Regeneron to continue VENICE trial of aflibercept


According to a media release from Regeneron Pharmaceuticals, the company plans to continue the randomized, multi-center, Phase III VENICE clinical trial, designed to evaluate the efficacy and safety of aflibercept (ZALTRAP™) in combination with docetaxel in the first-line treatment of patients with metastatic, hormone-refractory prostate cancer.

The VENICE trial was initiated in late 2007 and has randomized 1,224 patients to either docetaxel + prednisone (or prednisolone) + aflibercept or to docetaxel + prednisone (or prednisolone) + a placebo. All patients enrolled into this trial had to be chemotherapy-naïve at the time of enrollment, but they did have to have evident metastatic disease and a rising PSA after surgical or medical castration. Patients must also be maintained on standard hormone therapy during the course of the trial.

It is perhaps a little surprising that this trial has not shown a clear positive or negative result as yet, although the estimated date of study completion is July 2012. Of course the longer the trial continues, the less likely that it becomes that the addition of aflibercept (also known as VEGF Trap) to docetaxel chemotherapy will have a significant impact on patient survival. The decision to continue the trial was taken based on the recommendation of  the study’s Independent Data Monitoring Committee after a pre-planned interim data analysis.  The time to complete the trial would also depend on how long it took to fully enroll the necessary 1,200+ patients.

Regeneron has partnered with Sanofi in the development of aflibercept, which is also in clinical trials for the treatment of other forms of cancer.

8 Responses

  1. You wrote: “Of course the longer the trial continues, the less likely that it becomes that the addition of aflibercept (also known as VEGF Trap) to docetaxel chemotherapy will have a significant impact on patient survival.”

    I know that it’s been a while since you wrote this but I just read this and now I am intrigued by this comment. Can you explain this comment a little bit more? Do you mean since the VENICE trial was not stopped at the interim, you don’t expect HR to be significant? Or do you refer to the fact that this trial will take >2 years to report after full enrollment (au contraire to what you wrote, I find this delay promising).

    Thanks

    Summer

  2. Dear Summer:

    We know (from large, randomized clinical trials) that men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel + prednisone have had a median overall survival from the start of treatment of the order of 18 months.

    Since the men randomized to the docetaxel + prednisone + placebo arm of the VENICE trial were also all men with mCRPC, there is good reason to believe that the men in this arm of this trial would also have a median overall survival of about 18 months or so.

    The VENICE trial started enrolling its 1,224 patients in late 2007, but we don’t know the data of the enrollment of the last patient. However, the last update to the trial information data on ClinicalTrials.gov was in February 2010. It is not unreasonable to think that that was the date at which the company posted the statement that they were no longer enrolling patients. That was almost exactly 18 months ago as of now, but significant numbers of the patients in both arms of the trial must have started treatment way over 3 years ago.

    So, as of now it is becoming increasingly unlikely that more than 50% of the patients in the docetaxel + prednisone + placebo arm of the trial can still be alive.

    Given the size of this trial, and comparison to the structures of other, earlier trials, it also seems highly likely that this trial is powered to be able to detect a median survival benefit of about 2 months or more in favor of the docetaxel + prednisone + aflibercept arm of the trial. Conversely, no large, randomized clinical trial of any drug has ever shown more than a 7-month survival benefit over the comparator in metastatic prostate cancer, so it would be optimistic in the extreme to believe that patients on the aflibercept arm of the trial might show a median survival time of (say) 30 months, which would translate into an approximate survival benefit of 12 months compared to the non-aflibercept arm. And so we have to be close to even the most optimistic estimates of what aflibercept might be able to achieve in combination with docetaxel + predisone.

    So … In one sense you are correct, if alfibacept is a miracle and can extend the survival of men with mCRPC by well over 12 months when used in combination with docetaxel + prednisone, then the longer the trial goes on the better. However, then we have an ethical issue. If the drug is clearly that good, should we not stop the trial so that the men in the trial who are not getting aflibercept could get it (if any are still alive)?

    Conversely, to go back to what I already wrote, in a scenario where aflibercept may only be able to give a small survival benefit (2 to 3 months or less), then extension of the trial starts to look like any survival benefit will be tiny, and, even if it is statistically significant, the real clinical value is very questionable. (For example, how clinically valuable would a median survival benefit of 2 weeks be, even if the P value was < 0.05?) Remember that we have recently shown that abiraterone can extend survival by 4.6 months after first-line treatment with docetaxel + prednisone. It seems to me that aflibercept will need to do at least as well as that as a first-line chemotherapy combination if it is to be of important clinical value in the management of advanced prostate cancer.

    Does that help?

  3. Thanks.

    BTW, I don’t know if you know this but Medivation recently changed the second line MDV3100 trial design (after getting the FDA’s blessing of course) and now will report after only 650 events (for final analysis) and more importantly after 520 events for interim with required p value of 0.024 in a few months. I have the impression that they really want to end the trial at interim before getting into complex drug interaction issues.

  4. Summer:

    I suspect Medivation’s major motivation is to get MDV3100 on the market as fast as possible before everyone gets too used to prescribing abiraterone!

    :O)

  5. Don’t you think that since MDV3100 does not require prednisone, doctors will try it first, especially in earlier settings (assuming of course that MDV3100 works)?

  6. That is certainly one of the things that I assume Medivation will want to promote and that Johnson & Johnson will want to downplay. However, a great deal will depend on whether MDV3100 has similar or better efficacy and safety data to abiraterone acetate.

  7. Comparing MDV3100 to abiraterone will not be easy as Medivation allowed ketoconazole-treated patients in the the MDV3100 trial (AFFIRM) while J&J did not do so in the abiraterone trial. I still don’t know how J&J got away with that.

  8. Summer:

    Abiraterone actetate is really “just” a better form of ketoconazole. There was good reason, early on, to believe that men who had been treated with high-dose ketoconazole would not respond to abiraterone as well as ketoconazole-naive patients and/or would have worse side effects because of their prior exposure to keto. It really wasn’t a question of J&J “getting away with” anything in terms of the trial design.

    The prescribing information for abiraterone does include the clear statement that, “Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from [the pivotal Phase III] trial.” Subsequent, small clinical trials do appear to suggest that men can be treated with abiraterone after prior treatment with high-dose ketoconazole. However, if I was such a patient I would want my doctors to be watching my adrenocortical suffciency like hawks! I am mildly surprised that the full prescribing information does not include some specific statement of caution about the use of abiraterone in men with a prior history of high-dose ketoconazole therapy, but the FDA may well have decided that the potential benefits exceeded the risks. After all, we are talking about men who are running out of options rapidly.

    :O)

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