A paradigm shift is needed in the field of therapeutic cancer vaccine trials that would evaluate patient response rather than tumor response, according to an analysis of prostate cancer vaccine trials in the July 1 issue of Clinical Cancer Research.

Recent findings suggest that patients who receive therapeutic cancer vaccines respond better to subsequent chemotherapy or hormone treatment, and that immunotherapy may have a synergistic effect with other therapies that could be used in several cancer types, lead author Jeffrey Schlom of the National Cancer Institute says.

Because immunotherapies trigger a dynamic process in a patient's immune system, the clinical trial community should move away from evaluating tumor shrinkage and instead incorporate quality of life and survival into clinical trial endpoints for therapeutic vaccines, Schlom advocates.

"Response Evaluation Criteria in Solid Tumors (RECIST) … has served the oncology community well in the evaluation of passive therapeutic modalities such as chemotherapeutic agents and radiation therapy," Schlom writes. "With the advent of new targeted therapies, including cancer vaccines, however, the sole use of RECIST criteria as a clinical endpoint has now been called into question by, among others, several Cooperative Groups."

Dendreon's Provenge (sipuleucel-T) experience is a good example of how failing to power a trial for survival and relying on progression-free survival may not demonstrate the clinical benefit necessary for FDA approval. FDA did not follow the recommendation of its Cellular, Tissue and Gene Therapies Advisory Committee, which had issued a favorable recommendation on efficacy for the prostate cancer vaccine, the agency's first review of a therapeutic cancer vaccine (¹ Pharmaceutical Approvals Monthly November 2006, In Brief).

The agency instead issued a "complete response" letter, citing the need for additional clinical data in support of the BLA's efficacy claim, although Provenge did show a survival benefit in a post hoc analysis of two trials that failed to meet primary efficacy endpoints of delayed progression.

Schlom also points to Bayer/Onyx's effective use of progression-free survival in winning approval of their renal cell carcinoma drug Nexavar (sorafenib). During the Nexavar review, FDA had debated whether to grant the treatment full or accelerated approval due to demonstration of a PFS benefit but a failure to demonstrate an overall survival benefit. The agency ultimately granted a full approval with priority review (² Pharmaceutical Approvals Monthly May 2006, p. 31).

Cell Genesys recently completed enrollment in the first of two Phase III trials of its GVax immunotherapy for prostate cancer, for which the primary endpoint is an improvement in overall survival. The multicenter, randomized VITAL-1 study is comparing GVax to Taxotere (docetaxel) chemotherapy plus prednisone in hormone-refractory prostate cancer patients with metastatic disease. A pre-planned interim analysis of the data is scheduled for 2008.

GVax is an off-the-shelf allogenec therapy derived from two human prostate cancer cell lines - one from early disease and one from late disease - that have been genetically altered to produce and secrete granulocyte macrophage colony-stimulating factor, a cytokine that activates dendritic cells, Cell Genesys Chief Medical Officer Robert Dow explained in an interview with Pharmaceutical Approvals Monthly.

When designing a trial with progression-free survival as an endpoint, one "must be extremely confident about your definition of progression," Dow said.

"And, as several recent debates between industry sponsors and the FDA have [shown] … there is no consensus within the FDA or within the clinical community about what constitutes progression in several diseases. And, therefore you're faced with the struggle to look at an endpoint whereby some of it is very clear cut - death is a very clear endpoint - but being alive and without progression is not such a clear endpoint. It is extremely difficult to come up with a definitive endpoint that can be viewed as very objective."

Survival has historically been viewed as the "gold standard" endpoint for oncology trials, but FDA recently modified that stance in its final guidance on oncology endpoints released in May. However, even when alternative endpoints such as progression-free survival or time to progression are used, trials should still be powered for survival, the final guidance notes.

For progression endpoints, the disease state, the definition of progression and the proportion of patients who contribute to progression-free survival by either progressing or by dying, all need to be weighed, Dow said.

"For vaccines, not only do you have the problem of the debate about what constitutes progression or not, but you have an almost killing complication that your trial is not truly blinded," he said. For example, in the GVax prostate trials, the vaccine is injected into the skin, which produces a skin reaction. For a trial to be blinded, the placebo would have to produce an identical skin reaction, he explained.

The most rational way to conduct a survival trial is for it to be event-driven, with a specific number of events planned in an approximate time period when the treatment outcome is then analyzed, Dow said.

"Even if you're looking at survival as your primary endpoint, you will still look for the standard response rates of partial and complete response, although with immunotherapies that is just kind of observational," Dow points out. "We have no substantial expectation of causing PRs and CRs in a large number of people."

One of the differences between cytotoxic therapy and immunotherapy is dose response. Doses and treatment schedules for cytotoxic therapy are chosen based on their ability to shrink tumors and to prevent progression of tumors. Finding the maximum tolerated dose for immunotherapy is trickier because it may not have evident organ toxicity. Instead, clinicians look for indicators of immune activity such as formation of new antibodies and altered T-cell populations.

What is not known yet in this stage of the vaccine field, Dow said, is when the immune response created by the vaccine is initiated. It may take a few months of being on the immunotherapy, so it could be feasible that short-term progression would still occur, but that a survival benefit would ultimately be seen.

"Tumor shrinkage does not necessarily correlate clearly with survival anyway, so it may make the patient feel better, and it certainly makes the doctor feel better, but whether it makes their lives longer is subject to scrutiny. … And it really depends on the symptomatic benefit that you get from that short-term [tumor] shrinkage and also from the subsequent survival trials to find out whether the shrinkage really did translate."

Schlom also comments on the confusing clinical environment surrounding immune response: "Several clinical studies have reported statistical correlations between antigen-specific immune responses to vaccine and patient benefit, whereas others have not." The author notes several potential confounding phenomena, including bias toward measuring response in blood-borne T-cells instead of tumors and studies' lack of consideration with regard to T-cell "antigen cascade."

Cell Genesys' Dow agreed that combining immunotherapy with cytotoxic and other therapies would be "sensible," noting that preclinical data suggests that synergy can be created by combining cytotoxic therapy and immunotherapy.

Schlom's commentary also speaks to the combination topic, noting that combining therapeutic vaccines with chemotherapies has been shown to allow each agent to work "individually with the goal of additive antitumor effects."

Brain Cancer Vaccine's Swiss 'Authorization'

Bothell, Wash.-based Northwest Biotherapeutics received "authorization for use" in Switzerland for its autologous therapeutic vaccine for brain cancer, making it available at selected medical centers in Switzerland in the third quarter of 2007, the company announced July 9. Northwest clarified that DCVax-Brain's authorization for use does not equate to approval.

"It is not clinical trials, but it is not the complete unrestricted commercialization," Northwest's nonexecutive chairperson Linda Powers told Pharmaceutical Approvals Monthly. She likened the authorization to the process in place for bone marrow transplants whereby specific centers are cleared to conduct the procedure.

Northwest's DCVax products are autologous products that combine the patient's dendritic cells with cancer biomarkers from the patient's own tumor. The master immune cells are matured and activated and then injected back into the patient via an intradermal injection.

In a single manufacturing run, the company produces three years of product, which is frozen in single-dose vials. Producing the single batches and freezing them makes the economics dramatically more manageable, Powers said. Northwest expects the price of its DCVax-Brain to be comparable to other cancer drugs that treat brain cancer such as Schering-Plough's Temodar (temozolomide).

DCVax is given as an adjuvant to standard of care, which is surgery followed by radiation and chemotherapy. Northwest's pivotal Phase II/III trial is underway in the U.S. and will enroll 141 newly diagnosed patients with glioblastoma mulitforme grade 4 astrocytoma. The primary endpoint is progression-free survival with overall survival as the secondary endpoint.

PFS Is Valid As Surrogate, But Needs Validation

"Whether you can really call progression-free survival a clinical benefit is [debatable], but it is a surrogate marker and unless you validate it and prove it for your disease state, you are going to have to still do survival," Northwest Biotherapeutics CEO Alton Boynton said.

"What we hope to show is that there is a positive correlation between progression-free survival and survival. And that will allow us in future trials to use progression-free survival as the endpoint."

"For example, in our prostate trials, we measured antibodies and T-cells," Boynton added, "and it turns out in prostate cancer that an antibody response is a positive predictor of clinical outcome." He said those pieces of information become very useful in subsequent trials. For example, whether a patient produces antibodies to the antigen could be used as a validated endpoint if it correlated in an earlier trial.

Progression And Quality Of Life

Progression can have a drastic impact on patients in terms of quality of life. "In the prostate case, you get pain because the progression is bone metastasis, and in the brain you can have function issues," Powers said.

"Some things that you might think would be good surrogates or correlations of overall survival are not," Powers added. "And the best example is tumor shrinkage."

"That's one of the hurdles that immunotherapies have faced in working their way towards market is that the measuring criteria have gotten set up with other kinds of treatments in mind," Powers said. "Immuno-therapies usually are used to stave off the cancer recurring or progressing rather than being used to shrink tumors."

Boynton pointed out that drugs have been approved via accelerated approval and progression-free survival that did not have any survival advantage. "And, in many cases that is a problem of the trial not being powered for survival, but also it may not correlate," he said. "But the FDA also has never taken those drugs off the market either."

Northwest expects to complete enrollment in its pivotal Phase II/III DCVax brain cancer trial in the first quarter of 2008. The company anticipates filing its BLA in 2009, and will request fast-track status. The product has been granted orphan status in the U.S. and Europe. A Phase III pivotal trial in prostate cancer will be launched in 2008.

Biovest and Favrille are both racing to develop therapeutic vaccines for non-Hodgkin's lymphoma and could be filing BLAs within the year. Favrille's lead candidate, FavID is a patient-specific id/KLH active immunotherapy. Biovest announced in June that it plans to lock down the data from its 230-patient pivotal trial of BiovaxID in September and plans on filing for an accelerated approval. In addition, Genitope expects results by year end from its Phase III trial of MyVax therapeutic vaccine for patients with previously untreated follicular non-Hodgkin's lymphoma.

Sanofi-Aventis and Oxford BioMedica's TroVax is being evaluated in a Phase III renal cancer trial with results expected in 2009. Antigenics is also studying Oncophage in Phase III for renal cell carcinoma.

-Tamra Sami (t.sami@elsevier.com)

Therapeutic Vaccine Trials Should Focus More On Patient Response – Study

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