and the outcome will be communicated to the clinical site via email.
In order for a patient to be enrolled in the pseudoprogression study arm, they must
meet all eligibility criteria above, except the unequivocal absence of disease
progression following radiation with concurrent temozolomide chemotherapy.
Absence of disease progression must be confirmed by central independent review of
the Baseline Visit 2 MRI performed at 10 weeks post completion of radiation therapy
compared to the Baseline Visit (Visit 5), MRI.
The patients meeting these criteria are enrolled, and immediately randomized into
the treatment cohort or the placebo cohort of the pseudoprogression study arm
(enrollment and randomization happen concurrently)..
Randomisation of patients will be performed by an interactive voice-/web-response
system (IXRS). Upon receipt of Sponsor confirmation of a patient’s eligibility, the site
will call or log onto the IXRS to randomize the patient." Protocol.
From the consent form, CLEARLY it's a screening is regarded as the "initial evaluation Phase" which patients who were eligible and consented to having lysate collected from surgery would have been in the screening Phase:
"The clinical trial will consist of three phases: the initial evaluation phase (also known as the screening phase), the active treatment phase, and the follow-up phase. During the evaluation phase you will undergo some testing noted below to indicate whether you can participate. The next phase, the active treatment phase, is when patients are treated with DCVax-L or placebo. During this phase, which lasts up to 36 months, you will be asked to return to the clinic once every two months for MRIs and other tests as outlined below under Study Visits Procedures to determine how you are doing. During the follow-up phase, which starts after the 36 months is completed or after you leave the trial for any reason, you and/or a designated contact will be contacted every third month to collect medical history including data on long-term progression or re-growth of your brain cancer as well as survival data.. Please read the section titled
Follow-Up Information.
DCVax-L consists of two components: autologous (your own) immune cells called dendritic cells (DC) and part of a substance prepared from your tumor cells.
Dendritic cells (DC): They are a type of white blood cells involved in your immune system. Your white blood cells will be collected from your body and shipped to a laboratory where the DC will be purified and grown. Dendritic cells may be able to teach your immune system to recognize and destroy cancer cells.
The placebo for this trial consists of a preparation of your own white blood cells. This substance will not generate an immune response against your cancer cells.
Tumor cell derived material: When your tumor was removed during surgery, a small part of your tumor specimen was sent to a laboratory where the tumor cells were broken up to prepare the second component of the experimental study vaccine. The tumor tissue was treated with substances that initiated chemical reactions to obtain proteins from the breakdown of your tumor cells (“tumor lysate”). Your tumor cell-derived material will be combined with your DC so that the DC take up parts of the tumor cell substance and form the experimental study
Date of Preparation: 11/7/12
Protocol ID:IRB#11-000686 UCLA IRB Approved Approval Date: 11/20/2012 Through: 11/19/2013 Committee: Medical IRB 2
Consent Form for Medical Research Page 3 of 15
vaccine, DCVax-L. When the study vaccine is injected back into your body, it may activate your immune system to destroy brain cancer cells.
? PROCEDURES
All subjects who have undergone the leukapheresis will receive up to 10 injections of the study agent or placebo over the course of 3 years, except for those patients for whom it is determined that it is not safe for them to receive either treatment. All patients in the study will be followed for the collection of data related to progression or re-growth of brain cancer, and survival for a period of up to 36 months. In addition, long-term progression or re-growth of your brain cancer as well as survival, or overall survival will be followed beyond the 36 months of the clinical trial."- consent form
And so patients who consented to have lysate removed volunteered for the study. They then proceed to the pre-leukapheresis step. They need to have failed that to not pass that "screening" Phase step.
Consent form continues to state this:
"If you volunteer to participate in this study, we would ask you to do the following things:
Screening Procedures (Pre-Leukapheresis Visit)
For subjects enrolled under Protocol Version 4.0 in the Transitional Non-randomized Arm, please skip this procedure section and read and sign the Transitional Non- randomized Procedures Document. Your physician and study coordinator will know if you need to skip this section only and read and sign the Procedures document.
When if you
Undergo a physical examination.?Have your medical history taken.?Have your blood drawn, approximately 31/2 ounces (103 ml or 7 tablespoons). Give a urine sample of about an ounce (or 2 tablespoons).?Have a pregnancy test (if you are female and fertile).?Have your vital signs taken (blood pressure, temperature, pulse and respirations) as well as your height and weight.?You will be asked about any side effects, if any, that you may be experiencing.
all your pre-leukapheresis screening tests have been evaluated, you will be notified might be eligible to undergo leukapheresis for the clinical trial.
Preparation of Tumor Cells
Before you had surgery, you signed a consent form agreeing to donate a sample of your tumor for clinical research purposes. If you choose to participate in this clinical trial, the tumor cells will be used to prepare tumor cell material that will become part of the study vaccine, DCVax-L .
Leukapheresis
After your Pre-Leukapheresis Visit, if you meet the screening entry criteria and have been declared eligible for the DCVax-L clinical trial, your white blood cells will be collected by a procedure called “leukapheresis” at the UCLA Apheresis Unit. This procedure is similar to donating blood and may take up to 4 hours for one day. A needle is inserted into one arm and blood is withdrawn and passed through a machine that removes only
..." consent form.
You're not getting it. From the protocol, it's still 2+ months of screening even after leukapheresis (a screening step) before randomization. Once they get have a successful surgery and they get the tumor they are automatically qualify for that screening step. You're thinking that patients who were in a specific week of the Screening Phase (which is the Evaluation Phase (see first page of document!)) would be automatically excluded, and I'm telling you, it doesn't work like that. I disagree. Any patient who has a successful surgery that obtained lysate automatically moves to the next step. It's a process.
"All subjects who had a leukapheresis will undergo external beam radiation therapy (which may include intensity modulate radiation therapy or IMRT) and concurrent temozolomide chemotherapy as part of standard primary treatment, initiated as soon as possible, typically 3-4 weeks after surgery (Appendices A & B). Two weeks after completion of radiation and concurrent chemotherapy treatment, subjects will undergo the Baseline Visit, during which the final tests to determine eligibility are performed. Patients who do not have obvious evidence of progressive
disease at the Baseline Visit (as determined by MRI) are enrolled in the main arm of the study (intent to treat), and are randomized to receive DCVax-L in the treatment cohort or autologous MNC in the placebo cohort. Randomization and treatment assignment takes place within 1 week of the Baseline Visit. At the Baseline Visit, patients must be scheduled to return to the clinic 1 week later to receive their first immunization."
All patients would have passed surgery. We agree on that. Once they had tumor, the patients were officially in the Screening Phase. They were not pre-screening anymore. But you're free to believe that they were not allowed to make Vaccine for patients that they already collected tumor from surgery for.
No, if they allowed patients that had already made into the screening phase, they didn't eliminate any unless they failed to meet the eligibility criteria. Here's the consent form. Screening Phase is the "evaluation phase". You're getting caught on "semantics".
http://neurosurgery.ucla.edu/Workfiles/Site-Neurosurgery/Brain_Tumor_Program/11-000686-%20Main%20ICF%2007Nov2012.pdf
The pre-screening step is quick, patients enter screening upon surgery. Once they have the tumor, the patient moves onto the pre-leuk step. There were a number of points the patient could fail a screening Phase step. However, pretty much the first big hurdle started with surgery, and it is on the basis of that where the "enough" lysate step is determined.
Anyway, I brought it up as you're planning on releasing an article. I believe your article will help investors understand that the vaccine is effecting the study results. I imagine it's going to be well written and thought provoking piece. While I do agree that 4-6 weeks may not matter in the scheme of things -- after all over 300 patients were randomized by August 2015 -- I also know how that your PFS and OS timeline argument partially relies on your interpretation of facts. Much of what longs write on this iHub ends up being twisted out of context, sadly. The "in-context" writing needs to be accurate otherwise it could be used in an attempt to invalidate your opinions. I would hate to see you making "semantics" errors here and there, that the shorts and skeptics could then try to use in an attempt to distract, ridicule, and destroy your entire long statistical analysis thesis. I offered my interpretation of the "screening" facts to try and help avoid the not so friendly critiquing you're strong article in support of NWBO is bound to get. Hopefully that makes sense. I look forward to reading it while we wait. Thanks in advance for writing it.
Screening steps include "inclusion" criteria; not just "exclusion" criteria. Sufficient lysate is needed from surgery. They stopped accepting new patients into the process which starts with pre-screening steps.
From the protocol:
7. PATIENT ELIGIBILITY
7.1. INCLUSION CRITERIA
All patients, unless specified otherwise below, must meet the following inclusion
criteria at the indicated time points.
Determined at pre-screening
• Patients ≥18 and ≤70 years of age at surgery
• Patients must be able to understand and sign the informed consent indicating
that they are aware of the investigational nature of this study. The consent for
tumor donation may be signed by a legally authorized representative (LAR) if
allowed by the institution.
• Patients must have a life expectancy of ≥8 weeks
Determined at or around surgery, and prior to pre-leukapheresis
• Primary therapy must consist of surgical resection with the intent for a gross or
near gross total resection of the contrast-enhancing tumor mass as confirmed by
central review, followed by external beam radiation therapy and concurrent
temozolomide chemotherapy. Patients who have a resection with original intent
for gross or near gross total resection where the surgery can be said to be
beyond biopsy are eligible. Central confirmation is not required prior to the preleukapheresis visit, but is required before the patient can proceed to leukapheresis. Patients having a biopsy only will be excluded. Patients may be screened if they have had a previous biopsy and are scheduled for a subsequent gross or near gross total resection prior to commencement of other therapies.
• Patients with newly diagnosed, unilateral GBM2 (Grade IV) are eligible for this
protocol. An independent central neuropathologist will review this diagnosis
during the enrollment process. This confirmation is not required prior to the preleukapheresis visit, but is required before the patient can proceed to leukapheresis.
• All Patients must have sufficient tumor lysate protein that was generated from the
surgically obtained tumor material. This determination will be made by the
contracted manufacturer and communicated to the clinical site through the Sponsor, or its designee. This confirmation is not required prior to the preleukapheresis visit, but is required before the patient can proceed to
leukapheresis.
Determined at pre-leukapheresis
• Patients must have adequate bone marrow function (e.g., hemoglobin >10 g/dl,
white blood count 3600-11,000mm3, absolute granulocyte count ≥1,500/mm3,
absolute lymphocyte count ≥1,000/mm3, and platelet count ≥100K/mm3. Eligibility
level of hemoglobin can be reached by transfusion. These values are determined
by a central laboratory. Note: A waiver is not necessary if these laboratory results
are outside of the central laboratory’s normal reference ranges or the sample
ranges provided above but are not deemed clinically significant.
• Adequate liver function (SGPT, SGOT, and alkaline phosphatase ≤4.0 times
upper limits of normal (ULN) and total bilirubin ≤1.5 mg/dl), and adequate renal
function (BUN or creatinine ≤1.5 times ULN) prior to starting therapy. These
values are determined by a central laboratory.
Determined at baseline (or baseline2 for pseudoprogression patients)
2 For the purposes of this study, all histologically confirmed, newly diagnosed GBM includes the recognized variants
of glioblastoma (giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components).
• Patients must have a KPS rating of ≥70 at the Baseline Visit (Visit 5) (refer to
Appendix D, Performance Status Scales).
• Patients may have received steroid therapy as part of their primary treatment.
Steroid treatment must preferably be stopped; or if continued steroid use is
clinically indicated, be tapered down to 2-4 mg dexamethasone qd at least 7
days prior to the first immunization.
• Patients must be willing to forego cytotoxic anti-tumor therapies except
temozolomide while being treated with study drug. DCVax-L and placebo must
be given as described and temozolomide must be given essentially according to
the Stupp Protocol (see Appendices B and C for temozolomide schedules and
detailed treatment guidelines).
• A minimum of 5 immunizations must be available for treatment as determined by
the contracted manufacturer.
7.2. EXCLUSION CRITERIA
Patients may not be enrolled in the trial if they have any of the following exclusion
criteria, at the indicated time points:
Determined at pre-screening
• History of prior malignancy except for adequately treated basal cell or squamous
cell skin cancer or in situ cervical cancer or other cancers that were deemed fully
resolved 5 or more years prior to Visit 1 (surgery) of the study. Prior lower grade
gliomas are acceptable unless treated with chemotherapy, and provided that all
other eligibility criteria are met.
• History of immunodeficiency disease or unresolved autoimmune disease such as
rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis,
scleroderma, polymyositis-dermatomyositis, juvenile onset insulin dependent
diabetes, or vasculitis.
• Known HIV-1,2, HTLV-1,2 or Hepatitis B, C infection
• Pregnancy
• Inability to obtain informed consent because of psychiatric or complicating
medical problems.
• Any known genetic cancer-susceptibility syndromes.
Determined at or around surgery
• Bilateral or metastatic disease detected at diagnosis, during surgery or at postsurgical
magnetic resonance imaging (MRI). Tumors may cross into, but not beyond the corpus callosum.
• Post operative MRI scan evidence of biopsy only without significant tumor resection.
• Implantation of Gliadel® wafers (polifeprosan 20 with carmustine implant) at surgery.
Determined at pre-leukapheresis
• Positive HIV-1, HIV-2, HTLV-1, 2, hepatitis B surface antigen, or hepatitis C
antibody.
• Patients with organ allografts.
• Allergies to reagents used in this study.
• Patients who are unable to stop or taper steroid treatment to less than 8mg of
dexamethasone qd prior to leukapheresis are excluded from the trial; steroid use
should be stopped or tapered down to the lowest clinically acceptable dose (e.g.
2 mg per day) approximately 7 days prior to the first leukapheresis.
• Inability or unwillingness to return for required visits and follow-up exams.
• Any previous cytotoxic drug therapies.
Determined at or prior to baseline
• Patients with suspicion of pseudoprogression as determined by central review are not eligible for the main arm of the study and will return at 10 weeks post completion of radiation therapy for a repeat baseline visit (Baseline 2).
• Patients may not be taking medications that might affect immune function and
that have documented anti-tumor activity: The following are exceptions:
nonprescription strength doses of NSAIDS, acetaminophen (paracetamol) or
acetylsalicylic acid (aspirin). A list of such medications will be provided to
investigators and updated as required.
• Patients may not have radiographic evidence of disease progression at Baseline
2 (Visit 5a) compared with the Baseline Visit MRI as determined by central review.
• Patients with disease progression as determined by central review will not be
eligible for the study.
Safety considerations, determined at baseline: the following exclusion criteria
preclude patients from being enrolled in the study:
• Acute infection: any active viral, bacterial, or fungal infection that requires specific
therapy. Antibiotic therapy must be completed at least 7 days prior to the first
immunization.
• Active uncontrolled infection. Examples are a sexually transmitted disease
(STD), herpes, uncontrolled tuberculosis, malaria, etc.
• Fever ≥101.5oF (38.6 oC). If considered possibly transient, retesting is allowed.
• Unstable or severe intercurrent medical conditions such as unstable angina,
uncontrolled arrhythmias, Crohn’s Disease, ulcerative colitis etc.
• Females of child-bearing potential who are pregnant or lactating or who are not
using adequate contraception (abstinence, surgical, hormonal or double barrier,
i.e. condom and diaphragm).
8. TREATMENT PLAN
8.1. TREATMENT PLAN OVERVIEW
After the informed consent for the collection of the tumor has been signed, all
subjects will undergo surgery at a center participating in the trial or at surgical
centers trained in the study specific tumor processing procedure. As much as
possible of the tumor material obtained from surgical resection will be placed in a
sterile container and shipped to the contract manufacturer for manufacturing of the
tumor lysate antigen preparation.
Following recovery from surgery, patients for whom it has been established that
sufficient tumor lysate was generated will undergo a pre-leukapheresis visit to
determine viral status and bone marrow function. Patients with negative viral status
and adequate bone marrow function proceed to leukapheresis to harvest the DC
precursors, prior to initiation of external beam radiation therapy with concurrent
chemotherapy. Patients for whom insufficient DCVax-L is manufactured, i.e. less
than 5 doses, will be eligible to undergo additional apheresis if it is determined that
the leukapheresis can be completed and DCVax-L manufactured and released prior
to the Baseline Visit (approximately 40 days). Peripheral blood mononuclear cells
(MNC) are purified from the leukapheresis material at the contracted manufacturer,
and an aliquot of the MNC is cryopreserved for use as placebo for patients who are
randomized to the placebo cohort. The remainder of the MNC is used to prepare
DCVax-L. Both DCVax-L and the placebo are tested at the contracted manufacturer
prior to release to the study site. Patients for whom sufficient DCVax-L was not
generated are not eligible to continue on this protocol.
All subjects who had a leukapheresis will undergo external beam radiation therapy
(which may include intensity modulate radiation therapy or IMRT) and concurrent
temozolomide chemotherapy as part of standard primary treatment, initiated as soon
as possible, typically 3-4 weeks after surgery (Appendices A & B).
Two weeks after completion of radiation and concurrent chemotherapy treatment,
subjects will undergo the Baseline Visit, during which the final tests to determine
eligibility are performed. Patients who do not have obvious evidence of progressive
disease at the Baseline Visit (as determined by MRI) are enrolled in the main arm of
the study (intent to treat), and are randomized to receive DCVax-L in the treatment
cohort or autologous MNC in the placebo cohort. Randomization and treatment
assignment takes place within 1 week of the Baseline Visit. At the Baseline Visit,
patients must be scheduled to return to the clinic 1 week later to receive their first
immunization.
Screening of new patients was halted sometime around August 2015. But from what I understand from evidence presented on iHub, and also conversation that were apparently confirmed by Les, is that it was just screening of "new" GBM patients that was halted. There were already patients that were in the screening cue, meaning surgeries complete, first step of screening done with tissue collected. Once the first screening consent form was signed, the patients were on their way to be towards the final screening steps, second consent collection of WBC precursors and all other final test done at BASELINE visit. They didn't turn the patients that began the initial surgical consent screening steps away. As such, given the first screening step, of tissue consent collection signed, can actually be about 3 months before the last screening step of BASELINE visit, the last patient was probably randomized sometime in October 2015. That said, all 331 patients would have had their surgeries on or before August 2015, as again, all randomized patients had already started the screening process of tissue collection consent from surgery. Obviously, most surgeries would be before then.
"In the Phase III trial, PFS and survival times will be calculated from time of randomization, which is expected to occur approximately three months after initial surgery." -- protocol
Thanks Senti. Appreciate the recap. :)
Okay, I see what you're thinking. It's appropriate to check to make sure they have appropriate progression data on all patients. I agree with you there. Not sure I agree that it can be used to move progression dates later on patients. But then again I also see that RANO criteria takes care of early Pseudoprogression concern, so there's that. :)
One of the purposes of using PFS endpoint is because it's not confounded by other therapies. That's part of the charm of using PFS as an endpoint. They can't move progression dates later as patients were already on salvage therapies after the blinded central review deemed patients crossed progression. Doing so would introduce confounding to the primary endpoint, and that would make looking at PFS statistic more difficult. But, moving date earlier or actually applying a progression date that does not exist, well that's certainly possible. No confounding to apply progression to an earlier date, as patients would still only be on standard of care. If there are any patients that have not yet progressed, they will need to make sure that those patients truly didn't cross any progression threshold. They also need to make sure that the dates they have on progression go back to the scan they should be on. If they do find patients that should be considered progression earlier, they will mark it as earlier. The data gathering steps are normal. None of this is a reason as to wait for OS to data lock. The company specifically told us they were accumulating more progression events as they reach OS endpoint. Only reason to do that is to capture more of the 331 potential progression events IMHO.
They are not locking PFS because they are capturing the long tail data on PFS. That data will be reflected in the tail end of the KM curve (depending on the cohort it occurs in).
They can't change PFS after the fact. And they won't need to. You forget it is blinded Central Imagine Review that made the determination on progression. There is no back determining of dates after the fact. That's an impossible task. The progression patients will have went on to salvage treatments at that point (includes crossover patients). Progression events can only be done in real time and the ONLY time they delay that determination is early on. It is only the month 2 scan that gets a question mark. Central Image Review will have only ruled scans that worsened as PFS -- within the field of radiation -- according to the new standardized approach of having a decision tree to confirm "true" progression. Just as the CUA did a confirmation scan, the imaging taken on Month 2 will have needed to go through a confirmation step or other imaging modalities to confirm any possible progression patient was true progression. They would have been on the lookout to keep Psuedoprogression patients on standard of care therapy -- per the new standard of making calling progression events more difficult early on. A concept that is lost on many.
And for the record, the median PFS endpoint for both cohorts will not change. It was reached. The Company is not locking the progression data because they are capturing the progression events of more than 248 patients. That progression data is undisturbed by subsequent treatment after progression and can further show benefit for the vaccine if it is the reason why TUMOR progression events are delayed. At this point all patients are out at least 20 months out from surgery, and so any events that occur now will likely be well after they should be expected for standard of care (placebo) patients. It's data that can be used to demonstrate survival advantage. It should show why DCVax-L "early" is of benefit assuming the product is helping to improve patients immune systems to mount a response to their respective TUMOR.
The protocol states this about Progression after enrollment:
Neuro Oncol. 2011 Mar; 13(3): 353–361. doi: 10.1093/neuonc/noq203
Clinical trial end points for high-grade glioma: the evolving landscape*
David A. Reardon, Evanthia Galanis, John F. DeGroot, Timothy F. CLOUGHESY, Jeffrey S. Wefel, Kathleen R. Lamborn, Andrew B. Lassman, Mark R. Gilbert, John H. Sampson, Wolfgang Wick, Marc C. Chamberlain, David R. Macdonald, Minesh P. Mehta, Michael A. Vogelbaum, Susan M. Chang, Martin J. Van den Bent, and Patrick Y. Wen
Abstract
To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the “gold-standard” end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being.
The identification of optimal end points for high-grade glioma (HGG) clinical trials has become an increasingly complex challenge, in part because of advances in diagnostic techniques, assessment of sequential imaging, and therapy. Traditional radiologic response guidelines defined 20 years ago that use 2-dimensional measurement of abnormal enhancement as a surrogate of tumor size and activity1 have become less applicable and reliable in the current therapeutic era, in which temozolomide chemoradiotherapy is routinely used for newly diagnosed patients and angiogenic inhibitors, such as bevacizumab, are administered at recurrence. Greater uncertainty in accurately defining progression due to pseudoprogression and pseudoresponse has, in turn, made the use of progression-free end points more problematic. The recently defined Response Assessment for Neuro-Oncology (RANO) criteria2 and technological advances in neuroimaging are expected to address some of these challenges. Although overall survival has traditionally been “the gold standard” for HGG clinical trials, active salvage therapies, such as bevacizumab, may impact survival and thus weaken the association between presalvage therapy and survival. As overall survival is improving, metrics of patient function and well being are increasingly valued by patients, caregivers, clinicians, and regulatory agencies and thus warrant consideration as end points of importance.
The RANO working group, consisting of leaders from European and North American neuro-oncology organizations and cooperative groups, includes neuro-oncologists, neurosurgeons, radiation oncologists, neuroradiologists, neuropsychologists, and biostatisticians, who are updating guidelines for evolving and complex clinical scenarios affecting patients with brain tumors. In addition to the criteria for response assessment in HGG, updates for response assessment for low-grade gliomas and for neurosurgical interventions are in preparation. The current article provides a review of the literature as well as consensus recommendations from the RANO working group for commonly employed end points in HGG clinical trials, and it discusses their applicability in the design of clinical trials for newly diagnosed and recurrent patients. We also highlight auxiliary end points that may play a growing role in the design and interpretation of future clinical trials. End points are ultimately relevant in the context of their application to specific clinical trial designs. Faulty study architecture may yield misleading or uninterpretable study results, regardless of selected study end points. Therefore, a separate manuscript dedicated to reviewing key controversies and considerations of clinical trial design for patients with malignant glioma is warranted and planned.
Radiographic Response
As with other solid tumors, the assessment of overall radiographic response (ORR) has been an important end point for HGG clinical trials, especially those that use cytotoxic chemotherapy. Reduction in tumor size may correlate with symptomatic improvement and longer survival and therefore may provide a surrogate for clinical benefit. Twenty years ago, Macdonald et al3 proposed criteria for ORR in patients with supratentorial HGG based on 2-dimensional measurement of contrast enhancement partly resulting from imaging-based responses of oligodendrogliomas to chemotherapy.4 Similar to the brain tumor response criteria proposed by Levin et al,5 Macdonald and colleauges' criteria integrated clinical status into the definitions of both response and progression, as well as corticosteroid use, into the definition of response. The latter was based on the observation that corticosteroid use can substantially decrease tumor contrast enhancement on both CT6 and MRI scans.7 Macdonald and colleagues' criteria have subsequently remained the adopted, de facto standard for response assessment in HGG clinical trials. Although a number of studies suggest that 1-dimensional tumor measurements using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria8 may be equally effective, these criteria have not been widely adopted for patients with brain tumor9,10 Volumetric imaging may potentially be more accurate but is currently neither widely available nor standardized.11,12 Finally, change in tumor size as a continuous variable has been advocated as a measure of activity,13 but this approach also requires validation for patients with HGG.
The use of ORR as a primary end point has several advantages. ORR is a direct measure of therapeutic effect and is not affected by disease natural history, which may affect duration-based end points. It can also be determined relatively rapidly. In addition, there are extensive historical ORR data for a variety of salvage therapies, including cytotoxic chemotherapy14,15 and bevacizumab-based regimens,16,17 that can serve as comparators to the activity of planned study therapies. Furthermore, ORR is not affected by subsequent salvage therapies. For these reasons, some have argued that ORR is the only reliable end point for single-arm studies. Finally, regulatory agencies such as the US Food and Drug Administration (FDA) continue to place emphasis on ORR as an end point.18 In fact, durable ORR was the primary criterion cited by the FDA in their recent accelerated approval of bevacizumab for recurrent GBM.
However, the utility of ORR as a primary end point has potential limitations. First, the ability of ORR to consistently predict meaningful clinical benefit is variable.10–12,19 One possible explanation is that extravasation of contrast material across leaky intratumoral blood vessels, the surrogate used to determine tumor burden and thus ORR, can be influenced by several factors, including use of corticosteroids, inflammation, seizures, surgery, ischemia, and radiation effect on tumor, normal brain, and vascular permeability.20–22 Variations in radiological techniques can also influence contrast uptake.11 Furthermore, numeric cutoffs to define ORR were originally derived from the World Health Organization's solid tumor criteria, which may or may not be valid for CNS tumors. Importantly, ORR does not credit prolonged disease stabilization. Many new therapies, including targeted molecular agents, are predominantly cytostatic and are likely to produce stable disease rather than tumor regression. Furthermore, most classical cytotoxic agents do not yield significant ORR rates, yet they may show efficacy in terms of progression-free survival (PFS) or overall survical (OS) when given to patients with newly diagnosed conditions (eg, temozolomide). Such tumor control generally represents meaningful clinical benefit among patients with HGG. For cytostatic agents, other end points such as PFS at 6 months (PFS-6), may better reflect antitumor activity. Finally, radiographic assessment can be challenging because of difficulties in measuring irregularly shaped tumors, interobserver variability, lack of guidelines for assessment of multifocal disease, and the inability to measure nonenhancing tumor.11 A strategy to offset some of these issues is the use of blinded central imaging review to reduce bias and subjectivity in tumor measurement, thereby improving reliability. However, centralized review may not be practical for many phase II studies and may neglect clinical deterioration.
The utility of ORR based on contrast assessment is further limited by 2 clinically relevant scenarios, particularly in the current era. Although it has been noted after radiotherapy alone,23 an increase in contrast enhancement and edema, with or without accompanying neurologic findings, referred to as pseudoprogression, has been reported in up to 30% of patients with newly diagnosed HGG following completion of temozolomide chemoradiotherapy.24–26 In addition, pseudoprogression has been observed with other therapies, including biodegradable chemotherapy polymers,27 immunotoxins administered by convection-enhanced delivery,28 viral gene therapy,29 focal irradiation with brachytherapy or stereotactic radiosurgery,30 and immunotherapies.31Although the underlying mechanism is not fully understood, these changes are felt to reflect increased permeability and/or vascular damage. Unfortunately, no currently available imaging modality reliably distinguishes pseudoprogression from true progression with sufficient sensitivity and specificity for routine use. In such situations, progression can only be reliably defined if it occurs at a distant site, is confirmed histopathologically, or worsens on sequential imaging.
Paradoxically, the second scenario limiting current radiographic assessment is the phenomenon of pseudoresponse. Pseudoresponse refers to improved contrast enhancement due to diminished vascular permeability that does not necessarily reflect a true underlying anti-tumor effect. For example, rapid and marked improvement in contrast enhancement has been noted less than 1-2 days after antivascular endothelial growth factor (VEGF) therapy.32 In other cases, despite improved enhancement, progressive, infiltrative nonenhancing tumor as assessed by FLAIR/T2 sequences has been noted.33
The recently announced RANO criteria34 build on the foundation established by the criteria of Levin et al5 and Macdonald et al1 and were developed to address the radiographic findings associated with pseudoprogression and pseudoresponse. In addition, pending experience and evaluation of the RANO criteria, concerns remain regarding the interpretation of ORR as an end point for trials investigating therapeutic approaches that are associated with either pseudoprogression or pseudoresponse. Future studies that include an evaluation of the potential correlation of ORR, preferably using the RANO criteria, with OS, will be particularly helpful to better define the value of ORR as an end point in the modern era.
OS
OS is considered the definitive primary end point for patients with both newly diagnosed and recurrent HGG, because it reflects a clinically meaningful benefit that can be objectively and unequivocally assessed. Furthermore, the natural history of HGG does not typically include long periods of disease quiescence, as may occur in low-grade gliomas. Therefore, improvement in OS is believed to directly reflect therapeutic efficacy.
However, the use of OS as a primary end point can have drawbacks. Factors unrelated to current treatment (eg, factors related to underlying disease biology) may affect survival time more than PFS or ORR and may therefore introduce greater variability in outcome. Studies based on OS also inherently require longer assessment time than do other measures, such as PFS or ORR. In addition, the impact of study therapy on OS may be less pronounced than its impact on PFS or ORR, resulting in the need for larger sample sizes. These factors may increase study duration and sample size and, hence, expense. Finally, start times may also vary across studies which can impact time to end point measures including OS. This potential variable highlights the need for studies to clearly specify start times and for clinicians to appropriately take study start time into account when comparing outcome across studies and control groups.
Another important potential drawback of OS as a primary end point is the impact of effective salvage therapies administered at recurrence, which may increase subsequent OS and lead to an apparent disconnect between a salvage therapy and OS improvement. Specifically, given the rapidly expanding use of bevacizumab for patients with HGG and its accelerated approval by the FDA in May 2009 for recurrent GBM, the interpretation of ongoing and future GBM studies will likely need to take into account the potential effect of such salvage therapies on OS. Future studies should consider documenting salvage therapy administered after study failure to better assess their potential impact on study OS. A strategy to help deal with the potentially confounding effect of salvage therapy, particularly for definitive or registration studies, is to include a statistical design that is sufficiently powered to evaluate a second end point that is not affected by salvage therapy.
For single-arm phase II studies that include historical controls, differences between the study and control groups, such as eligibility criteria, start times, or salvage therapy use, can impact end point comparisons including but not limited to OS. In addition, OS may improve over time due to general medical advances, such as earlier diagnosis, improved care of tumor symptoms and therapy complications, and better neurosurgical and radiation approaches. These factors coupled with the impact of random biases, such as patient selection, argue strongly for the incorporation of a contemporaneous and comparable randomized control group, particularly for advanced phase II studies.35,36 Nonetheless, there remains a need for study designs for early, small phase II trials to rapidly evaluate potentially advantageous treatments. For such studies, PFS at a defined time point may be a preferable end point. Although such studies may provide a signal of anti-tumor activity, definitive conclusions, including the decision to proceed to a pivotal phase III study, will be more appropriately based on a randomized study design.
For exploratory phase II trials designed to determine whether proceeding to a randomized phase III study is appropriate, OS rate measured at a defined time point for which there are established historical data, such as OS at 12 months (OS-12), can shorten trial length while still providing a measure of treatment efficacy. However, required accrual may increase for OS at a specified time point compared to overall median OS. Alternatively, clinical trial designs that incorporate a “run-in” phase II component to evaluate a more rapidly measured event (such as OS-12 or PFS-6) can be performed before transitioning into a randomized phase III trial that incorporates a median OS primary end point. Statistical models exist to permit a seamless shift from phase II to phase III.37
PFS
Several metrics have been used to gauge the durability of treatment antitumor activity. PFS measures time from treatment initiation to either progression or death from any cause. PFS end points have several potential strengths. First, the duration of time without tumor progression is usually clinically meaningful and, in general, reliably reflects treatment effect, because HGGs do not typically exhibit prolonged disease inactivity (in contrast to low-grade glioma). Second, PFS end points are not affected by subsequent therapies. Third, PFS-based studies are typically completed in a shorter time frame than OS-based studies because the outcome occurs sooner. They may also require smaller sample sizes because treatment effect is often greater on PFS than OS. Quicker, smaller studies are more feasible, economical, and rational in view of the large number of drugs under development.
Another value of PFS end points among patients with recurrent HGG is that they were recently shown to correlate with OS in 2 independent meta-analyses of cooperative group phase II trials.38,39 Similarly, recent retrospective data suggest that PFS-6 also correlates with OS among patients with newly diagnosed conditions.40 However, all of these data were generated prior to the routine use of bevacizumab salvage therapy and defined PD based on enhancing tumor measurement according to the criteria of Macdonald et al.1 The association of PFS-6 and OS for both patients with newly diagnosed GBM and those with recurrent GBM will require reevaluation among patients treated with anti-VEGF therapy and should include parameters to define PD that assess nonenhancing as well as enhancing disease such as the RANO criteria.34
There are potential disadvantages of PFS end points.18 First and foremost, determination of PFS is critically dependent on a reliable, standardized, objective means to define tumor progression. Such a definition must be quantifiable and able to be confirmed by external review and auditing. Current radiographic methods to define progression are problematic due to confounding factors including pseudoprogression and pseudoresponse, as discussed above. Improved guidelines, such as those defined by the RANO criteria, are expected to lessen the impact of these issues.19,34 The use of blinded independent central review of PFS can lessen the potential bias involved in determining PFS, but it is also not practical in all trials.41,42
Another potential drawback of PFS is evaluation time bias due to variably timed planned and unplanned patient assessments within and across clinical trials. One strategy to circumvent this issue is to assess PFS at a fixed time point. PFS-6 is usually preferred for patients with recurrent HGG, because 6 months is believed to represent a clinically meaningful period. In addition, meta-analysis of PFS-6 across comparable trials can provide a useful historical benchmark.38,39,43
Auxilliary end points
This section briefly examines alternative imaging assessments and measures of patient function and well being that may be considered as auxiliary or secondary end points in future clinical trials. Unfortunately, an extensive review of such measures, as well as the potential association of tumor biomarkers and outcome, is beyond the scope of this manuscript.
Alternative Imaging Approaches
Ideally, alternative imaging approaches should provide either an early predictive marker of an established clinical benefit (ORR, PFS, or OS) or a more accurate measure of tumor burden or extent compared to established techniques. However, before implementation, new techniques must be standardized, validated, and made widely available in terms of both access and cost.
Volumetric tumor assessment
Studies comparing 1-, 2- and 3-dimensional measurements and volumetric assessment suggest that there is good concordance between methods in determining radiologic response in adults with newly diagnosed and recurrent HGGs.9,10 However, given the geometric complexity of both contrast enhancement and T2/FLAIR changes associated with most glial tumors, volumetric evaluations may improve accuracy, whereas computerization of such measures may lessen interobserver variability.11
Assessment of microvascular changes: blood volume, blood flow, and permeability
MRI can be used to define surrogates of vascular effect, such as cerebral blood volume and flow, as well as vascular permeability using techniques such as dynamic susceptibility contrast imaging, arterial spin labelling, and dynamic contrast enhanced MRI .32,44 A recent analysis suggests that multivariate algorithms of such indices may provide an accurate strategy to predict outcome following anti-angiogenic therapy.45
Magnetic resonance spectroscopy
Evaluating major tissue metabolites such as choline, creatinine, N-acetyl-acetate, lipids, and lactic acid using magnetic resonance spectroscopy can help define the complex biology of HGGs.46 Although these data have yet to be successfully integrated into HGG trials, the ability to noninvasively interrogate tissue metabolites over time is attractive as a method to monitor treatment effects.
Imaging cell density
Diffusion-weighted imaging measures the diffusivity of water within brain tissue and can provide information on cell density and characteristics of tissue architecture through either the creation of apparent diffusion coefficient (ADC) maps47,48 or white matter tract morphology via fractional anisotropy maps.32 Preliminary analyses suggest that ADC values correlate with response to therapy.48–50 A recent report also suggests that diffusion MRI may be able to detect nonenhancing tumor progression in patients receiving anti-VEGF therapy.51
Positron emission tomography (PET)
PET52 can monitor glioma therapy using radiolabeled, biologically relevant ligands such as fluorodeoxyglucose, amino acids and fluoro-L-thymidine.53,54 Each ligand is associated with potential merits and limitations and such approaches offer promise for a wide array of therapeutics.53,54 For example, in a recent study of patients with recurrent HGG treated with bevacizumab, a ≥25% reduction in tumor fluoro-L-thymidine uptake was predictive of PFS and OS.55
Assessment of Patient Function and Well Being
Importantly, “established” outcome parameters such as ORR, PFS, or OS are truly of clinical benefit only if they stabilize or improve patient function via tumor control and do not worsen patient function or well being due to treatment toxicity. Patient function and well being are particularly meaningful because they directly reflect the patient perspective. Objective assessment of patient function and well being is generally preferred as it reduces self-report biases and other confounders. For example, neurocognitive testing provides an objective approach to evaluating patient function that reflects neurologic integrity.56 In contrast, subjective self-reporting of neurocognitive status by patients is not well correlated to objective neurocognitive function and is more often associated with symptoms of depression or fatigue.57 However, some patient experiences (eg, symptoms such as pain, health related quality of life [HRQOL]) require use of a patient reported outcome (PRO) scale.
Several practical concerns warrant consideration as metrics of patient function and well being gain interest as potential clinical trial end points. Effective assessment tools must take into account the heterogeneity and complexity of neurologic manifestations caused by brain tumors and must also strive to minimize subjectivity, bias, and interobserver variability. Ideally, assessments could distinguish the effects of comorbid events (eg, strokes, seizures, and infections) or concurrent use of medications from those of underlying tumor. Just as imaging end points are often aided by the incorporation of clinical data (eg, information regarding comorbid, events such as strokes and seizures, or use of concurrent medications), inclusion of such data in the interpretation of patient assessments can be valuable.58 Furthermore, because long-term data regarding these measures among survivors are sparse, it may be difficult to distinguish a treatment effect from that of the natural disease course in uncontrolled, noncomparative studies. Other challenges of such end points include the relatively short period to progression in many patients, and the practical limitations posed by assessment frequency. Compliance and missing data can also be critical issues and may limit data analysis.59 Finally, because better-functioning patients are more likely to participate with such evaluations, attempts should be made to apply assessments broadly across good and poor performance patients.
Objective assessment of these dimensions may help to establish differences in antitumor activity, treatment-related toxicity, and time to neurological deterioration, the latter being of clinical importance, even in the absence of an objective antitumor response. The value of these alternative end points in HGG trials is partly dependent on the phase of the trial and the mechanism of action of the tested agent. For example, interpreting the impact of therapy on neurocognitive function or quality of life in uncontrolled phase II studies of novel agents with unproven activity may be impractical. However, once evidence of antitumor activity has been established, and a randomized phase II or III trial is developed, data from auxiliary end points assessing objective neurocognitive function and subjective patient reported outcomes become increasingly important.
Corticosteroid use
In patients with HGG, corticosteroids are commonly used to decrease vascular permeability, mitigate peritumoral edema, and improve neurologic function. However, long-term corticosteroid use can contribute substantially to morbidity due to impairment of immune function, diminished wound healing, and the development of proximal myopathy, osteoporosis, mood and sleep disorders, hypertension, weight gain and diabetes. Given the negative effects of corticosteroids and the association of their use with tumor burden, it is reasonable to consider a decrease in corticosteroid dose as a clinical benefit. Furthermore, ~70% of patients with newly diagnosed GBM60 and 50% of those with recurrent GBM16 are receiving corticosteroids. These relatively high percentages make it feasible to power a study incorporating the reduction of corticosteroid dose as an end point. However, there is currently no uniform approach to initiating and adjusting corticosteroid dosing among patients with HGG, making the use of corticosteroid adjustment as a reliably measurable end point problematic. Nevertheless, reduction in steroid requirements was a positive effect noted in the recent FDA accelerated approval of bevacizumab for recurrent GBM.16
Neurologic status
Even though the neurologic examination is modularized and neurologic scales exist for a number of neurologic disease categories, there is no clear method to define significant neurologic decline for brain tumor trials. Pretreatment patient performance, a widely evaluated metric across many oncology trials, provides a consistent and statistically significant prognostic factor for OS in brain cancer trials.61,62 Using change in performance status to indicate clinical progression is attractive given the ease and pertinence of its evaluation. However, HGG trials have yet to identify the performance status scale of choice for consistent use across studies. In addition, changes in performance status due to comorbid events or concurrent use of medications must be distinguished from those attributed to underlying tumor progression.
Neurocognitive assessment
Neurocognitive dysfunction is ubiquitous among patients with HGG, is associated with diminished independence in activities of daily living,63 and can impact HRQOL along with several other factors.63,64 Furthermore, neurocognitive function can predict prognosis58,65,66 and may decline in advance of imaging evidence of progression.66–68 Previous research has demonstrated that assessment of more specific signs (eg, cognitive function) and symptoms (eg, fatigue) in patients with brain tumors are more prognostic than assessment of global constructs such as overall HRQOL.69 The assessment of neurocognitive function in clinical trials involves a compromise between the desire for sensitive and extensive testing and practical constraints posed by available resources and patient compliance. The absence of neuropsychological expertise at each center limits the extent to which cognition can be thoroughly tested. Therefore, a practical neurocognitive assessment in clinical trials should be brief, sensitive, and repeatable; have known psychometric properties, such as test-retest reliability and published norms; and be able to be administered by trained nonneuropsychologists. In a large multiple-center trial, neurocognitive assessments have demonstrated value.56
Clinical trials may consider implementing a small core set of neurocognitive tests for all participating patients or centers and incorporate more extensive testing at select centers with appropriate neuropsychological expertise. A core neurocognitive test battery that is inexpensive and poses low patient burden developed at the MD Anderson Cancer Center has been widely used in several Radiation Therapy Oncology Group trials.58 The tests have been translated into a limited number of languages for use in multinational trials.
Although assessments of mental status, such as the Mini-Mental Status Examination (MMSE), can be administered quickly and easily, these measures are most useful for evaluating delirium or dementia and are insensitive measures of neurocognitive function in patients with brain tumors.70 Nonetheless, MMSE assessment was found to be prognostic for OS in some HGG trials71 and may provide an early cue of tumor progression.66 Therefore, baseline MMSE can be considered in future trials as a possible stratification factor; however, the longitudinal evaluation of neurocognitive function is more sensitively achieved by formal testing.
Symptoms and HRQOL assessments
Any assessment of a patient's perceived level of function, symptom experience or HRQOL is a PRO, which is inherently subjective in nature. Although HRQOL and self-reported symptom questionnaires are both subjective measures of an individual's health status that come directly from the patient, they are conceptually distinct forms of patient reported outcome (PROs). In terms of PRO measures, symptom questionnaires have been described as a preferred approach to HRQOL questionnaires to determine the impact of disease and treatment in a clinical trial as symptoms are thought to be closer to the biologic and physiologic factors impacting the patient than HRQOL. Specific symptom questionnaires (eg, Brief Fatigue Inventory52) as well as brain tumor specific multisymptom questionnaires (M.D. Anderson Symptom Inventory-Brain Tumor Module72) have been developed.
HRQOL has been defined as “the physical, psychological, and social domains of health, seen as distinct areas that are influenced by a person's experiences, beliefs, expectations, and perceptions.”73 Beliefs and expectations regarding health and the ability to cope with limitations and disability can greatly affect a person's perception of health, satisfaction with life and reporting on HRQOL questionnaires. Susceptibility to response shift over time and other biases further limit the use of HRQOL questionnaires to assess clinical benefit in clinical trials. Nonetheless, validated HRQOL questionnaires for patients with brain tumors can assess the physical, psychological, and social impact of the disease and its treatment.74 The general Functional Assessment of Cancer Therapy questionnaire combined with the Brain Tumor module (FACT-BR) addresses physical, social, emotional, and functional well being to provide a broad view of HRQOL issues with robust psychometric properties. Similarly, the QLQ-C30 developed by the EORTC as a general oncology questionnaire, which interrogates 5 main functional areas and provides symptom scales for fatigue, nausea/vomiting, and pain can be combined with a brain-tumor-specific questionnaire (BN20), which provides additional queries of neurologic and treatment parameters.
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Discussion
Recent clinical trials have identified therapeutic agents and strategies that meaningfully improve outcome for both newly diagnosed and recurrent patients with HGG. On the basis of laboratory advances that have significantly enhanced our understanding of cancer biology, a large number of therapeutic agents with diverse mechanisms of action are in clinical development. It is therefore now more important than ever to recognize the strengths and potential pitfalls associated with various clinical trial end points to evaluate these agents as efficiently as possible. Although OS remains the gold standard for phase III trials and most trials involving newly diagnosed patients, some of these trials may be enhanced by an additional end point that is not affected by subsequent salvage therapy, such as PFS at a defined interval. For most phase II studies, particularly for those involving patients with recurrent conditions, median OS and PFS at a defined time interval represent appropriate primary end points. Imaging response remains of value for selected situations but is potentially confounded by several factors including pseudoprogression and pseudoresponse. Application of the RANO criteria2 may lessen the impact of these factors and improve assessment of ORR as well as defining progression. Given the limitations of commonly used imaging assessment techniques, the development of alternative imaging approaches as secondary end points for clinical trials is encouraged. Finally, validated metrics of patient function and well being are available and increasingly valued as secondary end points.
Summary of considerations for selection of clinical trial end points for HGG
1. End points of therapeutic clinical trials should be clearly defined and based on a rationale statistical hypothesis.
2. Although ORR is an important end point, its reliability is problematic in studies evaluating agents or regimens with cytostatic potential or that are associated with either pseudoprogression or pseudoresponse, particularly anti-VEGF therapies.
3. Metrics of clinical and radiographic evaluation should be standardized and should incorporate the recently defined RANO criteria.
4. Overall survival remains the gold-standard; however, if potentially compromised by salvage therapy, an additional end point of outcome should be considered that is independent of salvage therapy, such as ORR or PFS.
5. FS, including assessment at a fixed time point, is an appropriate end point for most phase II studies, especially among patients with recurrent conditions. Correlation of PFS end points with OS should be further explored in the current era and ideally validated with the RANO criteria. PFS end points can enhance studies with an OS primary end point if subsequent salvage therapy may affect OS.
6. To optimize study end point value, appropriate comparison groups should be used. Although concurrent controls are preferable in general, a historical comparison group may be considered but should reflect patients with comparable eligibility, chronological era of care, study start times, and subsequent salvage therapy.
7. Objective tests of neurocognitive function and subjective patient reported outcome measures are highly valued and should be practical, reliable, and validated in controlled study designs.
The following question is from ASCO SEP, Second Edition: • A 55 year old man presented with syncope, a history of lightheadedness which had worsened over several months, and mild personality changes. Imaging revealed a right frontal mass measuring 7.3 by 6.3 cm which was associated with a 1.9 cm midline shift. He underwent resection followed by standard temozolomide/radiation. Four weeks after the conclusion of combined therapy he is being seen in the office with a repeat MRI, just prior to the start of cycle one of temozolomide at 150 mg/m2, 5/28 days. Clinically the patient is doing well. His energy has returned. He has no complaints of lightheadedness and his wife is relieved to report that he seems like himself. The MRI, however, shows an increase in enhancement surrounding the surgical cavity as well as at the inferior aspect of that cavity. The next step in his treatment should be: a)• • Bevacizumab 10 mg/kg every 14 days. b)• • Participation in a clinical trial. c)• • A discussion of hospice. d)• • Continue with temozolomide 5/28 as planned.
Answer: Continue with temozolomide 5/28 as planned. • Rationale : • Pseudoprogression describes the frequently observed, non-tumor related increase in enhancement on MRI following initial radiation or chemoradiation to the brain. These radiologic changes, appearing in the first 12 weeks following the completion of chemo/radiation, do not prompt a change in the therapeutic plan and resolve with time. Persistent increases in enhancement may prompt a biopsy to determine the presence of viable tumor.
"Hindsight may allow a more accurate determination of progression and is now a formally described part of the outcome assessment procedure."
It is like I stated, the Month 2 scan is not an immediate elimination of patients. ALL patients need to come back and have their next scan to CONFIRM if what was seen on that first Post Treatment BASELINE scan is true early progression. And given the phenomenon of early "false" progression is understood to be mixed in, ALL trials need a early "Pseudoprogression" decision tree. This trial exclusion criteria will have removed a bunch of "pseudoprogression" but it will not have removed all. Not all RT/TMZ induced Pseudoprogression shows immediately on the first POST RT MRI scan. There will be a smaller percentage of Pseudoprogression patients in both arm and so it is impossible to not use the standardized approach that RANO working group, which UCLA head, was a part of. They used hindsight to confirm the Month 2 scan. It doesn't matter how much of an inflammation response DCVax-L may have caused.
Again once TMZ was added up front with radiation, after STUPP approval, it started to become apparent that they were falsely removing patients for progression. And so it became more and more common to have more and more patients come back for a confirmation scan. The percentage of falsely removed progression patients started to go down because of the use of a "confirmation" scan early on. And RANO criteria essentially formalized the approach so that doing some kind of "confirmation" scan to rule out "Pseudoprogression".
The folks who continue to insist that a formalized "confirmation" scan was not be used in this Phase III either doesn't understand that the neuro-oncology community wants to get the readings right. Or they want to ignore a positive; and that is a decision tree to keep "Pseudoprogression" patients in this trial. Like it or not, it's fact. I know what I'm talking about as I understand the topic. Size of scans don't matter on Month 2. What matters is that the size between Month 2 and the subsequent scan does not grow another 25%. And the fact that the indeterminate patients in the CUA scans did not get worse, makes it easy to see that it shouldn't get worse for the main arm patients. And as we know, Linda Liau stated that those 10 patients who are alive are without a PFS event, confirms that a confirmation MRI -- a hindsight scan -- is needed to confirm true progression "early" on.
Abstracts from the 9th Meeting of The European Association of NeuroOncology, September 16–19, 2010, Maastricht, The Netherlands:
O.09. UPDATED RESPONSE ASSESSMENT CRITERIA FOR HIGH-GRADE GLIOMAS (HGG): REPORT FROM THE RESPONSE ASSESSMENT IN NEURO-ONCOLOGY (RANO) WORKING GROUP
M. van den Bent 1, D. MacDonald 2, S. Chang 3, M. A. Vogelbaum 4, and P. Y. Wen 5; 1Daniel den Hoed Cancer Center, Rotterdam, Netherlands; 2London Regional Cancer Center, London, ON, Canada; 3UCSF,San Francisco, CA; 4Cleveland Clinic, Cleveland, OH; 5Dana Farber/ Brighams and Womens Cancer Center, Boston, MA
Accurate determination of response and progression is crucial to evaluate new brain tumor treatments and care for patients. Macdonald’s criteria (Macdonald et al. J Clin Oncol. 1990; 8:1277 – 80), based on measuring cross-sectional enhancing tumor area, taking into account changes in steroid dose and neurological status, have been widely used. Limitations include difficulty in measuring tumors with complex shapes or indistinct borders, nontumor factors that produce imaging changes, reaction to local therapies, posttreatment changes that may mimic tumor, and lack of applicability to nonenhancing tumors. Anti-angiogenic therapies, which reduce MRI enhancement by restoring the blood-brain barrier, while nonenhancing tumor may enlarge, highlight the difficulty of assessing novel treatments. The RECIST criteria use unidimensional tumor measurements, do not consider steroids or neurological status, and have the limitations of Macdonald’s criteria. The RANO group is an ongoing unofficial international multidisciplinary consensus-building effort to develop new response criteria. The now published RANO criteria for HGG measure cross-sectional enhancing and nonenhancing tumor area, and account for the changes in steroid dose and neurological status (Wen et al. J Clin Oncol. 2010;doi: 10.1200/JCO.2009.26.3541). Within the first 12 weeks of completing chemo-radiation, progression requires either new tumor outside the high-dose radiotherapy field or biopsy-proven tumor, to avoid “pseudoprogression.” T2/FLAIR images receive more emphasis, particularly in trials on anti-angiogenetic agents. Hindsight may allow a more accurate determination of progression and is now a formally described part of the outcome assessment procedure. Increase of steroids alone is still not perceived as sufficient evidence of progression.
Hi Tadasana, Sweet. Thanks.
AF and I just have a difference of opinion about the science. I actually appreciate that he calls things as he sees it. I also think he is very good writer. He doesn't strike me as someone who needs or wants my help. :) I do though think he is extremely harsh with his opinions at time. He probably feels I'm too optimistic with my viewpoints. I'm not one to care if someone agrees with me and don't take it personally if they don't. He strikes me as the same in that respect. :)
GBM trials are hard to come by. Particularly immunotherapy ones. This trial primary endpoint was PFS. GBM trials do not have drop out rates. Those that are tracking events until progression, in theory should have less (shorter commitment on patients' time). Anyone who says this trial drop out will be high is extending their biased opinion; they are invested short or not invested at all, but they stalk for the best entry. For whatever reason they post opinion as if it's fact. It isn't. In my opinion it is clear that that they don't understand that the time to recurrence isn't long and that their high-drop out speculation has no merit. There shouldn't be a high drop out rate because this trial has a crossover at progression. This is a study positive for patients. And if patients change their mind upon reaching PFS -- which is typically an event which occurs within the first year of therapy -- and want to try something different then they can do so then. The patient moving on to another study then is not considered a drop out. Instead it's an end of study notation. Those non-crossover patients are still followed until death. And their OS counts towards the trials secondary endpoint.
Here is the PR. She didn't hype anything. Your reaction to the PR is so over blown. You state your opinion as if it is fact and it isn't fact.
December 2013: First Interim Analysis Trigged?
http://www.nwbio.com/first-interim-analysis-of-nw-bios-phase-iii-gbm-trial-triggered-by-reaching-required-number-of-events/
If they opted for that path it could be because they had no more vaccine IMHO. The psychology of the patient and their families comes into play. Knowing that the vaccine is there in the event of progression was a draw of this study. Sadly it doesn't help everyone and because of the health of patients and the 3 month window, not all patients will get it. It's quite clear that placebo patients were interested in crossing over from the number she shared. Remember prior to that crossover, patients would not be any wiser as to whether they were privy to vaccine before at nGBM point. And so, one has to imagine that the same percentage of patients would at least try to get their vaccine. This works regardless of when progression hit. So for instance, if PFS is early, a patient might be under the impression that they were not on vaccine, and they would want their personal therapy upon progression. And then the same goes if the patient experienced a late progression event; those patients would also want to restart their vaccine schedule, if they perceive their late event has anything to do with possibly being in the vaccine cohort. It would only be the patients that run out of vaccine that get turned away or more onto to something else. And then there are the small percentage of patients that might miss the 3 month crossover eligibility window (due to surgery recovery, a late finding of progression event (back dating progression on Month 2 scan patients) or something like that) or possibly were simply too sick to qualify for anything that can help at that point.
All we know is that they updated their NCT guidances and that they estimated it should occur by November 2016. Since they didn't give us exact timeframe, then it's probably safe to assume that it didn't occur later than then.
In prior Phase I/II the vaccine was generated in the UCLA lab. This study will be the first to be a possible cell constitute -- if NW Bio patents to get D.C. precursors are superior. Then, this is the first study that allows up to 10 injections (5 vaccine supply being the minimum manufacturing for study inclusion). Prior Phase I/II had many patients receiving only 3 injections. Some less and some more. And also, this is the first that allows patients to continue on treatment, begin the injection schedule again, upon crossover to open label assuming study supply is there. Given that there may have been instances where patients breached a PFS event on mere size alone, it doesn't necessarily mean that they wouldn't have benefited had injection schedule continued. And next, this is the first study where all patients will be privy to Bevacizamub at first recurrence confirmation. Given Bevacizamub reduces circulating immunosuppressive cells, in my view that is bound to equate to better efficacy upon crossover. And lastly, this study is the first to actually test patients who are by all means progression free upon study start. The longer patients go without progression the higher the likelihood that they can qualify for a second surgical resection and that means less residual cell load upon progression. And so I'm expecting that a large majority of the patient population will live over 3 years. If this study sees a significant rise in surgical patients living past 3, 4, 5 year compared to historical norms, then it will unmuddy the data relatively fast. After PFS events virtually 100% of all patients die within 18 months. It is rare to have long term GBM survivors. No portion is the standard of care used in this trial changed that. Most patients do not live another year after progression. PFS2 is short in all rGBM trials. And so the time between progression and death, particularly if it's quality life months (less steroids and complications) if promising and above what they are used to seeing, then it will be easy for regulators to see the merit in Immunotherapy.
There is information you are not accounting for as you have to read everything to find it and you also would need a copy of the old confidential protocol.
The Company used 312 patient count as their intention was to make the trial seem larger than it was then. At that point in time they only had clearance to enroll 240 main arm patients and up to 48 PsPD (outside the main arm) and then another 24 lost to follow-up patients. They did not have final permissions for Germany to join the trial yet, so they were creative with the numbers they used to account for an enrollment ramp. Anyway, the enrollment guidance they gave us was for that date and time in 2013. Once they officially became a 348 patient trial and added 21 Canada and 87 Germany patients (up from 240 patients (only included 216 US and 24 UK enrollment)) they also had a bunch of new clinical sites added to officially recruited at. My ramp includes all the data.
"3.4. ESTIMATED ACCRUAL
It is estimated that accrual will average 0.5 – 2 participants per month per site, at approximately 50 clinical sites participating in the study. The total study accrual is approximately 288 patients; approximately 240 patients will be randomized into the main arm of the study to test the primary and secondary hypotheses; approximately 48 additional pseudoprogression patients will be randomized into the pseudoprogression arm and included in the tertiary analyses.". --protocol
Hi Tadasana,
I imagine there are no more than 10% of placebo PFS events outstanding from the 2015 period (30 placebo patients = 3 patients). I suspect that it is less than that and may even be like 5% or less of the overall study that never events (111 placebo = 6-7 PFS non-eventers). But best case scenario for patients is closer to 10%. Since the study has gone on for so long the 3-5 year late events will have crossed a PFS threshold and so that's why I think 6-7 patients at most.
Remember, you own shares so if you ever decide to add you want to be highly selective where you add. You've heard me say this many times. Please follow it.
When it comes to late stage biotech's and news might come after capital raises, so it's important that you not let images of rewards cloud your judgement. Try to avoid adding too early. Make sure you're down significantly before you even consider adding more. After all you were very content with your share count before. You had no plans to add more when it was $.40, so don't let any old drop get you to change your mind. Be very strategic. A sale isn't a sale unless you truly had intentions of adding. And it's not worth adding while blinded if you are not going to fix the downward spiral you're in.
I know you realize that IF you were to buy new shares, the ones you would but here would not be diluted. But the old ones, depending on the share issuance and subsequent fall, very much so. That alone isn't a reason to buy. But, if you did have capital reserved to not have this investment opportunity ruined for you on the account of management needing to do capital raises to get to the end of the study, then you'll have been waiting with money on the sidelines to potentially add one day, like I have been. So for instance, my share cost is $.42. So using myself as an example, I'm fine with my share count. If this never dropped, I would have been sitting pretty. But the reality is that it did. Other than adding a few K after this current dilution, you won't find me investing more until I'm down significantly. [I will only add a little to lower my cost but only at small risk at a time (will release my $.34 shares for my $.24 shares that I picked up here if it ever goes up in the short term.)]. If in a few months this stock in the teens, and I find myself down 75% or more, I will begin to consider adding additional risk there. If I'm down 75% then I can easily lower my cost basis to only be down to a mere fraction of additional risk capital. But if I wait until I think all possible bad news has hit my share value, I may even be better off to wait and add there. Remember, there is no fear of me missing out of any great rise, as remember I own shares. But, there's also no fear of me watching my balance fall as I start a position, and I never go all in. I risked an amount I could stomach holding through dilutions. I'm what you would describe as careful. One needs to be diversified and careful when investing in clinical stage biotech's. Investing in what I perceive as winning science based on my due diligence - that results are blinded -- takes years. With biotech's significant drops can occur on the mere capital raise news. This last one dropped us about 35%. That requires a big move to recover -- over a 50% GAIN to just break even. And one should know it's much harder to rise when the market sentiment isn't there .. yet. Resistance above is strong at this time. Any momentum move up could be manipulated by swing traders. Anyway, point is to be VERY picky where you add and to not let every drop entice you to buy. Wait for a few drops to do so. Hopefully this chart I made below will help add perspective.
IF You're Down % then here is the GAIN Required to Break EVEN.
Down. GAIN NEED TO BREAK EVEN
5%. 5% GAIN
10%. 11% GAIN
15% 18% GAIN
20%. 25% GAIN
25%. 33% GAIN
30%. 43% GAIN
35%. 54% GAIN
40%. 67% GAIN
45%. 82% GAIN
50%. 100% GAIN
75%. 300% GAIN
90%. 900% GAIN
Again, you have a position. Wait until when you think news will come or even after news comes in to add. Your last money buys should be highly selective IF you decide add. If you learn one thing from me, learn that.