Tivozanib Survival Data Go Wrong Way With One-Way Crossover Design

Aveo’s decision to allow only patients on the pivotal trial’s comparator arm to cross over to subsequent targeted therapy was a design flaw that made it impossible to assess the true picture of tivozanib’s effect on overall survival, FDA advisory committee members said.

Aveo Pharmaceuticals Inc.’s decision to use a one-way crossover design in the tivozanib clinical program not only undercut its ability to gain FDA approval for the renal cell carcinoma drug with a single pivotal study, it’s likely to add to the debate over the wisdom of employing crossover designs in oncology drug registration trials.

At its May 2 review of tivozanib, FDA’s Oncologic Drugs Advisory Committee criticized the company’s decision to allow only those patients in the pivotal trial’s comparator arm, which used Onyx Pharmaceuticals Inc./Bayer HealthCare LLC’s Nexavar (sorafenib), to cross over to subsequent targeted cancer therapy upon disease progression.

“This is a textbook example of why we recommend against crossover,” ODAC statistician Dodd said.

This one-way crossover, coupled with the geographic makeup of the study, led to an imbalance between the arms in the percentage of patients who received second-line tyrosine kinase inhibitor treatment and clouded the picture of tivozanib’s effect on overall survival.

“This is a textbook example of why we recommend against crossover,” said temporary voting member Lori Dodd, a statistician at the National Institute of Allergy and Infectious Diseases. Dodd was among the 13 panelists on the 14-member committee to recommend against approval. “We don’t know whether sorafenib worked well and tivozanib didn’t, or whether tivozanib worked well or whether the survival signal is just noise.”

Not Just A Neutral Showing On Survival

In oncology, crossover design studies are frequently used so that patients are not denied potentially effective therapy if their disease progresses while on trial. However, use of such post-progression therapies can muddy the true picture of an investigational drug’s impact on survival.

It is not uncommon for an investigational drug to demonstrate a significant benefit in progression-free survival – an endpoint not affected by crossover – but nevertheless fail to show a significant benefit on overall survival.

What makes tivozanib unusual is that while the drug met its primary endpoint of progression-free survival in the TIVO-1 pivotal trial, it looked worse than sorafenib in the final survival analysis. The investigational drug was associated with a 25% increased risk of death. Although this finding did not reach the level of statistical significance, FDA officials found it concerning and wanted Aveo to conduct a new study (Also see "Approval Or New Study? That’s The Question For Tivozanib Panel Review" - Pink Sheet, 30 Apr, 2013.).

“Multiple drugs have been approved for metastatic renal cell cancer, but none of them had this concerning issue,” Division of Oncology Products 1 Deputy Director Amna Ibrahim said at the ODAC meeting. “In fact, no approved oncology drug has raised this kind of concern for a detriment in survival in recent trials that served as a basis for … approval.”

Aveo attributed the adverse survival trend to the one-way crossover design and the large concentration of patients from Central and Eastern Europe, where access to targeted cancer therapies is limited (see related story (Also see "Aveo’s Tivozanib Troubles Reflect Perils Of Ex-U.S. Studies" - Pink Sheet, 6 May, 2013.)).

Attracting Patients Onto Study

Aveo Chief Medical Officer William Slichenmyer said crossover was not built into TIVO-1 as it was initially conceived and discussed with U.S. and European regulators.

“It was only after moving ahead towards implementation of the study, talking with investigators at study sites, that they said that they really wanted the study to be designed in a way so that all of their patients could have access to tivozanib,” Slichenmyer said. “It was in response to that, then, that we wrote the protocol for [extension] Study 902 to allow patients to receive the drug and cross over.”

However, FDA Office of Hematology and Oncology Products Director Richard Pazdur questioned the company’s rationale for the one-way design.

“Usually in a randomized study when you have a known effective therapy, such as sorafenib here, at the time of disease progression you would cross patients over that were on the experimental arm to receive the standard therapy because … you don’t have proof that the experimental drug has any activity,” he said. Pazdur questioned whether the trial investigators were “in equipoise when they were … making that decision.”

“From an ethical point of view, if one was talking about crossover, one would want to ensure that patients that were on an experimental drug received the standard therapy, not the flip situation,” Pazdur said.

“I wonder about the ethics of allowing the crossover only on one arm when … people in other countries are desperate for subsequent therapy,” ODAC Chair Sekeres said.

“That’s exactly the direction I was going with this,” ODAC Chairman Mikkael Sekeres, Cleveland Clinic, said. “You have the majority of your patients deriving from Eastern or Central Europe where the case has been made … that they may not have access to the standard therapies that we do in North America or Western Europe. And I wonder about the ethics of allowing the crossover only on one arm when, frankly, people in other countries are desperate for subsequent therapy.”

Robert Motzer, Memorial Sloan-Kettering Cancer Center, was the trial’s principal investigator and appeared at the advisory committee meeting on behalf of Aveo. He said that at the time the study was designed, there was a lot of investigator enthusiasm about tivozanib based upon Phase II data and what was known about the compound’s safety profile.

“With regard to people going on the study, we felt that since there were multiple treatment options available at the time – pazopanib [GlaxoSmithKline PLC’s Votrient], sunitinib [Pfizer Inc.’s Sutent], sorafenib – that one of the reasons that patients would choose to go on the trial when there’s multiple other options available would be to have access to tivozanib.”

“In retrospect, I think we at the company wish that the study had had a two-way crossover,” Aveo’s Slichenmyer said. “But at the time, based on what we knew, the decision was just to go ahead and make tivozanib available to all patients. … We did anticipate it might have a bit of an effect on improving the overall survival outcome of the patients in the control arm. We did not anticipate that that would be a bad thing.”

Committee members said they found the crossover design flawed.

Temporary voting member Marc Garnick, Harvard Medical School, said the study’s design was “simply inadequate, especially given that only one Phase III study has been conducted, and in the sponsor’s own words, the single Phase III study was a comparison of single-line therapy versus those who received two lines of therapy. How simple would it have been to provide, in a clinical study which must have cost millions of dollars to conduct, access to either sorafenib or sunitinib or any of the other TKIs for second-line therapy?”

Dodd said she would have “advised strongly against crossover, and if it was deemed absolutely necessary from an ethics perspective then I would have recommended against allowing a one-way crossover. This saddens me because we want to speed up the drug development process, but when a trial is poorly conducted we get fuzzy answers.”

Despite Slichenmyer’s acknowledgement that a two-way crossover may have been more appropriate, Aveo President and CEO Tuan Ha-Ngoc defended the trial’s design during a brief conference call after the ODAC meeting.

“We are very disappointed with the outcome and strongly disagree with the views expressed today by members of the advisory committee,” he said. “Although we recognized that the confounding nature of the crossover would be the … topic for discussions at ODAC, we were dismayed by the sentiments expressed today by members of the panel.”

The study was designed in collaboration with key opinion leaders in the renal cell carcinoma field, and the PFS primary endpoint, which has served as the basis of approval for all other TKIs in this indication, was achieved, Ha-Ngoc said.