Federal drug regulators on Tuesday released briefing documents that pose questions about the effectiveness of Provenge (sipuleucel-T), Seattle-based Dendreon Corp.’s experimental prostate cancer vaccine. On Thursday March 29 the Cell Tissue and Gene Therapy Committee (CTGT) will accept submissions from interested parties. The committee will then review the drug and recommend to the FDA that it be approved – or not be approved.

Prostate cancer advocates, acutely aware of the paucity of treatments available for men with hormone refractory prostate cancer, plan to attend the meeting to lobby for acceptance of Provenge.

The FDA committee’s questions pinpoint drug stability, efficacy and safety. A slightly higher rate of adverse events including explained and “unexplained” death (see below) occurred in men who took the vaccine.

FDA’s decision will be based on results of randomized trials, which tested Provenge against placebo (for which a dummy vaccination procedure was used). However, a subset of patients received Taxotere when their cancer progressed — either after Provenge, or after placebo or after placebo followed by a course of frozen-stored vaccine.

Bloomberg News report carried in the Seattle Post Intelligencer on Tuesdaysays “FDA staff says drug for prostate cancer works. Dendreon’s Provenge may get OK Thursday.”

Dendreon is banking on studies that show men taking Provenge lived longer even though their disease progressed. Regulators have highlighted the fact that the drug did not meet its targets, while adding that some data did support use of the therapy.

Dendreon’s main evidence comes from one relatively small double-blinded, placebo-controlled Pivotal Phase 3 Study (D9901). According to the company and lead clinical investigator Eric Small, M.D., results showed that the group of men with symptomatic, metastatic, androgen-independent prostate cancer who received the vaccine gained a median four and a half months’ life extension compared to men who received placebo.

FDA said this study failed to meet certain effectiveness targets and a second study did not strengthen the case . Specifically, the overall group taking Provenge experienced progression of their cancer almost as quickly as men taking placebo. Agency staff allowed that taken together with data from a third study, results provided some evidence to support use of the vaccine.

In the third study, the group of men who received Provenge gained a 41 percent overall reduction in the risk of death. In addition, 34 percent of patients receiving Provenge were alive 36 months after treatment compared to 11 percent of patients randomized to receive placebo. Patients in the Provenge arm had a 31 percent delay in their time to disease progression compared to patients in the placebo arm (this was less than expected). Furthermore, patients receiving Provenge had an approximately 8-fold increase in their T-cell immunity after treatment compared to the placebo group.

Question raised by the FDA ahead of this week’s meeting.
are online under the title Draft Advisory Committee Questions.

Expressing some concern about stability or consistency of the vaccine (which is made with immune system cells extracted from the patient’s own blood), FDA is asking “whether/how the variability in each product dose, in respect to total cell number and range in cell ratios, can be expected to affect product quality, safety, or effectiveness.”

They also ask about cerebrovascular accidents (strokes), which were higher for patients taking Provenge than for patients taking placebo.

A peer reviewed report last year in the Journal of Clinical Oncology mentioned fever and chills as commonest side effects from the Provenge vaccine.

But FDA says out of 461 patients taking vaccine, 7 died of a cerebrovascular event compared to 2 out of 231 patients who took the placebo (dummy vaccination). In addition 4 patients taking Provenge died of “unknown causes” compared with zero such deaths in the placebo arm.

FDA says: “The efficacy claim . . . is based on an observed survival difference between those patients treated with sipuleucel-T (APC-8015) compared with those treated with placebo in study 1 (D9901). However, studies 1 (D9901) and 2 (9902A) failed to achieve any of their primary or secondary objectives. Please discuss the persuasiveness of the efficacy evidence . . . .”

In study 1 (D9901), median time to cancer progression in patients on Provenge was 11 weeks, and for patients taking placebo, 9.1 weeks. Median survival on Provenge was 25.9 months and with no treatment (placebo) was 21.4 months.

In study D9902A, median time to progression on Provenge was 10.9 weeks and without treatment, 9.9 weeks. Median survival on Provenge in this study was 19.0 months and on placebo 15.7 months.

Mario Eisenberger, a Johns Hopkins oncologist who has designed and tested prostate cancer drugs and who reviewed a Provenge study, two years ago was skeptical of Dendreon’s methodology in designing the trial with a croosover arm to Taxotere and in analysizing the results (Which Drug is the Real Hero of Vaccine Trial? ). Eisenberger has questioned the usefulness of targeting prostatic acid phosphatase (PAP).

“The study was originally designed to look at men who had metastatic prostate cancer and who had failed hormonal therapy, to determine whether treatment delayed progression of the disease. Unfortunately,” he says, “it didn’t cause a delay. There was no significant difference in the time it took cancer to progress — which means that the primary end point of the study was negative.”

How was it, then, that men who had randomly been assigned to the vaccine group survived four months longer than men who were treated with placebo” “How could that be?” Eisenberger asks, “How could there be a survival advantage, if the vaccine failed to prevent progression of the disease?”

Eisenberger said the answer might be in understanding what else these men received. In all of the men — those who received the vaccine, and those in the placebo group — the overall median time to progression was under 3 months. Men in the place arm who progressed
were treated with the vaccine. The men who had already taken the vaccine were immediately given Taxotere (docetaxel). Taxotere chemotherapy for prostate cancer was FDA approved after it was proven to extend survival in men with advanced prostate cancer. Eisenberger, in 2005, suggested that what helped men in the Provenge trial the most may have been receiving Taxotere as soon as the cancer progressed (earlier than the men in the placebo group).

In 2006 at the Chemotherapy Symposium of New York Daniel Petrylak, M.D., who ran the clinical trials that achieved FDA approval for Taxotere (docetaxel) , presented on Provenge and Taxotere. His topic was “Defining the Optimal Role of Immunotherapy and Chemotherapy: Advanced Prostate Cancer Patients Who Receive Sipuleucel-T (PROVENGE) Followed by Docetaxel Derive Greatest Survival Benefit.” “The results of this analysis suggest that the use of PROVENGE as a first-line treatment followed by the chemotherapy docetaxel upon disease progression may provide patients with a substantially prolonged survival benefit.”

Petrylak revisited data from the Phase 3 Studies D9901 and D9902A to assess the influence of PROVENGE on clinical outcome in patients who received Taxotere after PROVENGE. He focused on survival data from 82 patients who received Taxotere following initial treatment with either PROVENGE or placebo. The median survival observed in the PROVENGE treated patients who subsequently received Taxotere was 34.5 months compared to 25.4 months for patients randomized to receive placebo who went on to receive Taxotere, a difference of 9.1 months (HR = 1.90; p-value = 0.023).

About 68 percent of the patients randomized to receive placebo also subsequently participated in a cross-over salvage protocol that allowed them to receive active cellular immunotherapy with APC8015F, a version of PROVENGE generated from cells gathered from the individual patients’ blood at the start of the trial and freeze-stored.

• For men who received placebo only and subsequent treatment with Taxotere, median survival was shorter — 20.2 months.
• For men who received placebo followed by the freeze-stored APC8015F followed by docetaxel, median survival was 25.7 months.
• For men who received initial treatment with PROVENGE followed by docetaxel, median survival was 34.5 months

Prognostic model for predicting survival in men with HRPC: Journal of Clinical Oncology, 2003; 21(7):1232-7).”

The researchers concluded that these results provide more evidence that Provenge is effective in the treatment of hormone refractory prostate cancer.

Among other vaccines in the pipeline, Cell Genesy’s GVAX has been tested with Taxotere and an ongoing trial is recruiting patients across the USA. (Cell Genesys Initiates Second Phase 3 Clinical Trial Of GVAX® Vaccine For Prostate Cancer).

Another approach is with vaccinia virus Vaccinia-based Vaccine Shows Promise for Treating Nonmetastatic Hormone Refractory Prostate Cancer

References

FDA: PROVENGE® (Sipuleucel T) BLA # 125197
Draft Advisory Committee Questions

Prostate Cancer Discovery, Volume II, Autum 2005
Which Drug is the Real Hero of Vaccine Trial?

Study of APC8015F Immunotherapy in Prostate Cancer Patients Who Participated in Study D9902B and Have Experienced Disease Progression and Disease-Related Pain

Petrylak D, et al. Defining the optimal role of immunotherapy and chemotherapy: Advanced prostate cancer patients who receive sipuleucel-T (PROVENGE) followed by docetaxel derive greatest survival benefit. 14th Annual Meeting of the Chemotherapy Foundation Symposium. New York, New York. November 8-11, 2006.

Press Releases and Medical News at psa-rising.com 2004 – 2007

Dendreon’s Phase 3 Trial Shows Provenge Vaccine Extends Survival in Patients with Advanced Prostate Cancer Oct 28, 2004

Dendreon Reports Preliminary D9902A Trial Data For Provenge in Patients With Advanced Prostate Cancer Jan. 11, 2005

Dendreon Announces FDA Grants Fast Track Status for Provenge Nov 7, 2005

Provenge prostate cancer vaccine linked to longer survival for asymptomatic hormone refractory stage. June 28, 2006

Dendreon Announces New Data Analyses Presented at Prostate Cancer Foundation Scientific Retreat Oct 20, 2006

Dendreon Announces New Data Analysis Presented at Chemotherapy Foundation Symposium Nov 10, 2006