Medarex/BMS Working To Shift Ipilimumab Trial Endpoint

Overall survival is more valid than freedom from progression in Phase III melanoma trial, firm says.

Medarex took pains to differentiate its CTLA-4 immunotherapy ipilimumab from Pfizer's failed tremelimumab during a July 10 R&D update.

Ipilimumab, a fully human cytotoxic T lymphocyte-associated antigen-4 antibody partnered with Bristol-Myers Squibb, is in Phase III testing as a first-line therapy for advanced melanoma.

Medarex, in Princeton, N.J., expects FDA feedback this quarter on a protocol change that would allow a switch from progression-free survival to overall survival as the primary endpoint on the study.

The goal is to analyze trial data in the second half of 2009, though the timeline could be more protracted, depending on the results, executives said during the R&D presentation.

New York-based BMS and Medarex had planned an ipilimumab BLA for mid-year based on results from earlier trials in second-line melanoma, but shifted their timeline to await the Phase III front-line data (¹ (Also see "Medarex, BMS Stall Ipilimumab’s BLA" - Pink Sheet, 25 Apr, 2008.)).

Phase II studies of the drug as a second-line treatment, released at the American Society of Clinical Oncology meeting last month, showed an intense 10 mg dosing regimen was ideal. The studies also indicate the antibody boosted survival by 6 percent to 16 percent in the initial phase of therapy and worked twice as well when delayed responses were taken into account (² (Also see "Bristol/Medarex’s Ipilimumab Toxic, But Could Extend Life" - Pink Sheet, 2 Jun, 2008.)).

The timing of the response assessment and the definition of response for immunotherapy need to be different from those used for standard cytotoxic chemotherapies, Jedd Wolchok, director of immunotherapy clinical trials at the Memorial Sloan-Kettering Cancer Center said during the R&D day.

"We're not saying that you need to rearrange the rules. We're saying that you need to look at the only thing that matters - overall survival," he said.

Rather than directly killing the tumor, ipilimumab allows the immune system to more easily recognize the tumor and then kill it, a process that takes time, he explained. In some cases, progression of tumors is seen prior to response, so short-term radiographic assessment may not be appropriate.

"Doing a conventional CT scan at 12 weeks does not capture the activity of this drug," Wolchok said.

Ipilimumab is unlikely to face the same fate as Pfizer's CTLA-4 inhibitor tremelimumab, which recently failed to show a benefit over standard chemotherapy in a Phase III trial, the company stressed (³ (Also see "Weak Result Stops Pfizer’s Tremelimumab Phase III Trial" - Pink Sheet, 2 Apr, 2008.)).

Medarex is testing an IgG1 subtype, whereas the Pfizer antibody is an IgG2 subtype, Wolchok pointed out. "These are different antibodies," he said.

Dosing regimens for the two are different, and there are important differences in first-line trial design that could have a strong influence on outcomes. For example, the tremelimumab trial excluded the worst-performing patients, which could have skewed survival results, Medarex theorizes.

"We've had a chance to look at the Pfizer experience and digest that with experts and with BMS," Geoff Nichol, senior vice president of product development, said. "We feel that our study and our dose regimen have set us in a good place by comparison. We and BMS remain strongly committed to a broad development program with ipilimumab."

Based on other data presented at last month's ASCO meeting, ipilimumab seems to have a similar effect in prostate cancer as in melanoma.

"We have great encouragement to move forward to a Phase III study in second-line prostate cancer. That study is being written, planned and negotiated with the FDA as we speak," Nichol said.

Medarex anticipates enrolling patients late this year or early in 2009.

A Phase II study of ipilimumab with standard care therapy in advanced lung cancer also recently got under way.

Meanwhile, the firm is planning to file two new INDs every year. The antibody furthest along in development targets the CXCR4 receptor, which is overexpressed in leukemias, lymphomas and multiple myeloma as well as in cancers of the lung, pancreas, breast, ovaries and colon.

Medarex is planning an IND at the start of 2009 and begin a Phase I trial in relapsed or refractory leukemias thereafter, said Nils Lonberg, senior vice president and scientific officer.

The firm is also progressing in research with antibody drug conjugates, cytotoxic agents chemically linked to antibodies, which allow better targeting of chemotherapy to diseased tissue.

The concept has been around for 40 years, but the field has not achieved much success in generating marketed products, Lonberg said. Medarex says it has found ways to overcome stumbling blocks.

"We have been very good students and have learned from the history of antibody drug conjugates," he said.

- Emily Hayes ([email protected])