This week, (10th February) the FDA's Oncologic Drugs Advisory Committee will be meeting to review the filings from Cell Therapeutics ($CTIC) and ChemGenix ($CXSPY) for pixantrone and omacetaxine, in relapsed refractory NHL and CML, respectively.
I've just taken a few minutes to read the briefing documents and here are my initial thoughts.
Cell Therapeutics, a Seattle based biotech company, are going to have a very tough morning on Wednesday in DC for the following reasons:
- The pivotal study had a very poor accrual with only 140 out of 320 patients enrolled.
- Substantial cardiac and hematologic toxicities.
Risk:benefit trade-offs are always going to be a question for debate in the third-line setting, but CTI may well have shot themselves in the foot by closing enrollment early. This led the FDA to raise an important question about the study and whether there was sufficient information:
"the level of evidence necessary to draw conclusions from this Phase 3 study and the reliability of these conclusions."
After recent trials and tribulations over studies in elderly patients with AML had problems with a placebo comparator, it was good to see that in PIX301, patients were randomized 1:1 to single agent pixantrone or the following choice of comparators:
- Etoposide (PO/IV)
- Gemcitabine (only at U.S. sites)
- Rituximab (only at U.S. sites)
Patients were treated for up to 6 cycles.
However, perhaps the most damning part of the FDA briefing document is the impact of halting enrollment early:
"The pivotal trial, PIX301, was discussed at an End of Phase 2 meeting on October 8, 2003. At this meeting, FDA stated, “Accelerated approval could be based on an interim analysis of a surrogate endpoint with completion of the trial demonstrating an improvement on a clinical benefit endpoint (survival or symptom benefit).”
FDA recommended that the trial assess complete response and the duration of complete response. Subsequently, agreement was reached concerning a Special Protocol Assessment for PIX301.
On March 28, 2008, CTI notified the FDA of an early halt to enrollment for PIX301. The study was not stopped at a planned interim analysis and early study stopping invalidated the applicant’s Special Protocol Assessment."
Based on this history, I think CTI will have a tough time arguing for approval on the basis of a shortened 140 patient study. It is clear in the FDA's analysis that they do not believe statistical significance was reached for the key efficacy measures.
Meanwhile, ChemGenex, a biotech company based in Australia with an office in San Francisco, are applying for approval of omacetaxine (Omapro) as treatment of adults with chronic myeloid leukemia (CML) who have failed prior therapy with imatinib and have the Bcr-Abl T315I mutation.
Interestingly, the FDA had completely different concerns with this filing.
The main issue with omacetaxine was that a commercially available assay does not exist for the T315i mutation and the company apparently didn't submit any information on how they were going to address this going forward. It's one thing to have central labs and academic labs do testing for trials, but given the majority of CML patients are seen by community oncologists in the US, a commercial assay is crucial for enabling decisions to be made on when to start therapy if the T315i mutation appears.
I would be surprised if a such a test hasn't been considered, but we will see what happens at ODAC on Wednesday. Approval may possibly be delayed until one is made available.