Relapse survey: Is bigger dose better?

Fewer year-plus patients on larger Gleevec doses experience relapse

A majority of GIST patients on Gleevec for more than a year continue to do well. For those whose cancer becomes resistant to Gleevec, a few new drugs are in development.

Those were two of the key points made March 31 when a quartet of Life Raft Group members traveled to the Novartis Oncology office in Florham Park, New Jersey, U.S.A.

The meeting began with a ceremony inducting the 10 participating Novartis officials as “honorary” members of the Life Raft Group. Each Novartis participant was given one of the new Life Raft Group pins.

Norman Scherzer, the Life Raft’s executive director, then led a review of the Life Raft’s informal relapse poll that surveyed members with metastatic GIST have been treated with Gleevec for more than a year, and who experienced tumor shrinkage.

Those Life Rafters reporting relapses after initial tumor shrinkage numbered 18, while 65 reported continued stability while on Gleevec, said Scherzer. Also, the informal survey indicated that the higher the dosage, the less likely the chance of relapse.

• Of those who started and stayed on 800 mg. Gleevec, only one person reported disease progression.
• Of those who started at 800 mg. and had their dose reduced to 600 mg., four relapsed.
• Of those who started at either 800 or 600 mg and had their dosage reduced to 400 mg, five patients relapsed.
• Of those who started and stayed on 600 mg., no relapses were reported.
• Of those who started and stayed on 400 mg., eight relapsed.

“The consensus of the meeting participants was that the relapse group was too small — thank God — to draw firm conclusions,” Scherzer commented after the meeting. Instead, he said, “the data should be considered preliminary and used to raise sensitivity levels to possible correlations, rather than to draw any conclusions at this time.”

Nonetheless, it may be prudent if a patient is on 600 mg. or above, and not having significant difficulty with side effects, to remain at that dosage until more is learned about long-term drug effectiveness.

There was a discussion about whether GIST should be treated with a traditional cancer treatment paradigm — which utilizes the maximum tolerated dosage — or continue to follow the clinical medicine paradigm — which utilizes the minimum dose needed to produce a result. There was no consensus other than any approach needs to consider individual needs.

An interesting focus of the Life Raft Group analysis was that 46 percent of all patients responding reported one or more dosage changes. That raised the issue of whether such changes are factored in by clinical researchers when they compile their reports and analyses. The answer: Generally not. Researchers usually follow the U.S. Food and Drug Administration rule that calls for reporting by the “initial intent to deliver dose” — the starting dosage. There was a developing consensus at the meeting that this approach should be reconsidered.

Other Drugs:

The Novartis RAD trial is for GIST patients not responding to Gleevec. The trial calls for 600 mg. of Gleevec plus the new RAD drug given daily RAD is similar to another drug called Rapamycin (or Rapamune), made by Wyeth.

The trial started last fall in Belgium with seven patients. One was removed from the trial for a lack of response while six patients remain on the trial and it can be surmised that they are at least stable. A second trial for six patients will soon begin at Dana-Farber Cancer Institute in Boston. This is another new Novartis drug, PKC412, that is expected to go into clinical trials within the next year if nothing untoward develops during pretrial research. This drug will be given along with 600 mg. of Gleevec. Next in the Novartis pipeline is PTK787, another drug which targets C-Kit.

These drugs are in addition to the new Sugen drug for GIST patients resistant to Gleevec, now in phase l trials at Dana-Farber and at Memorial Sloan-Kettering in New York City.