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Clinical / Regulatory / Litigation Calendar
[Please keep these entries up to date! See
the updating procedure at the end of this post.]
NOTE: ANYONE MAY UPDATE THIS FILE
Edit: MSHL
ABT – Certriad PFDUFA date early Apr 2010 (NDA submitted 6/5/09).
ACHN – ACH-1625 HCV protease inhibitor: top-line results of all phase-1b cohorts Jan 2010 (first cohort reported 12/15/09); present full dataset Apr 2010 at EASL; start phase-2 trial (with or w/o a partner) 1H10.
ACHN – ACH-1095 HCV NS4A inhibitor: submit pre-IND package to FDA 4Q09. (See http://investorshub.advfn.com/boards/read_msg.aspx?message_id=41217537 for status of GILD partnership.)
ACHN – Unnamed HCV compound with novel MoA: reveal initial details to investors 1H10.
Actelion – BUILD-3 phase-3 trial of Tracleer in IPF: PFS primary endpoint any day (guidance was Dec 2009).
AGN – Botox for migraine: sBLA submission done in late 3Q09 (not PR’d); no reply yet from FDA on possible priority review.
AGN – Botox for spasticity: reply to FDA’s CRL submitted in Oct 2009 (not PR’s); Class-2 response from FDA 1H10.
AMGN – Denosumab BLA: FDA issued CRL on 10/19/09. Prompt approval likely for treatment of osteoporosis; new trials required for prevention of osteoporosis. See http://investorshub.advfn.com/boards/read_msg.aspx?message_id=42814924 for additional details.
AMLN – Exenatide LAR: PDUFA date early Mar 2010 (NDA submitted 5/5/09 and accepted for review 7/7/09).
ANDS – ANA598 phase-2 trial: safety and RVR data from 400mg arm: 1H10; SVR data from all arms: 2H10. (Safety and RVR data from 200mg arm was reported on 12/17/09.)
Bayer – Xarelto: see JNJ.
Bayer – VEGF Trap-Eye: see REGN.
DNDN – Provenge BLA PDUFA date 5/1/10.
ELN – AAB-001 phase-3: final data mid-2011 (est.). (First patient dosed 12/21/07.)
ELN – ELND005 for AD phase-2: final data 1H10 (est.) (The two highest doses were dropped due to toxicity on 12/15/09.)
GILD – GS9190 HCV non-nucleoside polymerase inhibitor: start phase-1/2 combination studies with GS9256 protease inhibitor 1H10. (The refocusing of the GS9190 program and the existence of GS9256 were disclosed on GILD’s 3Q09 CC: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=42717806 .)
GILD – Elvitegravir phase-3 vs Isentress: complete enrollment 4Q09. GILD – TMC278 + Truvada combo pill: complete bioequivalence studies and submit NDA/MAA 2H10 simultaneously with, or soon after, JNJ’s NDA/MAA submissions for standalone TMC278.
GILD – ‘Quad’ and GS9350 phase-2 studies: report 48-week (final) data from ‘Quad’ vs Atripla study and GS9350 vs ritonavir study at unspecified medical conferences during 2010. (Bare-bones 24-week data from both studies were reported on 1/6/10.)
HGSI – Zalbin/Joulferon (Albuferon): PDUFA date Sep 2010 if standard review (BLA submitted 11/25/09; MAA submitted 12/15/09).
HGSI – Benlysta in SLE: submit BLA/MAA early 2010. (Data from 2nd phase-3 trial reported 11/2/09.)
IDIX – See http://investorshub.advfn.com/boards/read_msg.aspx?message_id=44790070 .
ITMN – ITMN-191: see Roche.
ITMN – pirfenidone: FDA PDUFA date 5/4/10; MAA submission 1Q10.
ITMN – ITMN-520 qD pirfenidone analog for IPF and other conditions: IND filing mid 2010..
JNJ – TMC278 for HIV: report phase-3 data early 2010; submit NDA/MAA mid 2010. (See GILD me TMC278 + Truvada combo pill.)
JNJ – TMC278 + Truvada combo pill: see GILD.
JNJ – Xarelto: reply to FDA’s CRL 4Q09.
JNJ – PurTox botulinum toxin: submit BLA calendar 4Q10 after completion of two ongoing phase-3 trials. (First phase-3 trial reported positive data 10/1/08.)
JNJ – Telaprevir: see VRTX.
MDVN – dimebon phase-3: final data Jan 2010.
MNTA – See http://investorshub.advfn.com/boards/read_msg.aspx?message_id=44689215 .
MRK – Isentress sNDA for qD dosing: submission 2011. (Phase-3 trial called QDMRK started 4Q08: Isentress BID + Truvada vs Isentress qD + Truvada in first-line setting.)
MSHL - Jan 2010 - Phase III OVATURE results due
NVS – FTY720 in RRMS: NDA and EU MAA to be submitted in late 2009. (Positive data from the FREEDOMS trial were reported on 9/30/09. The FREEDOMS trial plus the TRANFORMS trial and a portion of the FREEDOMS-II trial will comprise the NDA/MAA package.)
NVS – Albuferon: see HGSI.
ONTY – Phase-3 trial in Stage III NSCLC: first interim analysis (at 50% of deaths relative to trigger for final analysis): 2H10.
REGN - Rilonacept in flare prevention upon initiation of allopurinol - results expected in 2010
REGN - Rilonacept in flare treatment - results expected in 2010
REGN - Aflibercept in 3 different ph iii's (total enrollment expected is ~4000). VELOUR (2nd line colorectal + chemo cocktail), VITAL (2nd line NSCLC with docetaxel), VENICE (1st line HRPC with docetaxel + pred)
REGN - VEGF Trap-Eye: results from ph-3 trials in AMD 4Q10.
Roche – ITMN-191 (a/k/a/ RG7127): phase-2b trial of SoC ± ITMN-191: RVR data from some arms 1Q10; report phase-1b data with ritonavir boosting early 2010.
Roche – RG7128: phase-2b in geno-1 trial passed interim safety hurdle of first cohort 11/23/09, enrollment complete for second cohort late 1Q10. Start second (longer-duration) phase-2b in geno-1 1H10. Start separate phase-2b in geno-2/3 1H10.
Roche – INFORM-n series of all-oral HCV trials: start INFORM-2 1Q10; start INFORM-3 (with SVR primary endpoint) 1H10.
SGP – Boceprevir NDA: 2011-2012.
TSPT – Intermezzo: FDA meeting scheduled for 1/20/10.
VRTX – Telaprevir phase-3 ADVANCE and ILLUMINATE trials in 1st-line setting: SVR data from ADVANCE in 2Q10 and from ILLUMINATE in 3Q10.
VRTX – Telaprevir phase-3 REALIZE trial in 2nd-line setting: SVR data 3Q10.
VRTX – Telaprevir NDA in first- and second-line settings: 4Q10.
VRTX – Telaprevir ± VX-222: start phase-2 combo study 1Q10; report interim data (not SVR) mid 2010.
VRTX – VX-509 JAK3 inhibitor: start 12-week phase-2 trial in RA 1Q10, interim data 2H10.
VRUS – RG7128 and INFORM-n series of trials: see Roche.
VRUS – PSI-7851 pyrimidine-analog nuke: start phase 2a 1Q10; interim data 3Q10.
VRUS – PSI-938 purine-analog nuke: file IND and start phase-1 1Q10, interim data 3Q10.
VRUS – PSI-879 purine-analog nuke: file IND 4Q10.
ZGEN - Atacicept 48 week Ph ii in MS - clinicaltrials.org expects data 1H10
--
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Biggest winner (biotech version)?
As a matter of interest, what was the least amount spent by a biotech company to get its first cancer drug approved by the FDA?
Statistics
If an analysis is due after X events in a trial, does the ratio of events in each arm change as a function of the rate of recruitment and, if so, does this affect P value calculations?
I'm closely monitoring a trial in which an analysis is triggered after 95 PFS events. If the trial had kept to its original timescale and average PFS was 14 weeks and 20 weeks in the two arms, I had calculated that 62 of the first 95 events would have been from the control arm, compared to 33 from the treatment arm.
But if recruitments slows, does this not allow more treatment-arm patients to become an 'event' by the time 62 control-arm patients become an event? If the ratio then becomes say 57 to 38, am I right to think the P value is higher even though average PFS remains the same at 14/20 weeks?
Any help would be appreciated. Be gentle!
Ouch! Aren’t they one of David Miller’s picks?
Has BSR David ever done anything right?
NVGN/MSHL
It will soon be possible to work out whether phenoxodiol is delivering the goods in its pivotal Phase III trial.
Novogen is an investment idea for masochists. The company has been dogged by poor communication, but it is clear that management has recently been given a kick up the arse. The following press release caught my eye:
http://finance.alphatrade.com/story/2008-04-15/MRW/200804151725MRKTWIREUSPR____0385825.html
Press Release Source: Novogen, Limited
Novogen's NV-128 Is a Unique Inhibitor of mTOR Dephosphorylation Leading to Caspase Independent Death in Chemoresistant Cancer Cells
Tuesday April 15, 5:25 pm ET
SAN DIEGO, CA--(MARKET WIRE)--Apr 15, 2008 -- Pre-clinical studies reviewed during an oral presentation here today at the annual meeting of the American Association for Cancer Research demonstrate that the Novogen drug candidate NV-128 engages a novel mode of cell death targeting the akt-mTOR pathway in multi-drug resistant ovarian cancer cells. The data were presented by Dr. Ayesha Alvero, MD, and Associate Professor Gil Mor, MD, Department of Obstetrics and Gynecology, Yale University School of Medicine.
NV-128 is unique in that it does not induce caspase-mediated apoptosis which can be non-functional in chemoresistant cancer cells due to accumulated mutations in tumor suppressor/promoter genes and over-expression of anti-apoptotic proteins. Rather, NV-128 uncouples the akt-mTORP70S6K signal transduction cascade which has a key role in driving protein translation and uncontrolled cancer cell proliferation. Further, NV-128 induces mitochondrial depolarization via a novel pathway involving the autophagy protein Beclin-1 and Bcl-2, thereby resulting in endonuclease G translocation to the nucleus and cell death.
"We consider that the capacity of NV-128 to trigger mTOR dephosphorylation leading to caspase-independent cell death, in otherwise chemoresistant ovarian cancer cells, opens new possibilities for the use of NV-128 as a potential addition to conventional chemotherapy targeting ovarian cancer cells," said Dr. Mor.
In the context of developing therapies indicated against late stage ovarian cancer, Dr. Mor said, "The demonstration of a functional caspase-independent cell death pathway in apoptotic-resistant ovarian cancer cells is a key step to the development of alternative targeted therapy for refractory patients."
Structurally, NV-128 is an analogue of triphendiol (NV-196) and phenoxodiol, both of which are investigational drugs that have been licensed by Novogen to Marshall Edwards, Inc. Phenoxodiol is currently in a multinational, multi-center Phase III clinical trial for patients with late stage ovarian cancer. Triphendiol has recently been granted orphan drug status by the FDA for pancreatic and bile duct cancers, and late stage melanoma.
"The ability of our suite of analogues to invoke discreet modes of cell death suggests that they have potential to be used synergistically, thereby inhibiting alternative modes of cancer cell survival which may be invoked post therapy. This could lower the incidence of residual disease clinically," said Professor Alan Husband, Group Director of Research, Novogen, Ltd.
Unlike analogues of rapamycin, like temsirolimus and everolimus, which target only mTORC1, NV-128's capacity to dephosphorylate mTOR enables it to inhibit both mTORC1 and mTORC2 activity. This blocks growth factor driven activation of AKT and the potential for development of chemoresistance. Further, unlike NV-128, rapalogs invoke caspase-mediated apoptosis making them less effective in those cancer cells that have developed rapalog-resistance and have a dysfunctional apoptotic cascade.
Also presented in Dr. Alvero's paper was a proof of concept study in an animal model of drug resistant ovarian cancer, where it has been demonstrated that NV-128 not only significantly retards tumor proliferation, but is more efficacious than other standard of care drugs. It was also reported that phosphorylated p70s6K was decreased, and endonucelase G was increased in tumors taken from mice dosed with NV-128 thereby confirming that the NV-128 mechanism of action in vivo is the same as that observed in vitro, and that both proteins can be employed as markers of NV-128 efficacy.
"We are just now beginning to realize the depth of oncology drug candidates that our technology will uncover," said Professor Husband. "We anticipate that refinement of our proprietary molecular scaffold driven by computer-based molecular modeling, will continue to yield novel derivatives not only indicated as oncology leads, but also for cardiovascular and inflammatory diseases."
About NV-128:
In contrast to phenoxodiol and triphendiol, NV-128 has been shown to induce caspase-independent DNA degradation and cancer cell death. It appears that in conjunction with autophagy induction, NV-128 induces caspase independent cell death via the AKT-mTOR pathway resulting in beclin sequestration of Bcl-2, Bax up-regulation and mitochondrial depolarization. As a consequence, endonuclease G translocates to the nucleus where it initiates DNA degradation and cell death. This offers an opportunity for use as a monotherapy in chemoresistant cancers and enhanced efficacy against cancer targets less susceptible to phenoxodiol. The option for co-administration of combinations of these drugs is also under investigation to extend the potential therapeutic range of this unique class of oncology compounds.
Untested drugs for terminally ill
"Cancer drugs which have not been tested on humans are to be given to terminally ill patients by the NHS.
St Bartholomew's Hospital in London will be the first to administer the drugs, followed by 18 other centres....
http://news.bbc.co.uk/2/hi/health/7309016.stm
Re TELK lawsuit
The detailed complaint can be found at:
http://www.lerachlaw.com/cases/telik/complaint.pdf
The 43 pages of detail in the complaint indicates that the law firm had drafted the document and was just waiting for an excuse to launch.
The defendants are:
Telik
Wick
Butitta
Underwriters UBS, Lehman, Bear Stearns, Needham, Lazard, Fortis, JP Morgan
This could get ugly.
TELK
Lerach Coughlin Stoia Geller Rudman & Robbins LLP Files Class Action Suit Against Telik, Inc.
http://tinyurl.com/2orbuk
"The complaint alleges that during the Class Period, defendants made false and misleading statements about the Company's business and prospects, including that they were on track to obtain FDA approval for the use of TELCYTA in the treatment of platinum-resistant or refractory ovarian cancer and small-cell lung cancer, and that TELCYTA was safe and effective for public use and the Company had conducted sufficient clinical studies to prove it. The complaint further alleges that, unbeknownst to the investing public, subjects in the TELCYTA trials were dying at alarming rates and doctors were pulling other subjects out early, compromising the data being gathered. As a result of defendants' false and misleading Class Period statements and omissions, Telik's stock traded at inflated levels during the Class Period, trading as high as $29.04 per share by April 2004, whereby the Company sold over $322 million worth of Telik stock in the Offerings. The Registration Statements and Prospectuses issued in connection with the Offerings were also false and misleading as they misstated the known safety and integrity flaws in the TELCYTA clinical trials.
TELK - Assist-3
What should we make of this part of the Assist-3 presentation at ASCO:
"Patients were treated until disease progression, as determined by radiologic evaluations at each site, or unacceptable toxicity. A central, blinded independent radiology review also was conducted.
Assessment of the primary endpoint, objective response rate by RECIST, may have been compromised because approximately 25% of patients were prematurely discontinued from the study for disease progression, as assessed by the independent radiology review. Median progression-free survival, the secondary endpoint of the trial, assessed by independent radiology review, was 3.5 months on both arms".
If 25% were prematurely discontinued for disease progression, how would this compromise the objective response rate? Is the company trying to say that some patients experienced initial tumor shrinkage that would qualify as a Partial Response, but 25% were prematurely withdrawn from the study because of tumor growth before the shrinkage could be confirmed four weeks later in accordance with RECIST?
I could see the secondary endpoint of PFS being messed up, but is it plausible that the primary endpoint of ORR was compromised?
What is the patent position?
http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2006105481&F=0
LOW-CONCENTRATION CAPSAICIN PATCH AND METHODS FOR TREATING NEUROPATHIC PAIN
states that "Accordingly, it would be desirable to have low-concentration capsaicin patches for the treatment of neuropathic pain, as they may be better tolerated than high-concentration patches and high-concentration capsaicin creams".
Wouldn't this be an obvious development?
It’s shame that you can’t see what kind of poster you’ve become because almost everyone else can
Pot...kettle...
YM BioSciences announces termination of the tesmilifene Phase III pivotal trial in advanced breast cancer
http://www.cnxmarketlink.com/en/releases/archive/January2007/30/c2871.html
The Data Safety Monitoring Board advises the trial is very unlikely to demonstrate a survival benefit for the tesmilifene arm
Conference call scheduled for Wednesday, January 31, 8:30 a.m. ET
NFLD
This was posted on IV in December by "Mousecat", who is responding to criticism of EMT's who were unable to maintain protocol for the trials, with the result that apparently the data got skewed....
Biotechnology at work in one real world...
------------------------------------------------
Now. In defense of my fellow paramedics.
We're running a trial. One thing that adds to the mix is record-keeping. In real life we do what we do and then we go back later, write it up and figure out some times as best we can. I'm sorry but the truth is that some of it is stuff we just make up.
WHAT?
Yes. Stuff we just make up because the forms require it and there ain't no other way. I hate it but it's so.
Look, here's the deal.
We go to a guy who has been solidly bitten four times by a seven foot Eastern Diamondback Rattlesnake. It takes us 30 minutes to get to him. By the time we get there the guy is FTD (Fixin' To Die). He's in shock. His pressure is bottomed out. He's the color of a fish's belly. He and his clothes are soaked in sweat. He can't properly communicate. He doesn't know where he is - he doesn't even know who he is. He has NO peripheral pulses. No CRT (Capillary Refill Time). His skin is cold and wet.
And it will take another 30 minutes to get to the closest hospital.
The EMT gets in the front, turns on the lights and siren and takes off down a dirt road as hard as he can go. The paramedic is being thrown forward and back, left and right. He's being bruised and cut. He's being slammed around.
There are two people in the back of that truck: the patient and the paramedic. TWO. And only one of them is working.
High flow oxygen (find the mask, hook it to the flow meter, turn on the tank, turn on the flow meter, fill the bag, put the mask onto the patient). Good. Got it.
Start two 18 guage IV's, one in either arm, go for the antecubitals (pull out the fluids, check for leakage, check the dates, hook them up to 10 drop sets. Open a start pack, put on a tourniquet, sterilize with alcohol, find an 18 guage catheter. use your teeth to open it - you're still getting thrown all over the back of the truck - find the vein, stick the needle in, dig around until you get flashback, feed it forward, feed the catheter in, find the IV line, pull the cap off, pull the needle out, put the line into the catheter, fasten it in place with a tegaderm and tape, adjust the flow. Do the same thing again in the other arm. Stilll getting slammed by the washboard road. Run in fluids. Calculate a Dopamine drip. Get your key out. Still getting slammed. Unlock the cabinet, get the drug box out. Unlock the drug box, get the Dopamine. Double-check the concentration - oops - the pharmacy used 800 instead of 1600. Recalculate. Hook it up. Set the drip rate. Wow - that was a bad one - is my arm broke - no, maybe not - climb out of the step and crawl back to the stretcher. Adjust the drip rate. Call it in to the ER. Whew, we're on the paved road. SLAM. Oh God, that car stopped right in front of him, he had to smash the brakes. Back to work - and on and on.
You get to the ER. Unhook stuff. Head inside. God my knee hurts. Stop at the nurses station. "Room T-2. No.. T-3. No, wait - mumble, mumble, mumble - no she's already gone home. Well, who's covering 4? Mumble, mumble. Go to 3A."
You go into the room. The bed's not made. You pick the patient up, sheet and all, and put him on the bed - never mind the blood that's already there from the last patient. A nurse comes in, goes to the computer. "Name?" "We don't know." "Date of birth?" "We don't know." She turns to the patient. "Sir? Sir? Can you tell me your name sir?" She goes to the door. "Shirley, can you help me?"
By the time this thing is going good there are seven Registered-Nurses, two physicians,one lab tech, one X-ray tech, and one cardiac tech in that room. Then one of the docs says "Call respiratory, get an anesthesiologist down here to intubate." And all the while there's a Registered Nurse sitting on a stool writing this stuff down and earning double what a paramedic gets.
And the patient hasn't had one single piece of intervention since he came through the door eight minutes ago..
And you want me to collect "data points." And if I mess one up I'm in the pay of a hedge fund?
Think about it for just a minute. Okay? For just one lousy minute.
You want an ambulance trial? Okay. But be prepared to get an ambulance trial. Friend, it ain't rocket science - they ain't but two of us in the back of that truck and one of us ain't working.
From JPM webcast:
Wick said that they were moving to more favorable patients, with less advanced disease, more sensitive disease, less tumor burden, less residual toxicity, using the drug in combination.
I was surprised when he said that scans in Assist-3 had been done every 8 weeks. Surely this can't be right?
TELK
> No matter how you slice it, it’s a screw-up of titanic proportions<
I shorted TELK at $18.20 in the middle of October.
The decision to delay Assist 1/2 results made this an obvious move, IMO. The Assist 3 debacle was simply icing on the shortcake.
TELK Discordance
The RECIST definition of Progressive Disease is an increase of 20% in the sum of Longest Diameters of target lesions taking as reference the smallest sum LD measurement recorded since treatment started, or the appearance of one or more new lesions.
The trial protocol for Assist-3 must have stipulated how Progressive Disease was defined - this was implied by this sequence in TELK's CC: Wick - "What we are discussing here is the radiologic decisions entirely". Brown - "Based on a radiologic criteria that was supposed to be applied".
But an error rate of 25% is surely inconsistent with a protocol that lays out a detailed RECIST definition of Progressive Disease. Let's suppose for a moment that the protocol simply stated that Progression was to be measured using RECIST criteria.
When Therasse et al created RECIST, they argued that a new definition was required because ... 3) (under existing criteria) the definitions of progressive disease are related to change in a single lesion by some and to a change in the overall tumor load (sum of the measurements of all lesions) by others ...
There appear to have been 223 US trial sites for 244 patients in Assist-3. In the 25% of cases in which Progression was prematurely defined, I suspect that a 20% increase had occurred in the LD of a single lesion, rather than the sum of Longest Diameters.
TELK will merge with CTIC
But a phone call to Dr. LaMattina from a Pfizer colleague early on Saturday delivered stunning news: Some 82 patients taking torcetrapib and Lipitor had died, compared with 51 taking Lipitor alone. Those findings had come from a monthly review released late Friday night by the independent safety board monitoring the trial.
So within one month the comparative number of deaths went from acceptable to disastrous. Hmmm.
We know that the DMC monitors SAE's in particular and can make inquiries of the statistical analysis personnel, data management personnel, the CRO, or the sponsor, through designated contacts - see "Overseeing Clinical Trials: The Role and Function of Data Monitoring Committees". http://www.saem.org/download/lewis3.pdf
Pfizer says that the relatively high number of torcetrapib deaths came as a complete shock, which suggests that they got no inkling the previous month - i.e. the DMC did not institute a special review because of concerns over the ratio of deaths in each arm.
Doesn't this suggest that the ratio 'exploded' in a short space of time?
>Honestly, would you enroll a loved one into this trial? You have a 50% chance of enrolling into an arm with absolutely no expectation of efficacy.
Get real! Patients have a 50% chance of receiving phenoxodiol + carboplatin, or a 50% chance of receiving the best standard of care for their advanced condition. Alternatively they can opt to not enroll for the trial at all, and have a 100% chance of death!
I wish it were otherwise, but these are the facts. If I had a loved one in this position, I would recommend she enroll for the trial and withdraw if CA-125 readings made it evident that she had been randomized to the control arm.
But once again you try to shoot the messenger. Why don't you set your prejudice aside and address the situation from the position of an investor?
MSHL Marshall Edwards
The first patient has been enrolled in OVATURE, a Phase III trial that seeks to establish whether Phenoxodiol plus Carboplatin is superior to Carboplatin alone when treating refractory/resistant ovarian cancer. The trial is covered by an SPA.
The start of OVATURE was delayed for almost a year. In the middle of SPA negotiations, the FDA changed the guidelines for Accelerated Approval by substituting PFS for ORR as their preferred surrogate endpoint; and insisted that a protocol that incorporated provision for AA should also require the sponsor to complete the full trial. But the longest delay can be attributed to the trial design itself.
MSHL wanted to create a trial in which there was absolutely no doubt that patients had an unmet need and that any response could be attributed to phenoxodiol. They wanted to retreat platinum-refractory patients with carboplatin to prove they were refractory, and only then would phenoxodiol/carboplatin be compared to salvage therapy. However, it became apparent that retreating patients in this fashion with the same regime they had just failed might lead to ethical and hypersensitivity concerns, so the trial design was modified.
OVATURE will involve 470 patients who have been treated with at least two lines of platinum therapy. Patients must have responded to platinum at some stage (no point in reversing resistance if carboplatin was never going to work!) but have failed their most recent platinum treatment and have a treatment-free-interval of less than six months. To overcome ethical concerns, patients will receive weekly carboplatin at AUC=2 rather than the typical every-three-weeks at AUC=5, with phenoxodiol added in the treatment arm. Eligibility for Accelerated Approval will be based on results of an interim analysis after 95 ‘events’, defined as disease progression or death or withdrawal from the trial.
This is a very stringent trial design. Patients must have recently failed platinum therapy and have to commence platinum therapy in OVATURE before multi-drug-resistance has had time to abate. We ‘know’ that the control arm will achieve stable disease at best, for a very limited time. What we want to know is whether the addition of phenoxodiol to carboplatin will lead to a significant improvement in PFS.
Accelerated Approval will be based on a straight comparison between the number of events in the control and treatment arms after a total or 95 events. Using Fisher’s exact test, one can calculate that the required P=0.005 will be met if the ratio is =>62 events in the control arm vs 33 in the treatment arm. In other words, to achieve Accelerated Approval there will need to be about twice the number of progressions in the control arm at interim analysis.
Phase II results show that PXD reverses resistance to platinum drugs. There must be a reasonable chance that phenoxodiol will boost the effect of carboplatin in the treatment arm. Whether this will meet the AA hurdle remains to be seen.
MSHL has a market cap of $191 million. It has the right to license all oncology drugs developed by Novogen (NVGN), an Australian company that specializes in isoflavone research. Novogen has created over 190 compounds that show activity against a range of degenerative diseases.
Re: Cancellation of Interim Analysis
Thank you Dew, pretty much as I thought. The question pertained to ASSIST-1, so perhaps this explains why TELK has decided to defer the release of results until those for three separate ASSIST trials are available.
If it was clear that Assist-1 was not going to hit its interim hurdle, it would make sense to save the alpha. This does not mean that Assist-1 will miss its final endpoint, of course, but if the interim analysis was based on reasonable expectations and it became clear in a blinded trial that results were not close (otherwise why cancel?), does this raise a red flag?
Interim analysis
If an SPA includes provision for accelerated approval based on an interim analysis, what are the implications if the analysis is not conducted?
Coenzyme Q10
A paper presented at the REDOX conference in Asilomar in 2004 noted that a pump involving coenzyme Q10 uses a Redox reaction to transfer waste hydrogen ions out of cells. When coenzyme Q10 is combined with hydrogen on the inside of the cell it is converted ito its reduced state and is known as quinol. Quinol releases the hydrogen when it reaches the exterior of the cell and then reverts to its oxidised state known as quinone.
The quinol/quinone pump in all living cells relies on the activity of a protein receptor known as NADH Oxidase or NOX. The NOX proteins that occur on normal cells are slightly different to those that appear on cancer cells and are known respectively as CNOX (constuitive, or normal NOX) and tNOX (tumor-specific NOX).
Inhibition of the coenzyme Q10 pump leads to an increase in Ceramide and a decrease in Sphingosine-1-Phosphate. The combined effect is to enhance pro-death signals (via Ceramide) and to remove pro-survival signals (via S-1-P).
Inhibition of tNOX specifically inhibits the quinol/quinone pump in cancer cells, which is a good thing, but less certain in my mind is the effect of reduced levels of coenzyme Q10 in normal cells. Would this lead to an increase of hydrogen within cells? If so, what are the implications?
Coenzyme Q10 - more than meets the eye.
This is such bullshit. Supplanting standard of care revolves around clinical benefit. Low p-values have nothing to do with clinical benefit.
With respect, I don't think the author contemplated the solitary use of P values to determine the result of a trial.
As the difference in p-values is simply a matter of numbers of patients in a trial and the application of the law of large numbers, does it not follow that a statistical plan that used a one-sided test with the full .05 would be preferable to a two-sided test?
One-sided or two-sided tests?
Vince Berger of the NIH Biometry Research Group published "On the generation and ownership of alpha in medical studies" in the journal Controlled Clinical Trials in 2004, in which he said:
5. One-sided testing or two-sided testing?
It might seem that the alpha level should also reflect whether the analysis is one-tailed or two-tailed. It is common, for example, to use 0.05 as the alpha level for two-tailed comparisons, but to use 0.025 for one-tailed comparisons. One argument in favor of this approach is that an active treatment can be worse than a control treatment, and that when it is, one would want to know that it is. This is true of course, but it is unclear why it implies that one would want to use a two-tailed analysis. Consider the purpose to which p-values are often put in the inherently asymmetric situation in which a novel treatment is being compared to the standard of care. Generally, these p-values are computed in an effort to demonstrate an effect and to alter the practice of medicine. If the standard of care proves superior, then it will remain the standard of care. If the trial is inconclusive, then again the status quo remains in force. Only if the experimental treatment is demonstrably superior will it supplant the competitor as the standard of care.
The very existence of a standard of care implies that the decision makers are making decisions for a larger group, and not just for themselves. That is, the action to be taken, supplanting the standard of care, is a policy decision that mandates a preponderance of evidence. One way to put into practice the notion of a preponderance of evidence is the attainment of statistical significance (a low p-value). Contrast this with personal decision making, in which evidence is generally accepted at face value. When selecting a meal in a restaurant, for example, no diner asks if one meal tastes statistically significantly better than another. Likewise, one may decide on taking an aspirin or not based on the effects aspirin have had in alleviating past headaches. In such a case, one is concerned only with the question of whether or not it is better to take the aspirin. Because there is no need to justify this action to anyone else, there is no need to contemplate the statistical significance associated with the benefit in taking (or not taking) the aspirin. Now the attainment of statistical significance may be required to supplant the standard of care, but it is not required to maintain it. As in the previous paragraph, inconclusive results lead to the same decision as a clear benefit for the control group. In the case considered, the only decision driven by a preponderance of evidence in the form of statistical significance is the changing of the standard of care. This is where all of the alpha needs to be applied, and so in this situation hypothesis tests should be one-sided. On the other hand, in a symmetric situation, such as if two treatments are developed at the same time, so that neither is the default standard of care in case of inconclusive results, two-sided testing would make more sense.
Questions:
1. Does this mean that the full .05 (or whatever value is left) can/should be allocated to a one-sided test?
2. If a two-sided test is used, is it possible to unevenly split the alpha value? (e.g. allocate .045 to superiority of drug over SOC and .005 to superiority of SOC over drug).
GPCB will submit the NDA and ask for Accelerated Approval based on the PFS data from the SPARC trial as specified in the SPA.
How will PFS be measured? Is it based on PSA?
tNOX and Phenoxodiol
tNOX is specific to cancer. It has not been found in healthy individuals or in non-cancer cells. It is the primary target of phenoxodiol. We now learn that there are isoforms of tNOX that are apparently specific to different forms of cancer. Professor Morre has developed a simple blood test that can (a) tell if you have cancer; and (b) show if the cancer is responding to therapy. It now seems that the test will be able to show what type of cancer is present. Professor Morre's work on tNOX has huge implication for cancer therapy
Press Release Source: Marshall Edwards, Inc.
http://biz.yahoo.com/prnews/060915/dcf005.html?.v=72
Early Study Provides Evidence That Investigational Drug Phenoxodiol Targets Prostate Cancer Protein
CHICAGO, Sept. 15 /PRNewswire-FirstCall/ -- A new study demonstrates that the investigational drug, phenoxodiol, may be effective in the treatment of prostate cancer through its ability to target a protein that appears to be selective for prostate cancer cells. Prostate cancer is one of the most serious and common types of cancer found in American men, killing more than 30,000 men in the U.S. every year.
In a new study, a research group headed by James Morre, Ph.D., professor of medicinal chemistry at Purdue University, obtained results supporting that phenoxodiol specifically targets a protein on prostate cancer cells known as tNOX 75 alpha.
The Purdue team has identified the protein, tumor-associated NADH oxidase (or tNOX), as a pan-cancer marker. The protein is critical to the ability of the tumor cell to grow and to survive. They also have shown that there are different forms of this protein, known as isoforms, and that different tNOX isoforms are associated with different forms of cancer.
The team has demonstrated previously that tNOX is the primary molecular target for phenoxodiol. The 75 alpha protein appears to be the particular tNOX isoform found in prostate cancer patients, and that is one of the isoforms targeted by phenoxodiol.
Prostate specific antigen (PSA) is another protein found exclusively on prostate cancer cells, and is used widely to diagnose prostate cancer and to determine response to therapy. However, no anti-cancer drug specifically targets PSA because the protein is not essential to tumor cell survival, so it is not a universally reliable marker of the efficacy of a particular drug. tNOX is essential for tumor cell survival, making it an excellent target for anti-cancer drug activity.
When phenoxodiol binds to tNOX, the protein is inhibited, blocking the cell from dividing, and switching off a variety of pro-survival signaling mechanisms within the cell. Where this inhibition reaches a certain level, the cell dies; where it is below a lethal level, the cell is blocked from dividing.
Results of the study, which involved 19 patients with late-stage, hormone- refractory prostate cancer, were presented today at the International Conference on Molecular Diagnostics in Cancer Therapeutics, held September 12th to the 15th by the American Association of Cancer Research.
In the clinical study, phenoxodiol was administered orally three times daily until patients showed disease progression. Blood samples were obtained prior to treatment, after two months of treatment, and at the completion of the schedule. All 19 patients had tNOX 75 alpha in their bloodstream; it has not been found in patients without evidence of cancer.
Blood analysis revealed that tNOX 75 alpha levels responded to administration of phenoxodiol in 11 of the 19 patients.
"The study demonstrates a clear association between tNOX 75 alpha levels, prostate cancer, and response to phenoxodiol therapy," says Graham Kelly Ph.D., Chairman of Marshall Edwards Inc., the company developing phenoxodiol. "In the study, tNOX 75alpha levels fell as the dosage of phenoxodiol increased, and patients responded by slowing down the rate of tumor growth. This supports that tNOX is the target for phenoxodiol, and that inhibition of this protein is an exciting new approach to the treatment of cancer."
About Prostate Cancer
According to data provided by the American Cancer Society (ACS), prostate cancer is one of the most common types of cancer found in American men, second only to skin cancer. ACS estimates that there will be more than 232,000 new cases of prostate cancer in the United States in 2005 and about 30,350 men will die of this disease. One man in six will get prostate cancer during his lifetime, and one in 34 will die of the disease.
Most cases of prostate cancer are sensitive to male sex hormones (androgen), and blocking the effect of these hormones is a common therapeutic process. Ultimately, however, most prostate cancers become insensitive to androgens, at which time the tumor is referred to as being hormone-refractory. The approved anti-tumor therapy for these patients is docetaxel (Taxotere®), which has been shown to provide a modest extension of survival in some patients, before the tumors become docetaxel-refractory. Hormone-refractory, docetaxel refractory patients represent the end-stage of this disease.
About Phenoxodiol
Phenoxodiol is being developed as a therapy for late-stage, chemo- resistant prostate, ovarian and cervical cancers.
Phenoxodiol targets the tNOX protein, which regulates a number of vital cell functions, including a hydrogen excretion pump. Inhibition of tNOX leads to inhibition of this pump and loss of the cell's redox potential, producing a generalized biochemical disruption including inhibition of phosphorylation of the key pro-survival sphingosine-1-phosphate and Akt signaling pathways. Inhibition of production of anti-apoptotic proteins including XIAP is a key biochemical outcome.
The mechanism of action of phenoxodiol suggests a potential to be used both as a single-agent therapy and in combination with standard anti-cancer drugs where it acts to enhance the efficacy of those drugs in chemo-sensitive patients and to restore sensitivity to those drugs in chemo-resistant patients. Phenoxodiol currently is undergoing clinical studies in the US and Australia.
Phenoxodiol is an investigational drug and, as such, is not marketed in the US.
More on tNOX
Newswise — Lung cancer is a formidable disease. While it is one of the most preventable cancers, with the vast majority of 160,000 annual deaths in the United States due to smoking, it is invariably difficult to find early when it is most amenable to treatment. As a result, it remains the top cancer killer in the nation.
But a new test for the early detection of lung cancer that involves measuring levels of a certain protein may provide hope for thousands of smokers worldwide. While the findings are preliminary and involve a small group of subjects, the researchers see their early results as extremely promising.
Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.
A team led by Dorothy M. Morre, Ph.D., professor of foods and nutrition at Purdue University in West Lafayette, Indiana, and D. James Morre, Ph.D., distinguished professor of medicinal chemistry at Purdue, wanted to come up with a robust lung cancer screening procedure for people who smoke.
“We’d like to have a means of detecting lung cancer early in individuals who smoke with a low incidence of false positives,” Dorothy Morre said. “There’s apparently no good method of finding this and there is a lot of interest at the National Cancer Institute in developing such a protocol.”
The Morres -- along with colleagues at Purdue, NOX Technologies, Inc., also in West Lafayette, and at Mount Sinai Medical Center in New York -- focused their efforts on a protein called tNOX, a member of a family of proteins that are involved in cell growth. Normal cells express the NOX enzyme only when they are dividing in response to growth hormone signals. In contrast, cancer cells have gained the ability to express NOX activity at all times. This overactive form of NOX, known as tNOX – for tumor-associated NOX – has long been assumed to be vital for the growth of cancer cells, because drugs that inhibit tNOX activity also block tumor cell growth in culture.
The researchers compared four different protocols to determine levels of tNOX in the blood of 421 volunteer subjects, including 104 patients with lung cancer, 175 smokers who had not been diagnosed with lung cancer, 117 randomly selected outpatients and 25 healthy individuals.
Two of the protocols used rapid high-throughput screening techniques and gave a low incidence of false-positive diagnoses of lung cancer. In contrast, the researchers employed a technique using two different antibodies that they created against the tNOX protein, which they found gave a definitive indication of lung cancer.
“In healthy individuals, we have 0 out of 25 false positives,” noted D. James Morre. “In lung cancers, 103 of the 104 patients were positive for tNOX. In smokers older than 40 years of age, 12 percent were positive, which is about the normal incidence picked up with high resolution scanning techniques.”
The researchers envision the tNOX test as serving as a screening tool for the early detection of lung cancer. Those who test positive would then be followed up with a medical examination and further tests, ostensibly including high resolution CT.
According to D. James Morre, current approaches to diagnosing lung cancer are costly and time consuming. “Our findings would provide a simple blood test that would indicate whether or not additional testing would be required,” he said. “We could screen very large smoker populations and eliminate perhaps 90 percent of them, while encouraging the other 10 percent to go on to the next stage of testing.
“This test is structured with the antibody we’re using to be specific for lung cancer in one form or another,” Dorothy Morre added. “It’s a specific diagnosis and it also distinguishes between non-small and small cell lung cancer.”
The scientists are already doing similar studies in colon, ovarian, prostate and breast cancers as well. They are planning three collaborative studies in which they will correlate tNOX antibody test results with medical evidence such as high resolution CT, physician examinations of patients – standard procedures for detecting early stage lung cancer.
http://www.newswise.com/articles/view/523329/
tNOX
Newswise — A team of researchers at Purdue University has found a protein in the blood that may prove to be more reliable than the standard prostate specific antigen (PSA) test in measuring the extent of prostate cancer.
According to D. James Morre, Ph.D., distinguished professor of medicinal chemistry at Purdue, the protein -- called tNOX -- is a member of a family of proteins that are involved in cell growth. Normal cells express the NOX enzyme only when they are dividing in response to growth hormone signals. In contrast, cancer cells have gained the ability to express NOX activity at all times. This overactive form of NOX, known as tNOX – for tumor-associated NOX – has long been assumed to be vital for the growth of cancer cells, because drugs that inhibit tNOX activity also block tumor cell growth in culture.
Morre’s group -- in collaboration with colleagues at NOX Technologies in West Lafayette, Indiana, and Marshall Edwards Inc. in New York -- wanted to determine if the tNOX protein could be used to monitor disease progression in prostate cancer. That is, could tNOX serve as a biomarker for not only detecting the cancer, but also in gauging the amount of disease.
Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.
Prostate cancer can be difficult to detect and track because of inaccuracies in current testing methods. The PSA test gives false-positive readings at least 20 percent of the time, resulting in unnecessary biopsies to confirm disease. The digital rectal exam in which a doctor physically checks the prostate is also plagued with reliability problems. At the same time, relying on changes in PSA levels to correlate with disease progression – whether with treatment or not – can be problematic.
In the study, Morre’s group collaborated with Marshall Edwards Inc., which was conducting a phase II clinical trial in Australia with an experimental drug called phenoxodiol in late-stage metastatic prostate cancer. Blood samples were taken prior to, midway, and at the end of the 12-week treatment, and analyzed for tNOX. They were compared to PSA levels in the blood that were taken at the same times.
Of 19 patients in the trial, nine -- who had prostate cancer that was continuing to grow based on PSA levels -- showed on average a 60 percent greater amount of circulating tNOX protein compared to those patients who had stable (7) or falling (3) PSA levels.
“It’s the first demonstration that we have – assuming that PSA levels indicate major tumor burden in some fashion – that tNOX levels also reflect tumor burden during and after therapy for prostate cancer,” said Morre. “That is, the more prostate cancer present as evidenced by PSA levels, the more tNOX protein that is present.”
He said that tNOX would probably find greater use in estimating the amount of cancer, rather than in detection, and could be another useful marker for monitoring an individual’s response to therapy. While rising PSA levels are usually associated with worsening disease, PSA scores can be erratic, he said. Individuals with substantial disease can still have a low PSA score, and those with moderate or even non-existent disease can show a high PSA.
“We think our marker may be more closely aligned to tumor burden than PSA,” Morre said. “It looks like it stands a better chance of being proportional to tumor burden and may be more reliable. It seems to be more uniform in terms of disease severity.”
In future work, the researchers hope to conduct more extensive clinical trials to try to link tNOX and PSA levels as estimates of tumor burden and to monitor responses to therapy of patients with late-stage metastatic disease.
http://www.newswise.com/articles/view/523331/
Abraxane/ODAC
Is this a clever way for the company to promote off-label use?
Phenoxodiol
http://www.sec.gov/Archives/edgar/data/1262104/000095013306004013/w24658e10vk.htm
The latest 10-K by MSHL provides a comprehensive review of phenoxodiol et al. I'm still reading the full document, but this section caught my eye:
We believe that our three drug candidates increase the potency of signal transduction inhibitors by targeting multiple signaling pathways, and in particular, those pathways vital to the survival of most, if not all, human cancer cells. In the term MSTR, “multiple” refers to the fact that more than one signaling pathway is targeted by the drug, and “regulator” refers to the fact that while the drug predominantly inhibits errant ‘pro-survival’ signaling pathways, it conversely can also activate ‘pro-death’ signaling pathways to facilitate cancer cell death.
We believe that our three drug candidates are able to exert a multiplicity of effects, including on both ‘pro-survival’ and ‘pro-death’ signaling systems, as a result of the primary target on the tumor cell being a protein whose function in the tumor cell is so fundamental to cell biochemistry that to shut it down produces a broad range of biochemical consequences.
The potential explanation for this effect on the fundamental biochemistry of tumor cells was provided by a discovery of a research team at Purdue University in Indiana. This team has a long-standing research interest in a family of proteins at the cell surface that are involved in the transport of waste electrons, particularly hydrogen ions (H+), across the cell membrane. This function is so fundamental to normal cell function and viability, that any loss of function of this electron pump will disrupt a wide range of biochemical processes as a consequence of elevated waste hydrogen levels. One of the key components of this electron pump mechanism is a protein known as NADH oxidase (abbreviated as NOX). NOX is situated on the outside of the cell membrane of all living matter, and regulates the flow of waste hydrogen across the cell membrane. The Purdue University studies have now shown that all forms of human cancer express a variant form of the constitutive (or normal) NOX, known as tumor-specific NADH oxidase (abbreviated as tNOX). Based on Purdue University studies, we believe that tNOX is a primary molecular target for phenoxodiol. Phenoxodiol appears to specifically block the action of tNOX, with the resulting inhibition of H+ efflux from the cell leading to extensive disruption to signaling pathways and to eventual inhibition of cell proliferation and activation of apoptosis, the process of programmed cell death by which a cell dies naturally. The Purdue studies also show that phenoxodiol has no effect on the normal form of NOX, providing an explanation for how phenoxodiol selectively targets cancer cells for its cytotoxic effects.
Purdue University studies recently have also shown that one of the important consequences of a rise in intra-cell levels of waste hydrogen ions is inhibition of enzymes known as kinases, which are critically important to the activation of proteins within a cell. One of those kinases is sphingosine kinase. This enzyme is responsible for the production of a compound within cells known as sphingosine-1-phosphate (abbreviated as S-1-P). S-1-P plays an important role in all cells in activating a wide range of ‘pro survival’ signal transduction mechanisms, including the production of proteins known as ‘anti-apoptosis proteins’ whose task it is to block the apoptosis process. S-1-P levels have been reported to be elevated in tumor cells, and in particular in tumor cells that have become resistant to standard chemotherapy drugs.
This finding is relevant because of results from laboratory studies at Yale University that have revealed that the killing effect of phenoxodiol on cancer cells occurs through the loss of the ability of the tumor cell to manufacture anti-apoptosis proteins such as XIAP and c-FLIP. Collectively, the Yale University and Purdue University results provide a rational mechanism of action of phenoxodiol starting with the inhibition of tNOX, leading in turn to the loss of S-1-P activity, leading eventually to the loss of anti-apoptosis proteins.
Recent laboratory studies conducted by Novogen and Yale University have confirmed that this chain of biochemical events following exposure of tumor cells to phenoxodiol also provides an explanation for why phenoxodiol is able to reverse resistance to standard anti-cancer drugs such as platinums, gemcitabine and taxanes.
Phenoxodiol appears to restore sensitivity to these drugs in cells such as ovarian cancer cells that have acquired resistance to these drugs. In addition, pretreatment of tumor cells with phenoxodiol considerably increases the sensitivity of non-resistant tumor cells to the cytotoxic effects of standard chemotherapy drugs. These effects are achieved without increasing the toxicity of the standard chemotherapy drugs to non tumor-cells.
Re Sphingomab
Sphingosine kinase phosphorylates the substrate, sphingosine to sphingosine-1-phosphate. S-1-P is an important stimulator of pro-survival mechanisms and appears to play a key role in facilitating the ability of cells to divide. Sphingosine-1-phosphate is also involved in the angiogenic process and has recently been shown to be involved in the VEGF signalling pathway.
Laureate and Lpath are too late: Dehydroequol inhibits S-1-P in abnormal cells but not in normal cells and is currently in Phase III.
Phase-3 Pixantrone
The study was powered based on a CR rate assumption of less than 5 percent for the control arm and a 10 percent improvement in CR rate for the pixantrone arm.
Hmmm
Do they mean to say a CR rate of 5% in the control arm versus 5.5% in the Pix arm; or 5% in the control arm versus 10% in the Pix arm; or 5% in the control arm versus 15% in the Pix arm?
OVATURE
I’m trying to estimate a realistic, conservative TTP for patients in the control arm, based on the assumption that these ladies will be highly refractory patients who last progressed while being treated with Carboplatin.
Doxil’s Phase II for ovarian cancer showed median PFS of about 10 weeks for resistant patients, but many of these would have progressed after therapy. My guess is that 10 weeks is the maximum TTP that can be expected if unresponsive tumors are treated with standard chemotherapy. I don’t like guesses.
Ovature patients will receive weekly Carboplatin rather than the old standard of Carboplatin every-three-weeks, so I am inclined assume that maximum TTP will double to 20 weeks. Is this a reasonable figure? Any idea what the minimum might be, based on unrestricted growth?
A question:
Is there a rule of thumb for the time it takes a non-responsive tumor to grow 20% in diamater?
In particular, I'm trying to determine how long it would take an ovarian tumor that had grown while last being treated to grow 20% in diamater if it was retreated with the same drug after a short interval - say three months.
TIA
Phenoxodiol newsletter may answer some questions.
http://www.marshalledwardsinc.com/pdf/MSHL%20Newsletter.pdf
OVATURE has 470 patients in two arms. The SPA includes agreed endpoints for accelerated approval based on PFS following an interim analysis (said separately to occur when all patients recruited and 97 events recorded - estimated to take 12-18 months) and that the company has conducted a pilot study to test the efficacy of oral PXD in the OVATURE setting. Also, from a recent conference: "It is well known that within 6 months of resistance it is very unlikely that any women will respond - if at all, only a few percentage. In our Phase III protocol we will only be selecting women who have failed on previous therapy within 6 months before entry into the PXD/Carboplatin regimen."
A 15 month odyssey
The Phase 3 OVATURE study has undergone considerable progress towards initiation over the past 15 months. MSHL has worked closely with the FDA on the OVATURE Study. The company retains the services of the Health Care division of one of the largest law firms in the US to advise on regulatory matters, including helping to guide the regulatory strategy and to coordinate the liaison with the FDA.
Mindful of the fact that a number of pivotal drug studies by other companies over the past 2 years have received criticism by the FDA for their inadequate design, MSHL has sought to design this pivotal study in a way that is compatible with the latest FDA guidelines. This is always challenging because of the inevitable shift in official thinking over time as different clinical studies conclude and yield data that varies from the unexpected to the contentious. There are few absolutes in the oncology field, each set of data being considered on its own merits, and often the cause of considerable debate between the sponsor and the agency.
The design of this pivotal study has been an exhaustive process that commenced with the appointment of a Steering Committee (comprising sponsor representatives and respected oncologists), which then consulted with senior oncologists from the UK and US who had agreed to participate in OVATURE and to be Principal Investigators for their hospitals. Overseeing the whole design process and liaising with the FDA, is the company’s Washington-based legal and regulatory representatives.
Pursuant to a meeting with the FDA in late 2004, a study design was selected that was finally ratified by a meeting of 20 international oncologists in Florida in April 2005. That design was duly submitted to the FDA for its approval under the IND (Investigational New Drug) scheme in May 2005, a default scheme where a trial can start unless blocked by the FDA for reasons such as safety concerns. That submission coincided with the completion by another major pharmaceutical company of a large study of an anti-cancer drug for use in late-stage lung cancer patients. The FDA had earlier granted Accelerated Approval status on the basis of an apparent delay in tumour progression but a continuation of the study failed in the FDA’s view to provide ultimately any overall survival benefit. The rescinding by the FDA of regulatory approval for that drug in that particular indication is the subject of ongoing discussion.
A major consequence of this experience was to cause the FDA to review its policy concerning Accelerated Approval, an entirely unanticipated outcome, but one which obliged MSHL to undertake a major re-design of the OVATURE study. A new design subsequently was discussed with the FDA, using a design that involved a novel approach by which reversal of chemoresistance could be tested. However, MSHL considered it prudent to test this novel, highly stringent approach in a pilot study using a small group of patients with late-stage ovarian cancer. Sufficient data subsequently was generated by that pilot study to allow the re-designed protocol to be lodged with the FDA in November 2005.
That protocol has now been agreed between MSHL and the FDA and will provide the basis for two determinations by the FDA – the first being consideration for Accelerated Approval following the interim analysis, and the second being consideration for New Drug Approval status following the final analysis. Based on this agreement OVATURE will now proceed, with patient enrolment commencing in Q306.
In the meantime MSHL, along with the Contract Research Organisation retained for project management, has used the available time to establish the trial infrastructure and to select and appoint hospital sites within the US, Europe, UK and Australia.
The ability to manufacture the considerable quantity of drug product required for a Phase 3 clinical trial also has been developed in this interim period.
So I guess the all important and extremely stringent requirement of readministering carbo to these carbo failures prior to phenoxodiol went out the window?
I find it surprising that an otherwise intelligent poster would so obviously demonstrate bias toward a company.
There was a very good medical reason why the protocol was changed to remove the 'rechallenge' aspect of the trial and instead recruit patients who have progressed while on therapy or shortly thereafter. A good scientist should be able to work out the answer.
I find it odd that they dropped the IV formulation for a 3 times a day oral pill.
I think they did it on a whim, for the fun of it.
Phenoxodiol gets SPA for OVATURE trial
(Washington, D.C. and Sydney, Australia - 16 May, 2006) Biotechnology company, Marshall Edwards, Inc., announced today that under the Special Protocol Assessment (SPA) process, it has reached agreement with the United States Food and Drug Administration (FDA) on the design of a pivotal study protocol for its investigational anti-cancer drug, phenoxodiol. The trial, known as the OVATURE study, is designed to test the ability of phenoxodiol to restore sensitivity of late-stage ovarian cancers to carboplatin, a standard form of therapy for ovarian cancer.
The SPA process allows for FDA evaluation of a clinical trial protocol that will form the basis of an efficacy claim for a marketing application, and provides a binding agreement that the study design, including patient numbers, clinical endpoints, and analyses are acceptable to the FDA.
Phenoxodiol received fast track designation for platinum-resistant or refractory ovarian cancer from the FDA in 2004 based on Phase II data, and is eligible for FDA’s programs that are designed to facilitate drug development and expedite marketing approval of drugs intended to treat serious or life-threatening disease and to address unmet medical need. As a fast track product, phenoxodiol will be eligible for accelerated approval and priority review of the marketing application.
"We are pleased that the FDA has completed the SPA review process and that we have a mutually-agreed design that provides us with a clearly defined regulatory pathway for pursuing marketing approval of phenoxodiol," said Professor Graham Kelly, Chairman, Marshall Edwards, Inc.
About Ovarian Cancer Treatment
Platinum-based drugs such as cisplatin and carboplatin are a standard form of chemotherapy in ovarian cancer, with a high initial response rate. However, at least 85-90% of these patients will experience disease recurrence, subsequently showing a lower level of response to both platinums and other chemotherapies. Most of these tumors ultimately become resistant to platinums, and platinum-resistant tumors invariably are resistant to other forms of chemotherapy.
About OVATURE
Four hundred and seventy (470) patients are to be enrolled and randomized to two treatment arms – (i) carboplatin + phenoxodiol, and (ii) carboplatin + placebo. The carboplatin will be administered weekly intravenously, and the phenoxodiol or placebo will be capsules administered 8-hourly on a continuous daily basis.
The trial will involve up to 60 sites in the United States, the United Kingdom, Europe, and Australia.
The primary endpoint of the trial is progression-free survival, representing death or disease progression, whichever comes first. Overall survival is a secondary endpoint.
Enrollment is not expected to open for at least a month. More information about the study will be available in due course at www.phenoxodiol.com or www.clinicaltrials.gov. These sites will contain information on when and where the trial is open for enrollment.
About PHENOXODIOL
Phenoxodiol is an investigational drug and, as such, is not commercially available.
Phenoxodiol is a novel-acting drug that inhibits key pro-survival signaling pathways operating via sphingosine-1-phosphate and Akt. Inhibition of these pathways leads to prevention of phosphorylation of key anti-apoptotic proteins such as XIAP. Loss of activity of these proteins restores the ability of chemo-resistant tumor cells to undergo apoptosis in response to chemotherapy. The putative molecular target for phenoxodiol is a tumor-specific protein, accounting for the highly selective nature of the drug.
I wonder whether the thinking here is that a reasonably large percentage of qualified patients would have been identified by the 50 institutions involved (<10 req'd per site) and are waiting for the trial to start, whereas the remaining patients would have to be recruited once they had progressed within six months of therapy.
Would this be reasonable?
Re: A question for statisticians
I'd guess they are hoping for a very large difference or are so scared there will be no difference they want to stop the trial before they waste any money.
I should have thought of that. Do many companies set up a pivotal trial with a primary endpoint they expect to miss?