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Off Topic.....Cryopreservation advances by Northwest Biotherapeutics are intriguing.
LP's UK presentation gave me the impression little NWBO may be the most advanced commercial cryopreservation company in the world.
If you get the chance, listen to that portion of the presentation again.
One can imagine other applications are attainable.
The next "data" update will give us further insight into that response rate. The correlation between time/# injections and response is extremely encouraging.
I agree. I think it was her best presentation to date.
Hi Fox, I'm glad you added this point. As you are the expert, it is probably the primary advantage, but I think there are others as well. Thanks again.
Triozzi study revisited, cancer bombs and other observations.
Triozzi's dream....
I thought Ms. Power's discussion regarding the 3 stages/phases of DCVax-Direct treatment were slightly more informative today.
I. Specifically, injections 1-3: tumor response is likely caused by the dendritic cell secreting massive amounts of cytokines on site.
II. Injections 4-6: tumor response is likely caused predominantly once the dendritic cells activate the T and B cells. Ultimately a systemic response is sought during this phase.
III. Immune Memory is likely determined thereafter.
What probably struck many of you is that this explains why Triozzi likely wanted in depth research to determine how to get to steps 4-6. Triozzi's study basically ended at approximately 2 to 8 weeks. He was likely seeing the first phase of dendritic biotherapeutic activity.
If one includes the phase 2 Direct abstract from UCLA and combines that with recent observations in this phase 1 trial, it appears we cleared the the second hurdle on at least 3 cancers. IMHO.
Cancer bombs....
Apparently the 1st 3 injections involve what some here refer to as the "bomb." This is when the patient's injected dendritic cells secrete massive amounts of cytokines. Of course the dendritic cells are also busy picking up fragments of biomarkers/aka antigens/aka proteins from the cells they just killed with those cytokines. In other words, for those of you who like to read between the lines, DCVax-Direct does not necessarily need chemotherapy/radiation/surgery to obtain dead tumor fragments. (Note: Cytokines have other roles besides killing tumor cells locally, so there is a fair amount of confusion here for some people.)
I'm going to take a leap on this bomb description. Tumor cells themselves can be rather leaky when injected with small molecules that cause tumor necrosis -- chemotherapy is one example where the leakage is so extensive and toxic to the patient that intra-tumoral chemotherapy injections need to be placed in a gel like containment vehicle. Anyway, my leap here is that the tumor response observed in tumors quite close to the injected tumor may in fact be initially due to excess cytokine material, and perhaps some escaped dendritic cells still conducting their first phase duties -- tumor killing and antigen uptake.
From cancer bombs to invading armies.
So phase I of DCVax-Direct dendritic biotherapy softens up the tumor (battlefield) with cytokine bombs. Once the DC carries information of the enemy back to the lymph nodes and spleen, the invading army t-cells (and b-cells) can attack the already battle weary tumor.
Maybe you can see what I am leading to.
What would be better than attacking one softened up tumor/battlefield where cancer already metastasized? That's right. Attacking many previously softened up tumors. Linda Powers states the obvious reason to inject many large tumors in a particularly fast moving aggressive cancer, but certainly another reason is that phase one biotherapeutic action by DCVax-Direct with "massive" loads of cytokines, can, in some cases, obviate the need for chemotherapy and/or surgery and/or radiation.
and beyond....
Large tumors typically create much stronger immune suppressive environments. Consequently, by injecting multiple large tumors, one simultaneously softens up the large theaters of war for the incoming invading army of t and b cells, while the smaller tumors and tumor cells with less organized defense systems are quickly mopped up by the supercharged immune system.
(You'd never know I am a peacenik)
I'll probably catch the replay. If not, I'll be fishing after the presentation is concluded.
Crew asked the ag and sec to look into AF's manipulation. Other than that, I honestly think any further complete updates on Direct, if they are somewhat in line with prior updates, will de-risk this company all the way to a tipping point. At that point, long investment institutions will dip more than their toes in. IMHO.
You and your wonderful family are in my thoughts and prayers. On a scientific note, I think the recent order you are following in therapy succession makes a great deal of sense. God bless.
They stated in a PR this summer after releasing early results on DCVax-Direct that investors would need to exhibit some patience while the enrollees move through their series of injections, but that NWBO would update results during the course of this trial. We did learn that apparently all 9 patients who were the first to receive four injections and exhibit response are apparently still alive. We also recently learned about Mr. Butler from National Geographic. His pancreatic tumor failed chemotherapy after four months and progressed to his liver and abdomen. We now know that after 18 months from original diagnosis, and apparently approximately 1 year of DCVax-Direct, he is doing well. We know the patient who was reported on last June with a lung carcinoma the size of a football is doing very well and quite excited about the program. We know Laurie Hodge is still seeking therapy at MD Anderson for DC Vax- Direct, and she reports "many people" feel that the doctor(s) that invented DC-Vax should win the nobel prize....
Thanks John, I went to the gofundme sight again after I saw this post. Laurie and Ben, I hope all is well!
I can only imagine the number of flights and hotel reservations the Hodges must book during this trial.
UCLA has been conducting a phase II DCVax-Direct trial -- this was/is likely a brain cancer study. The abstract on preliminary results appears to demonstrate its method of action works as expected, but the actual efficacy numbers are on the qt -- probably because enrollment is not complete in the parallel L trial. The preparation/manufacturing procedure for Direct is more advanced, and is meant to enhance the power of the DCVax program beyond L. Ultimately, L should be allowed to use the preparation enhancement that Direct takes advantage of, but the current L trial has statistical demands that prohibit changing horses midstream.
Aside from the UCLA trial, because this gentleman's cancer is inoperable, he may be able to qualify for individual compassionate use -- the case-by-case version. This will likely take willingness on the part of his local oncologist to help facilitate the application. http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/accesstoinvestigationaldrugs/ucm176098.htm
With all due respect. Tob, let's take a brief trip back to the facts. Linda Powers did not jump in front of Subbiah in November 2013 or May 2014. At Asco, the poster was done weeks before the release (and no release was done before the poster was made.) In November nobody presented anything, and NWBO did not release any data prior to that "event." What do people think? Subbiah got huffy??? Get real.
Something or someone likely shut him down. On two occasions he wanted to present data at two separate conferences. Next, AF's strange confrontation, half-quote half-demand(in an international article) to Subbiah at the poster presentation made certain Subbiah was not going to talk about presenting until the dosings were completed. Read it carefully. Still, Subbiah was fine with NWBO releasing information. So just to tidy things up (aka: shut down/isolate LP as well), AF/Buzdar announced to the world that MD Anderson's Buzdar thought NWBO was completely "inappropriate" for releasing data before final results were in. Do you think Buzdar, with decades under his belt, does not know that large pharma constantly releases phase 1 data early -- ethically and legally? Do you think he didn't have the opportunity to fix his quote? Buzdar failed to mention every piece of evidence that MD Anderson itself, the labs and the CRO reviewed and provided to NWBO, not just the "hospitals." Do you honestly thinks he believes MD Anderson did not review any data "at all" in an open label trial because enrollment was not complete??? Get real! Look at the 5 examples. Did MD Anderson ever wait to review phase one data, or did they do it every chance they could get (according to one of the doctors in the examples above? Of course they did! They were in charge of safety and determining response. There is no placebo folks! There is no Blind!
There is nothing, absolutely nothing that makes AF's call to MD Anderson justify the reason Newman and Buzdar stated something that simply was not accurate, hurt NWBO's reputation and delay critical funding. Newman and Buzdar had plenty of chances to back off their statements....nope. Newman states MD Anderson still is concerned about companies getting people's hopes up with early phase I releases.
I guess "these are not the droids [people] are looking for."
That's me venting....with all due respect.
p.s. "dragging out" Really?
Absolutely not.
1. Mr. Newman and Buzdar indicated that the timing of the data release was an absolute line that could not be crossed. (Obviously they are wrong.)
2. Moreover, as you'll notice, there are examples where other companies released the efficacy data, and MD Anderson was there with full knowledge.
3. Finally, on 2 occasions, Dr. Subbiah expressed his desire to share initial data at 2 separate presentations. For some reason, this desire was....short circuited.
Apparently Genetech does not even bother telling people their phase 1 trial is not fully enrolled when they give results. Apparently, MD Anderson supports them.
In the phase I study below involving Vemurafenib, Cetuximab, and Irinotecan in Advanced Solid Cancers, you might assume that Genentech had finished enrolling (they are still enrolling). You might assume they reached their primary completion date. You'd be wrong about that too. "February 2016 (Final data collection date for primary outcome measure)." Before I site the article to you, here is the clinical trial site link. http://clinicaltrials.gov/show/NCT01787500
You might notice this trial also deals with Multiple Solid Tumor Cancers.
You might notice MD Anderson is the lead investigator.
You might notice these "results" were presented at ASCO 2014.
Here is the article, emphasis in red is mine.
News Feature | June 2, 2014
Genentech Reports Positive Results From Two Phase I Cancer Studies
By Cyndi Root
Genentech has announced results from two Phase I cancer studies. One study of the investigational immunotherapy agent MPDL3280A found that it shrank tumors in 43 percent of metastatic bladder cancer patients. In another Genentech-funded study, researchers at the University of Texas MD Anderson Cancer Center announced that a combination of vermurafenib, cetuximab, and irinotecan induced a clinical response in patients with advanced colorectal cancer.
Genentech, a member of the Roche Group, presented both findings at the American Society of Clinical Oncology (ASCO) meeting in Chicago. Genentech announced earlier in May, that it would present data on nine approved and 18 investigational medicines in 320 abstracts and 40 oral presentations at the conference.
MPDL3280A
MPDL3280A is a monoclonal antibody, Fc optimized against the protein ligand PD-L1 (programmed cell death-1 ligand 1). It has immune-modulating and antineoplastic action, binding to PD-L1 and enhancing the T-cell-mediated immune response. The Food and Drug Administration (FDA) gave MPDL3280A a Breakthrough Therapy Designation in bladder cancer.
In the new Phase I open-label study, results showed the immunotherapy provided an overall response rate of 43 percent, shrinking tumors in people previously treated for metastatic urothelial bladder cancer (UBC) whose tumors were characterized as PD-L1 (Programmed Death Ligand-1) positive.
Sandra Horning, M.D., CMO and head of Global Product Development at Genentech said, "We are evaluating MPDL3280A in a broad range of tumors, and have begun pivotal studies that include a companion diagnostic test in lung and bladder cancers.”
Anderson Cancer Center Study
Roche and Genentech funded a study of the drugs vermurafenib, cetuximab, and irinotecan at the University of Texas MD Anderson Cancer Center. Patients with advanced colorectal cancer responded well to the combination treatment. The Phase I trial examined the drugs’ effect on a BRAF gene mutation, present in 5 to 10 percent of colorectal cancer patients. David Hong, M.D., associate professor of Investigational Cancer Therapeutics and the study’s lead investigator, said that this subgroup of colorectal patients often does not respond to standard chemotherapy.
Researchers combined escalating doses of the drugs and took radiographic images. Scans revealed that 50 percent of patients showed a favorable response to treatment. A Phase II trial of the combination therapy in BRAF-mutation colorectal cancer will begin by the end of the summer
On the MD Anderson Site itself!
MD Anderson announces early results on strictly phase I trial where only 67 of an eventual 81 patients were enrolled. Nonetheless, MD Anderson, who still carries this article on their own website, released the information. By the way, here is a link to the trial when it was actually complete and written up in 2012. http://www.ncbi.nlm.nih.gov/pubmed/23190221
Here is the early update from the MD Anderson website.
http://www.mdanderson.org/newsroom/news-releases/2010/phase-i-trial-indicates-ponatinib-may-thwart-most-resistant-cml.html
Phase I Trial Indicates Ponatinib May Thwart Most Resistant CML
Drug also acts against chronic myeloid leukemia with untreatable T315I mutation
MD Anderson News Release 12/04/10
A new drug appears to help chronic myeloid leukemia patients who are out of treatment options after first- and second-line drugs have failed them or because their cancer cells have a mutation that makes them resistant from the start, researchers reported at the 52nd Annual Meeting of the American Society of Hematology.
In a Phase I clinical trial, the drug ponatinib produced major or complete hematologic responses (absence of CML cells in the blood) and cytogenetic responses (absence of leukemia cells in the bone marrow) among two groups of patients:
Those who have tried two or three of the drugs that have revolutionized treatment of CML – imatinib (Gleevec), nilotinib (Tasigna) and dasatinib (Sprycel) – and developed resistance to them.
And those whose leukemia cells carry the T315I mutation, which resists all current therapies.
“Ponatinib seems to be filling the gap we had for patients who right now have no good treatments left,” said Jorge Cortes, M.D., professor in The University of Texas MD Anderson Cancer Center Department of Leukemia, who presented the group’s findings. “We are very encouraged by such strong results in the Phase I setting and have begun a pivotal Phase II clinical trial.”
Preclinical research had indicated that ponatinib, developed by ARIAD Pharmaceuticals, inhibits all mutations that cause resistance to drugs that stifle the BCR-ABL protein which drives CML. BCR-ABL is produced by the aberrant gene bcr-abl, which occurs when two chromosomes swap portions of their DNA from separate bcr and abl genes. The abnormality is called the Philadelphia chromosome.
As of July 2010, 67 patients were enrolled in the study: 57 with CML, including 42 in the chronic, or early, stage, seven in the accelerated stage and eight in the blast phase, the most advanced form of the disease. Three had Philadelphia-positive acute lymphoblastic leukemia, three had acute myeloid leukemia and four were divided among other blood malignancies.
A total of 48 patients were evaluable at the time of reporting. Of these:
30 of 32 patients (94 percent) in CML chronic phase had complete hematologic responses; 20 (63 percent) had major cytological responses, 12 complete and eight partial. Of these 20 cytogenetic responders, 18 remained on the treatment with no disease progression.
All 11 chronic phase CML patients who had the T315I mutation had complete hematologic response and nine had major cytogenetic responses, eight of which were complete.
For 16 CML patients in accelerated or blast phase or with Philadelphia-positive acute lymphocytic leukemia, five (31 percent) had a major hematological response and three (19 percent) had a major cytogenetic response.
Of nine CML patients in accelerated or blast phase or with Ph+ALL who also carried the T315I mutation, three (33 percent) had major hematologic response and two (22 percent) had major cytogenetic response.
Researchers also noted responses in patients with heavily resistant disease with no mutations and among patients with other mutations resistant to existing drugs.
The most common side effects were low platelet counts (24 percent of patients), headache (14 percent), nausea (14 percent), joint pain (13 percent), fatigue (13 percent), anemia (11 percent), increased lipase (11 percent), muscle spasms (11 percent), rash (11 percent), muscle pain (10 percent) and pancreatitis (10 percent). All dose-limiting toxicities were reversible.
The trial was funded by ARIAD.
Co-investigators with Cortes are Hagop Kantarjian, M.D., MD Anderson Department of Leukemia; Moshe Talpaz, M.D., and Dale Bixsby of the Comprehensive Cancer Center at the University of Michigan; Michael Deininger, M.D., Ph.D., and Michael Mauro, M.D., Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR; Neil Shah, M.D., University of California, San Francisco; Ian Flinn, M.D., Ph.D., Sarah Cannon Research Institute, Nashville, TN.; Thomas O’Hare, Ph.D., Oregon Health and Science University, Howard Hughes Medical Institute, Portland, OR.; and Simin Hu, Ph.D., Rebecca Kan, Victor Rivera, Ph.D., Tim Clackson, Ph.D. and Frank Haluska, M.D., Ph.D., of ARIAD Pharmaceuticals, Cambridge, MA
This MD Anderson phase I trial only had 11 of 40 patients enrolled when it started giving human beings hope. Efficacy and Safety was also announced here.
December 22, 2010
Threshold Pharmaceuticals Announces Promising Early Phase 1 Clinical Trial Results in Patients With Advanced Leukemias
Company Also Starts Preclinical Leukemia Collaboration With MD Anderson Cancer Center
REDWOOD CITY, Calif., Dec. 22, 2010 (GLOBE NEWSWIRE) -- Threshold Pharmaceuticals, Inc. (Nasdaq:THLD), today announced a preclinical collaboration with the MD Anderson Cancer Center and early Phase 1 clinical trial results of TH-302 in patients with advanced leukemias, which is also taking place at MD Anderson. TH-302 is a proprietary Hypoxia-Activated Prodrug (HAP) that specifically targets tumor hypoxia.
The objectives of the Phase 1 trial are to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety, tolerability, clinical activity and pharmacokinetics of TH-302 in patients with advanced leukemia. Eleven patients with either acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) have been enrolled in the trial to date. The starting dose in the trial was 120mg/m2 daily for 5 days of a 21-day cycle. The second dose cohort was treated with TH-302 at a dose of 170mg/m2 and the third dose cohort has completed enrollment at 240mg/m2. The dose of TH-302 will continue to be escalated until the MTD is established. To date no DLTs have been reported in any of the dose cohorts. Preliminary efficacy assessments have demonstrated activity in multiple subjects with relapsed/refractory AML and ALL as evidenced by stabilization or reduction of bone marrow blast counts.
"In the initial three dosing cohorts, TH-302 has been well tolerated with no significant drug related toxicities," said Dr. Deborah Thomas, M.D., Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. "We look forward to further assessing the safety and efficacy of TH-302."
The preclinical collaboration is being conducted with Dr. Marina Konopleva, M.D., Ph.D, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. The research collaboration will focus on characterizing the therapeutic efficacy of TH-302 as monotherapy and in combination with conventional chemotherapeutics in both in vitro and in vivo models of leukemia.
"There is already a strong preclinical rationale to evaluate TH-302 in leukemia patients," said Dr. Charles Hart, Ph.D., Threshold's Vice President of Biology. "While we continue to explore the proof of concept in the ongoing human clinical trial, we also want to fortify the preclinical basis for selectively targeting the hypoxic niches in leukemic bone marrow as a therapeutic strategy. Greater understanding may lead to the identification of specific patient subgroups most likely to benefit and the identification of biomarkers for patient selection."
Clinical Trial Design
Approximately 40 patients with advanced leukemias or other severe hematologic disorders affecting the marrow are planned to enroll in the clinical trial at the MD Anderson Cancer Center. Patients with relapsed/refractory chronic lymphocytic leukemia (CLL), ALL, AML, advanced phase chronic myelogenous leukemia (CML), high risk myelodysplastic syndrome (MDS) or advanced myelofibrosis (MF) will be eligible for the trial.
The initial dose escalation phase of the trial will enroll cohorts of up to 6 patients per dose. All doses of TH-302 are being administered as a 30-60 minute intravenous infusion daily for 5 days every 21 days. The primary objective of the dose escalation component of the study is to establish the MTD and dose limiting toxicities of TH-302 when administered daily for 5 days. The dose escalation phase of the trial will enroll up to 30 patients. Once the MTD has been established, up to 10 additional patients will be enrolled at the MTD in the dose expansion component of the trial. The objective of the dose expansion is to further assess the clinical activity of TH-302 in this population. Patients for whom no curative therapy exists are eligible for this trial.
Here is yet another phase I trial (2014) where M.D. Anderson was very hopeful long before enrollment completed. Efficacy and Safety were prominently announced, but apparently, MD Anderson's Susan O'brien may have a little chit-chat with Buzdar and Newman. In this phase I trial only, only 21 of the 100 enrollment was complete at the time data was used for this press release:
Hilighted Quote from their press release:
Dr. Susan O'Brien, Professor in the Department of Leukemia at[color=red] MD Anderson Cancer Center and Study Chair for the CLL patient group stated, "We have been very impressed with the safety profile and the level of activity observed to date in all patient groups[/color] with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease, including the difficult-to-treat CLL patients with 17p and 11q deletion, and the GCB subtype DLBCL patients. Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings."
July 21, 2014
TG Therapeutics' Novel Combination of TG-1101 (Ublituximab) and TGR-1202 Demonstrates Compelling Early Activity and Safety Profile in Patients With Previously Treated High-Risk Chronic Lymphocytic Leukemia (CLL) and Aggressive Lymphomas
100% of CLL/SLL patients had significant nodal reduction with either a normalization of or =80% reduction in Blood Lymphocyte Count
4 of 5 CLL/SLL patients achieved a partial response at first assessment, including a patient relapsed from a prior BTK-inhibitor, and the 5th patient with stable disease achieved a 44% nodal reduction pending next assessment
2 of 5 heavily pretreated DLBCL patients achieved a PR, including one patient with GCB subtype refractory to prior therapy
Combination appears well tolerated with no dose-related increases in toxicity observed among patients treated to date
NEW YORK, July 21, 2014 (GLOBE NEWSWIRE) -- TG Therapeutics, Inc. (Nasdaq:TGTX), an innovative, clinical-stage biopharmaceutical company, today announced preliminary clinical results from its ongoing Phase I study of TG-1101 (ublituximab), the Company's novel glycoengineered anti-CD20 monoclonal antibody in combination with TGR-1202, the Company's novel, once-daily PI3K delta inhibitor in patients with advanced CLL and non-Hodgkin's lymphoma. Data from the Phase 1 study is being presented by Dr. Matthew Lunning from the University of Nebraska Medical Center in Omaha, Nebraska during the 2014 Pan Pacific Lymphoma conference being held in Hawaii.
The poster presentation includes data from patients with advanced CLL, including 17p/11q del and a patient with Richter's Transformation, as well as heavily pre-treated, relapsed and/or refractory patients with Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL). In an effort to utilize this study to potentially identify patient populations with unmet medical needs that could benefit from this combination, the study was designed to enroll heavily pre-treated and high risk patients, including those with aggressive lymphomas, with no limit on prior therapies, including patients relapsed or refractory to prior treatment with other PI3K delta and BTK inhibitors.
This is a dose escalation study. Patients treated to date and included in the presentation utilized escalating doses of TGR-1202 with a fixed dose of 900mg of TG-1101 for patients with NHL and 600mg for patients with CLL. As of July 1, 2014, enrollment in the study is now utilizing escalating doses of the micronized formulation of TGR-1202 starting at 400mg in combination with a fixed dose of TG-1101 at 900 mg for all patients. As of data cutoff, 21 patients were evaluable for safety with 15 evaluable for efficacy (6 were too early for assessment).
Overview of the data presented on TG-1101 + TGR-1202:
Safety and Tolerability
TG-1101 in combination with TGR-1202 was well tolerated in the 21 patients evaluable for safety, with day 1 infusion related reactions (IRR) being the most frequently reported adverse event. All IRR events were manageable without dose reductions, and all but one event was Grade 1 or 2 in severity. Other observed adverse events included neutropenia, nausea, and diarrhea, with neutropenia being the only Grade 3/4 adverse event reported in > 10% of patients (24%). One CLL patient required a dose delay for neutropenia in Cycle 1, which met the criteria for a dose-limiting toxicity (DLT) necessitating additional patients to be enrolled into the CLL Cohort 1. No additional DLT's have been observed with full enrollment completed in Cohorts 1 and 2. Consistent with the data observed to date in the ongoing TGR-1202 single agent Phase 1 (presented at EHA 2014), no drug-related events of AST/ALT elevations were observed among the 21 patients treated to date in this combination study with TG-1101.
Clinical Activity of TG-1101 + TGR-1202 in Chronic Lymphocytic Leukemia (CLL)
Of the 8 CLL patients enrolled to date, 5 were evaluable for efficacy:
Of the 5 CLL/SLL patients evaluable, 4 achieved a PR per the IWCLL (Hallek, et. al.) or Cheson criteria (SLL) at first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at first assessment and > 50% reduction in ALC and remains on study.
All 5 patients (100%) achieved a > 50% reduction in ALC by the first efficacy assessment with one patient achieving complete normalization of ALC ( < 4000/uL) and the other 4 patients achieving a =80% reduction by the first efficacy assessment (see chart below).
A chart accompanying this release is available at http://media.globenewswire.com/cache/8790/file/27712.pdf
The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of TG-1101.
Activity of TG-1101 + TGR-1202 in non-Hodgkin's Lymphoma (NHL) / Richter's Syndrome
Of the 13 NHL or Richter's patients enrolled to date, 10 were evaluable for efficacy (5 DLBCL, 4 FL and 1 Richter's). Patients in this group were heavily pre-treated, with 50% refractory to their prior treatment regimen. In the DLBCL group, patients had a median of 3 prior lines and 3 of the 5 patients had the GCB subtype, with one patient classified as "triple-hit" lymphoma (overexpression of BCL2, BCL6 and MYC rearrangements). In the Follicular Lymphoma group, patients had a median of 6 prior lines of therapy and for the entire study population patients had a median of 2 prior lines of Rituxan-based therapy with a high of 7 prior lines of Rituxan-based therapy.
The disease control rate (Stable Disease or better) at first efficacy assessment was 90% (9 of 10), in this hard to treat population of high risk relapsed/refractory patients. Of particular note was the potential signal in DLBCL, where 2 of 5 patients with DLBCL had a partial response, including one GCB-subtype that was refractory to prior therapy. Both of these responses occurred at the higher dose of TGR-1202. Interestingly, in the single agent Phase 1 study of TGR-1202 a patient with GCB subtype DLBCL had a > 40% reduction in tumor mass and was stable for over 6 months.
Additionally, despite the advanced disease and multiple lines of Rituxan-based therapy, all of the FL patients were stable at first assessment and exhibited reduction in tumor mass, including one patient with ~45% nodal reduction, all pending subsequent assessments.
Dr. Susan O'Brien, Professor in the Department of Leukemia at MD Anderson Cancer Center and Study Chair for the CLL patient group stated, "We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease, including the difficult-to-treat CLL patients with 17p and 11q deletion, and the GCB subtype DLBCL patients. Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings."
Thanks for your action oriented approach! I really do think the truth shall prevail. I very much appreciate the way you lay out the ongoing results for Direct. Even though I've read the NWBIO press releases a hundred times, it still knocks my socks off.
Thanks Steppenwolf. It was very helpful to here from a Brain Surgeon currently on the front lines.
I just realized it looks like I wrote this about my parent. The related post was actually from AnotherDay, a poster on Yahoo.
anotherday1225 • Sep 8, 2014 11:47 PM
Pretty Sad
This week my step-father learned he has pancreatic cancer. Still figuring out the stage (biopsy was today) but sounds like stage 4 given it has spread to liver. I told my mother (a retired RN and our family expert on all things medical) about DCVax Direct and had her watch the National Geographic piece on Allen Butler in the phase 1 Direct trial. She was encouraged and said she would look into it. That was yesterday.
Tonight i called and among other things asked if she had looked further into the clinical trial. She said she started to read about it, but then saw some articles that said it was a scam; management was just promoting their stock. So she stopped reading.
I've been a long-term holder in NWBO and pretty much have not let the AF story line get to me as i think very long term. Ultimately the technology will decide the stock's future. But the real-life impact of AF's lies is showing up at a patient level. Not every patient has a long-term stock-holder encouraging them to look past the lies and seek out the treatment that could very well be their lifeline.
Shame on you AF. Less
Sentiment: Buy
Sentiment et al...
In the matter I am working on, I decided to do a more extensive review of MD Anderson's phase 1 ongoing presentations where efficacy was released early... I think it is important to lay out just how singled out NWBO really is. I will get back to you all tomorrow....
For example, here is a 2008 phase 1 with only 9 patients out 100 enrolled....
http://ir.exelixis.com/phoenix.zhtml?c=120923&p=irol-newsArticle&ID=1085792&highlight=
Exelixis Presents Encouraging Phase 1 Data For XL019, A Novel Selective Inhibitor of JAK2
ATLANTA, Dec. 10 /PRNewswire-FirstCall/ -- Exelixis, Inc. (Nasdaq: EXEL), today reported phase 1 data from an ongoing phase 1 trial of XL019 in patients with myelofibrosis, a myeloproliferative disorder (MPD). XL019 is an investigational small molecule that selectively inhibits the tyrosine kinase JAK2, one of four JAK family members activated in response to cytokines and hematopoietic growth factors. JAK2 is inappropriately activated in the majority of MPD patients and is deregulated in a number of solid tumors, including certain subtypes of lymphoma. Dr. Srdan Verstovsek from the M. D. Anderson Cancer Center, Houston, TX today presented data from an ongoing phase 1 study in an oral presentation session (Abstract #553) at the American Society of Hematology 49th Annual Meeting and Exposition, which is taking place in Atlanta, December 8th-11th.
"We are very encouraged by the results from this ongoing trial that show rapid decrease in spleen size and relief of disease-related symptoms at low doses of XL019. XL019 is a highly selective inhibitor of JAK2 that may have the potential to provide important benefit for patients with myeloproliferative disorders and other diseases driven by JAK2," said Michael Morrissey, Ph.D., president of research and development at Exelixis. "We believe that JAK2 is a critical target in myeloproliferative disorders, and effective inhibition of JAK2 may directly translate into clinical benefit. The strong linkage of JAK2 to MPDs provides a potentially quick route to market, with potential for additional opportunities in larger commercial indications. We are planning to initiate pivotal trials of XL019 in myelofibrosis patients in 2008."
Trial Design
The phase 1 dose escalation study of XL019 is ongoing in subjects with primary myelofibrosis (MF) and post-polycythemia vera/essential thrombocythemia MF. To date nine patients have been enrolled. The primary objective of this study is to determine the safety and tolerability of XL019 when administered orally once daily for 21 days in 28-day cycles. Secondary objectives include evaluation of the pharmacokinetics and pharmacodynamics of XL019, and to evaluate response using the International Working Group for MF consensus response criteria.
Results To-Date
Data (unaudited) from cohort 1 (100mg), cohort 2 (200mg) and cohort 3 (300mg) were presented today and the key findings by investigators include:
-- Preliminary clinical activity observed in most subjects, including: - Reduction in spleen size of 33 to 100% in five of six patients evaluated
- Reduction in erythropoietin-independent colony formation of up to 39% and up to 100% in two patients evaluated
-- Relief of constitutional symptoms, including pruritus, fatigue, back pain and abdominal fullness
-- Reduction in the number of cells with the JAK2 V617F mutation (allele burden)
-- Correlation between XL019 exposure and decreases in phosphorylation of STAT, a marker for JAK activity.
-- XL019 was generally well tolerated.
- Adverse events included Grade 1 nausea, headaches, equilibrium imbalance, dizziness, chest discomfort, visual disturbances, fatigue and hypertension.
- Grade 2 AEs of lightheadedness and decreased sensation in soles and one serious adverse event of confusion in a patient with baseline history of dementia were also observed.
-- No evidence of myelosuppression
The maximum tolerated dose has not been reached. The phase 1 dose escalating clinical trial continues
I'm alerting the proper....people.
I think we should be treated like Sunesis. Sunesis was allowed to present a great deal of efficacy data at a conference before their enrollment was half completed. This was done in coordination with MD Anderson. NWBO already has full enrollment in their phase I open label trial, so it will be that much easier for MDA to support NWBO presenting their ongoing findings with MDA from here on out.
Depinho's MDA did not allow NWBO to do likewise (like Sunesis). Instead MDA's Newman and Buzdar chastised/suppressed NWBO for sharing this data, hurt NWBO's share price and their potential enrollment accrual; all while helping a direct competitor, AVEO ONCOLOGY (Depinho's Company he created), share its findings on treating all solid tumor cancers in the same month it completed dosing.
This is awesome! Cancer doesn't stand a chance.
I doubt that. Still, I hope you can use it:)
Agreed.
LongUSA, allow me to share a bit more.
1. The President of MDAnderson is Dr. Ronald Depinho. See CNBC article and SEC investigation below.
2. Mr. Depihno extoled Aveo Oncology on CNBC while President of MD Anderson. See same below.
3. Aveo Oncology is not just any cancer company, it had a phase I study, but it was not just any phase I study. "A Phase 1 Dose Escalation Study of AV-203, an ERBB3 Inhibitory Antibody, in Subjects With Advanced Solid Tumors."
4. And this phase I trial on solid tumor cancers released results in the same month the last dose was given. Preliminary results were not supposed to be completed until October 2014 (according to clinicaltrials.gov).
5. But that was not just any month, it was May 2014.
6. There was a conference that month, but it was not just any conference, it was ASCO 2014.
7. It was not presented by just any investigator, it was presented by MD Anderson -- 5 months before preliminary results were supposed to be available.
8. Again, the creator of AVEO Oncology is Ronald Delpinho.
9. Ronald Delpinho became President of MD Anderson 8 months before his phase I multi solid tumor trial began at MD Anderson.
10. Once on November 7, 2013 and again on February 24, 2013, MD Anderson employees expressed their desire to share "initial data" on NWBO at a formal presentation.
11. Depinho was the man at the helm of MD Anderson as of September 2011 -- Current when both events did not transpire.
12. Please note that Depinho was also the man at the helm of MD Anderson when MD Anderson presented preliminary phase one data in a shared format with drug company Sunesis at ASCO 2014 -- please note that the results shared were extremely preliminary and more than half the patients were not even enrolled yet.
13. Please note that Sunesis was not chastised by MD Anderson for sharing real efficacy data this early in a trial, instead they were helped and praised by MD Anderson.
14. Please note that NWBO was trying to share preliminary results on a phase I trial treating Solid Tumor Cancers, which is the same exact condition AVEO Oncology was trying to treat in the very same phase trial. Sunesis was not trying to treat solid tumor cancers.
M.D. Anderson president goes on CNBC, extols his own company
Posted on June 1, 2012 | By Eric Berger
PRINT
During the last couple of weeks Todd Ackerman and I have been reporting on a controversial $20 million grant received by the University of Texas M.D. Anderson Cancer Center and Rice University.
The story broke on May 11 when Nobel laureate Al Gilman resigned as chief scientific officer of the Cancer Prevention and Research Institute, which has 10 years to appropriate $3 billion in taxpayer funds on cancer research.
DePinho
Gilman’s primary concern is that M.D. Anderson’s part of the proposal, which was to be funded up to $18 million, was approved by CPRIT “without scientific review, without a score, and in record time.” In other words, the grant review process was done outside his purview and, in his view, a questionable manner.
M.D. Anderson’s part of the grant has Dr. Lynda Chin as its principal
Path: investigator. Chin, a well-regarded scientist, is also the wife of Dr. Ronald DePinho, who M.D. Anderson hired last year to be its new president. Chin and DePinho are also co-founders of a modestly successful biotech company, AVEO Oncology.
The grant has proven problematic. M.D. Anderson has offered to resubmit it to CPRIT after questions were raised about it and the approval process, and CPRIT has agreed to re-review it. The UT System is also now probing the process. Chin’s involvement in the grant has heightened concerns among some M.D. Anderson faculty about how DePinho and Chin handle conflicts of interest. Many have contacted Todd and myself to express such concerns.
Ok, so that’s a long way of saying there is, at a minimum, a perception among some faculty at M.D. Anderson that DePinho has conflicts of interest.
This isn’t going to help that perception.
It’s a video — shot on May 18, after the CPRIT story had broken — of DePinho appearing on CNBC with Maria Bartiromo in advance of the biggest cancer meeting of the year, the ASCO Annual Meeting, which begins today. He does so as a cancer expert, and is clearly identified as the president of M.D. Anderson.
The interview starts off with DePinho explaining why he believes recent developments, including genomics, nanotechnology, gene manipulation and other research trends, are bringing cancer cures close to the clinic. It’s a historic moment, he says.
The interesting part comes in the middle. Here’s a transcript of three questions (Bartiromo is in bold):
Are there companies out there that you think are most promising?
In the biotech sector you have to be really careful because you have to understand which companies are driven by good management and driven by the kinds of scientific advancement that I’ve mentioned, and there are a few of them out there. Historically of course Genentech was one of the prime examples of this. More recently …
They were the first one to come out with a targeted treatment.
Right so you can think about Herceptin and so on, those are very important advances, and in fact some of the most effective drugs have come out of the idea of using science to shepherd cancer drug development. A company that I was involved in founding, Aveo Pharmaceuticals,
Something Strange happened the last time I copied this poster presentation in the related post. Here is the main portion again. I highlighted the repaired part at the end. I also underlined the emphasized points once again.
Dendritic cells (DC) are acknowledged to be quintessential in the armamentarium to mount anti-tumor immune responses and have been utilized in varying capacities for cancer immunotherapy. Recent advancements & lessons leant from prior DC therapies have revealed that major barriers hinder the efficacy of cancer vaccination with DC, principal of which is the hostile environment of the local tumor milieu that inhibits activation and subse- quent maturation of DC. This critical step is required to process and present antigens (tumor cell) to the down- stream cascade of immune mediators. The therapeutic goals of cancer vaccination are the induction of tumor regression secondary to the production of tumor specific immune factors and local inflammatory cytokines with enhancement of long term anti-tumor surveillance to prevent recurrences. DCVax® - Direct (Northwest Biotherapeutics, Inc. Bethesda, MD) are autologous den- dritic cells activated Ex vivo with BCG and IFNg for intratumoral injection and attempts to circumvent this barrier thereby maximize the induction of anti-tumor responses. Autologous DC will be harvested from peri- pheral blood monocytes via leukapheresis. Following Ex vivo DC maturation, inoculation of the tumors will be performed 2 weeks later utilizing image guidance to ensure activated DC deposition at the peripheral aspect of the tumor thereby enhancing DC exposure to antigens from dead or dying tumor cells. Vaccination will be per- formed at least every week for 3 weeks, and subsequently at longer intervals dependent on harvested DC avail- ability. Phase I/II study with DCVax®- Direct will enable evaluation of the safety, MTD, and responses in patients with solid tumors. The secondary objective addresses the feasibility, anti-tumor immune responses, PFS and OS. At the time of this poster submission, the ‘First-in-man’ patient has been consented for the study. We propose to present our initial findings at the SITC 2013 conference as more data will be available.
Authors’ details
1Interventional Radiology, MD Anderson Cancer Center, Houston, TX, USA. 2Investigational Cancer Therapuetics, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. 3Department of Stem Cell Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. 4Northwest Biotherapeutics, Inc., Bethesda, MD, USA.
Published: 7 November 2013
To me, the primary question has always been who delayed/blocked/interfered with MDA's twice announced desire to release preliminary data on Direct? AF apparently was at least serendipitously aligned with the idea, but who else? Big Pharma? Buzdar?
The Sunesis example puts Newman's defense to bed.
Subbiah -- Second time in 6 months MDA wanting to share preliminary data on DCVax-Direct.
The trials of DCVax-Direct involve 60 U.S. patients. The Phase 1 stage will focus primarily on safety, although hints of efficacy could emerge. The primary goal of the Phase II part of the study is to shrink or eliminate tumors.
Dr. Vivek Subbiah, an oncologist at M.D. Anderson Cancer Center in Houston who is leading the DCVax-Direct trials, said he may present initial data at the annual meeting of the American Society of Clinical Oncology that begins May 30.
Subbiah and his colleagues test scores of experimental cancer drugs, many having new mechanisms of action.
"This is not a 'me-too' trial," Subbiah said. "It is one of the interesting technologies. Twenty years ago it was chemo, 10 years ago it was targeted therapies, and for this decade it will be drugs that boost the immune system."
MDA sharing results before enrollment complete in 2014.
Hi again Sentiment. I really think Newman is disingenuous. Here is one of many examples on the internet where MDA joined a pharmaceutical company to share results before enrollment even stopped. (Ridiculous! MDA wanted to share NWBO phase I initial preliminary findings back in 2013, then crucified NWBO for sharing initial data while at the very same time presenting preliminary raw data with another pharmaceutical company conducting a half enrolled phase I trial).
Anyway, moving forward, MDA ought to treat NWBO like they do Sunesis.
(BTW: Of course no one should write MDA Anderson with racial slurs.)
http://ir.sunesis.com/phoenix.zhtml?c=194116&p=irol-newsArticle&ID=1916659&highlight=
Sunesis Announces Presentation of Positive Results From Ongoing MD Anderson-Sponsored Trial of Vosaroxin in AML and High-Risk MDS
Data Presented at AACR 2014 Annual Meeting
Company to Host Conference Call Today at 8:00 AM Pacific Time
SOUTH SAN FRANCISCO, Calif., April 8, 2014 (GLOBE NEWSWIRE) -- Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) today announced the presentation of results from an ongoing Phase 1b/2 University of Texas MD Anderson Cancer Center-sponsored trial of vosaroxin in combination with decitabine in older patients with previously untreated acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). The results will be presented today at the Phase II/III Clinical Trials Poster Session of the American Association for Cancer Research Annual Meeting 2014 (AACR) in San Diego, California. The poster (Poster #7, Hall A-E, Poster Section 38) is titled "Phase I/II study of vosaroxin and decitabine in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS)."
The Phase 1b/2 trial is expected to enroll up to a combined total of approximately 70 patients. As previously announced, the Phase 2 cohort of the Phase 1b/2 was initiated in October 2013, following successful completion of a Phase 1b open-label, single-arm dose optimization phase. Patients in the ongoing trial are being followed for rate of response, leukemia-free survival, overall survival and safety. To date, the combination of vosaroxin and decitabine has been found to be effective and well tolerated in older patients with AML and high-risk MDS. Twenty four patients are evaluable for response; 9 (38%) achieved complete response (CR), 5 (21%) achieved CR with incomplete platelet recovery (CRp), and 2 (8%) achieved CR with incomplete peripheral blood count recovery (CRi), for an overall response rate of 67%. The main grade = 3 toxicity was mucositis in 6 (6/29, 21%) patients. No patients died during the initial 30-day induction period. Enrollment in the trial is ongoing.
"The treatment of older patients with AML or high-risk MDS presents particular challenges, including many patients not tolerating or responding to existing therapies," said Farhad Ravandi, M.D., Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center, and a study investigator. "Emerging outcomes from this trial suggest that vosaroxin and decitabine hold meaningful promise as a potential new combination treatment option for this population. The high number of complete remissions with good tolerability are highly encouraging and make this trial a designated priority for our center."
"Vosaroxin's activity against genetically heterogeneous diseases like AML and high-risk MDS is driven by its unique characteristics as a first-in-class, anti-cancer quinolone derivative – properties that appear to combine well with the anti-leukemic activity of decitabine, a hypomethylating agent, to provide a much higher rate of remission than would be expected from decitabine alone," said Adam R. Craig, M.D., Ph.D., Executive Vice President, Development and Chief Medical Officer of Sunesis. "These encouraging results support our goal of elucidating vosaroxin's full clinical benefit in different patient segments as well as in new treatment combinations. We look forward to additional progress in this study and to working closely with MD Anderson and our growing list of experienced investigators to explore vosaroxin's value within AML and MDS."
The MD Anderson Cancer Center-sponsored trial is being conducted under the direction of Naval Daver, M.D., Assistant Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, and Dr. Ravandi. Dr. Ravandi is also a principal investigator of the Phase 3 VALOR trial, the company's randomized, double-blind, placebo-controlled, pivotal trial of vosaroxin plus cytarabine in patients with first relapsed or refractory AML.
Results in Detail
For the trial, patients were treated with vosaroxin (90 mg/m2) intravenously on days one and four in combination with decitabine (20 mg/m2) on days one to five. Vosaroxin dose was reduced to 70 mg/m2 in consolidation cycles, which were repeated in approximately four to five week intervals for a total of up to seven cycles. Dose adjustments and dose delays of one or both agents were allowed based on toxicity. Patients were eligible if they had AML or high-risk MDS (defined as having = 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG = 2) and organ function. Patients younger than 60 who were unsuited for standard chemotherapy were also eligible. The primary endpoint of the study is to determine the CR rate. Secondary endpoints include CR duration, disease-free survival, overall survival, safety and early mortality.
To date, 29 patients (25 AML, 4 high-risk MDS) with a median age of 73 years (range, 41-78) have been enrolled; 97% were older than 60 years and 59% were older than 70 years. Of these, 24 patients were evaluable for response; 9 (38%) achieved CR, 5 (21%) achieved CRp, and 2 (8%) achieved CRi, for an overall response rate of 67%. One patient without a response after cycle one is currently undergoing re-induction. Five patients are too early for response assessment. Patients have received a median of 2 (1-6) treatment cycles with median number of cycles to response being 1 (1-4).
The regimen was found to be well tolerated. The main grade = 3 toxicity was mucositis in 6 (6/29, 21%) patients. No patients died during the initial 30-day induction period.
OK, it looks like you've changed tracks. I'll stop posting refutations. Moving forward. Yes. Look again at my last post on the 2013 Subbiah/MDA's written desire to present initial findings with more data as far back as 2013. However, here are Buzdar's conflicts since entering MDA. Newman is very misinformed. In a little while, I'll see if I can suggest something that is more in line with their desire to present early data.
Thirdly he has massive conflicts of interests. This from a disclosure at the bottom of an article in Clinical Oncology dtd 2009 Vol 6 no 6. "Aman Buzdar is on the Speakers bureau and receives grant/research support from Astrazeneca and Genentech. He also receives grant/research support from Taiho, Lilly, Roche and Pfizer, and is on the Speakers Bureau for Amgen.
Sentiment, pay very close attention to this release by Subbiah. Please note the selection I bolded below. It proves MDA wanted to share Direct data results even earlier than NWBO. How can that....umm....representative cast blame at NWBO for sharing data 7 months later? I'll get another quote from 2013 where Subbiah declares his desire to share the data.
http://www.immunotherapyofcancer.org/content/pdf/2051-1426-1-S1-P238.pdf
DCVax®- DIRECT: autologous activated dendritic cells for image guided intra-tumoral vaccination in patients with solid tumors - a phase I/II clinical trial in progress
Vivek Subbiah2, Ravi Murthy1*, Chitra Hosing3, Indresh Kaur3, Gerald Falchook1, Marnix Bosch4
From Society for Immunotherapy of Cancer 28th Annual Meeting National Harbor, MD, USA. 8-10 November 2013
????????????????????????????????????????????????POSTER PRESENTATION Open Access
???Dendritic cells (DC) are acknowledged to be quintessen- tial in the armamentarium to mount anti-tumor immune responses and have been utilized in varying capacities for cancer immunotherapy. Recent advancements & lessons leant from prior DC therapies have revealed that major barriers hinder the efficacy of cancer vaccination with DC, principal of which is the hostile environment of the local tumor milieu that inhibits activation and subse- quent maturation of DC. This critical step is required to process and present antigens (tumor cell) to the down- stream cascade of immune mediators. The therapeutic goals of cancer vaccination are the induction of tumor regression secondary to the production of tumor specific immune factors and local inflammatory cytokines with enhancement of long term anti-tumor surveillance to prevent recurrences. DCVax® - Direct (Northwest Biotherapeutics, Inc. Bethesda, MD) are autologous den- dritic cells activated Ex vivo with BCG and IFNg for intratumoral injection and attempts to circumvent this barrier thereby maximize the induction of anti-tumor responses. Autologous DC will be harvested from peri- pheral blood monocytes via leukapheresis. Following Ex vivo DC maturation, inoculation of the tumors will be performed 2 weeks later utilizing image guidance to ensure activated DC deposition at the peripheral aspect of the tumor thereby enhancing DC exposure to antigens from dead or dying tumor cells. Vaccination will be per- formed at least every week for 3 weeks, and subsequently at longer intervals dependent on harvested DC avail- ability. Phase I/II study with DCVax®- Direct will enable
1Interventional Radiology, MD Anderson Cancer Center, Houston, TX, USA Full list of author information is available at the end of the article evaluation of the safety, MTD, and responses in patients with solid tumors. The secondary objective addresses the feasibility, anti-tumor immune responses, PFS and OS. At the time of this poster submission, the ‘First-in-man’ patient has been consented for the study. We propose to present our initial findings at the SITC 2013 conference as more data will be available.
Authors’ details
1Interventional Radiology, MD Anderson Cancer Center, Houston, TX, USA. 2Investigational Cancer Therapuetics, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. 3Department of Stem Cell Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA. 4Northwest Biotherapeutics, Inc., Bethesda, MD, USA.
Published: 7 November 2013
Sentiment:
(By the way, I'll try to find further links where Subbiah wanted to share data on Direct last fall 2013. Also, I'll try to find the links of Budzar's conflicts. I'll also try to locate some other contrary info in response to what Newman made. Finally, did you catch the hypocrisy of Newman not wanting to raise hopes by sharing data, but then supporting a case study example from patients on National Television?)
Notice the trial was ongoing still in 1999 as it took 5 years of dosing. Notice Budzar stated they could not yet know the value of this chemotherapy. He could not draw definitive conclusions. Etc.
In other words, he is pumping the product before he can say what it really can do.
http://www.cancernetwork.com/articles/paclitaxel-seems-equivalent-fac-neoadjuvant-chemo
Paclitaxel Seems Equivalent to FAC as Neoadjuvant Chemo
March 01, 1999 | Breast Cancer
- See more at: www.cancernetwork.com/articles/paclitaxel-seems-equivalent-fac-neoadjuvant-chemo#sthash.mxIrPR79.qkWUmKW4.dpuf
SAN ANTONIO? -- Preliminary results from an ongoing clinical trial suggest that neoadjuvant chemotherapy of breast cancer with paclitaxel (Taxol) alone produces response rates comparable to those achieved with the three-drug FAC (fluorouracil, Adriamycin, cyclophosphamide) regimen.
Speaking at a satellite symposium held in conjunction with the 21st Annual San Antonio Breast Cancer Symposium, Aman Buzdar, MD, expressed optimism for neoadjuvant use of paclitaxel, but he cautioned that the 23-month follow-up is too brief to draw definitive conclusions. ?With longer follow-up, we will know the true value of paclitaxel in neoadjuvant breast cancer therapy,? said Dr. Buzdar, a breast medical oncologist at M.D. Anderson Cancer Center.
The current trial has its origin in an M.D. Anderson study of 25 patients with metastatic disease treated with paclitaxel. The treatment led to objective responses in two-thirds of patients, including complete responses in 12%. Only one patient failed to achieve at least a minor response, Dr. Buzdar said.
Results of this small-scale evaluation subsequently were confirmed in a similar study at Memorial Sloan-Kettering Cancer Center. Almost three-fourths of 26 patients had major responses, including complete responses in 12%.
174 Patients Randomized
?On the basis of these encouraging results, we decided to put paclitaxel to the test in a neoadjuvant fashion to see what the effect would be on cytoreduction and antitumor activity,? Dr. Buzdar said.
Between 1994 and the middle of 1998, investigators randomized 174 patients to paclitaxel monotherapy or to neoadjuvant treatment with conventional FAC.
Paclitaxel was administered at a dose of 250 mg/m²?the same dose used to treat metastatic breast cancer. Treatment was repeated every 3 weeks for four cycles, followed by surgery, an additional four cycles of FAC, and radiation therapy. Patients older than 50 years also will receive tamoxifen (Nolvadex) for 5 years.
Patients in the two treatment groups had identical 79.3% overall response rates. Paclitaxel led to complete re-sponses in 26.4% of patients vs 24.1% with FAC. FAC resulted in more patients with no evidence of residual disease (17.2% vs 5.7%), whereas more pacli-taxel-treated patients had DCIS only (8% vs 4.6%) or minimal residual disease (26.4% vs 11.5%) after neoadjuvant therapy. Dr. Buzdar also noted that paclitaxel treatment was associated with a higher rate of breast-conserving surgery, 46% vs 37% for patients receiving FAC.
At a median follow-up of 23 months, patients in the paclitaxel cohort had superior disease-free survival rates at 1 year (100% vs 94%) and 2 years (94% vs 89%). Dr. Buzdar emphasized that longer follow-up is needed to provide a true indication of the impact of the two neoadjuvant regimens on survival
- See more at: http://www.cancernetwork.com/articles/paclitaxel-seems-equivalent-fac-neoadjuvant-chemo#sthash.mxIrPR79.qkWUmKW4.dpuf
May I suggest one caveat:
Northwest Biotherapeutics must continue with a sense of urgency. While NWBO competition currently "Sputniks" into orbit, this is still a race to the moon.
Highwayman,
One correction: Linda recently stated no patient had a fever immediately after injection that lasted more than 48 hours.
Hi High,
Due to your time constraints, and the fact I spent this morning with my son crashing his hard earned RC (remote control) speedboat on an unauthorized pond, I thought I'd mostly just reprint a post I penned to Staccanni a while back.
The point here is that UCLA already conducted a phase II trial on DCVax-Direct. Linda Liau supervised the study, and many big names in the field signed on. It confirms DCVax-Direct's mode of action. The title clues us in that this trial involved more than one patient. In other words, cells are not dying because they are being poked with needles:)
The abstract is provided at the bottom of this message.
Hi Staccani,
NWBO is not simply giving "more of the same" by increasing dendritic cells. I'm going to give the short answer, but I highly recommend you read the latest UCLA report on DCVax-Direct supervised by Linda Liau.
sttp.healthsciences.ucla.edu/abstract/sttp-abstract-current?abstract_id=2455
In a nutshell, partial maturation of the dendritic cell outside the body with BCG [and interferon] creates fired up trigger happy dendritic cells. Once exposed to tumor Lysate outside the body, as in DCVax-L, or injected into the tumor, as in DCVax Direct, the dendritic cell is in super uptake mode, but because it was only partially matured outside the body with BCG [and interferon], the full in vivo maturation process not only allows uptake of tumor antigens (in addition to the BCG biomarkers it previously encompassed ex vivo through dendritic uptake), it is still fully primed to express it to the T-Cells.
Now here is where the rubber hits the road for the second and most important time, the t-cells get massively fired up to look for a very familiar nemesis known as BCG antigens, but along with it, they are looking for all peculiar antigens from the tumor. Forgive my homely analogy, but this is like showing pictures of tweety bird and Road Runner to Wile E Cayote, and handing him some A-1 steak sauce.
The T-Cells proliferate and are supercharged/antagonized by the normal hunt (the patient has a 2-3 day fever), but they now cast a broader net for any anomalies within the cancer cell biomarkers as well. The cycle repeats and hones itself over time.
I'm leaving out other improvements for simplicity.
Short Term Training Program Student Abstracts
T Lymphocyte Activation and Proliferation with BCG Stimulation of Patients Receiving Dendritic Cell Immunotherapy: A Phase II DCVax-Direct Trial
Jeffrey Lin, Joseph Antonios, Sylvia Odesa, Horacio Soto, Robert M Prins, Linda M Liau
695 Charles E. Young Drive South Gonda 1554 Los Angeles, CA 90095
DCVax-Direct is an autologous cellular immunotherapy involving intratumoral injection to solid tumors as an adjuvant traditional therapies. The injection consists of autlogous DCs activated with bacillus Calmette Guerin (BCG) and interferon (IFN)-gamma. Culture with BCG and IFN-gamma activates DCs, upregulating cell surface proteins involved in antigen presentation and T cell stimulation. Patient peripheral blood monocytes (PBMC) and serum were collected at day 0, week 8, and week 16 before each vaccination. We hypothesize that the vaccine creates an inflammatory response, and exposure of PBMCs to BCG will cause T cell activation and proliferation. Luminex technology was used to evaluate cytokine levels in patient serum. PBMCs were labeled with Cell Proliferation Dye (CPD) and cultured with inactivated BCG, and T cell proliferation was assessed using fluorescent target array technology. Levels of proinflammatory cytokines were higher and anti-inflammatory cytokines were lower in serum collected at later time points. CD4+ and CD8+ T cells exposed to BCG showed increased proliferation in patient PBMCs collected at later time points. The data suggest that treatment with DCVax Direct promotes an inflammatory response that can decrease tumor burden through upregulation of proinflammatory cytokines. Activation and proliferation of lymphocytes exposed to BCG suggest that DCs are presenting BCG and likely tumor antigens to patient T cells allowing for a targeted immune response.
Submitted by jelin@mednet.ucla.edu, under the supervision of Linda, Liau M.D. Ph.D., submited on July 24, 2014
IMHO, NWBO's pancreatic ( x 1) and sarcoma case (x 1) examples (more than likely) resulted in complete systemic responses (this may not involve 'exoskeleton' tumor eradication). This is my personal opinion from integrating various pieces of information. I'm inclined to state that the metastatic Colon case (x 1) example also achieved a complete systemic response, but there is not enough information available yet. One layman's perspective.