Update on new drugs with GIST potential

Pfizer’s SU11248 is still the only one with a track record of success

By Jerry Call and Norman Scherzer

Recent newsletters have reported on the growing list of drugs that Gleevecresistant GIST patients may turn to. This is an update. For the latest information, GIST patients should consider joining the Life Raft Group, and both patients and GIST physicians should regularly check the Life Raft Web site at www.liferaftgroup.org

SU11248: The phase III trial for Pfizer’s Sugen drug (SU11248) continues to enroll patients around the United States and abroad. This is the only drug that has a track record of success for Gleevec-resistant GIST patients. About 60 percent of patients enrolled so far show some benefit, mostly stability. The trial has generated considerable controversy because patients must discontinue Gleevec for at least two weeks prior to starting the trial, and because a third of the patients receive a placebo.

SU11248: Inhibits KIT, PDGFRA, VEGFR, FLT3; simultaneously inhibition of multiple signaling pathways may be important for controlling resistant GIST; could interact differently with structural variants of new kinase mutants in GIST clones resistant to Gleevec.

AMG706: Amgen’s AMG706 is projected to begin phase II clinical trials, starting in the United States, in about a month. It is expected that there will be about 20 sites in the United States and 10 sites in other countries. Three known U.S. sites are M.D. Anderson Cancer Center in Houston, University of Michigan in Detroit and Northwestern University in Chicago.

In the interim, the Life Raft Group has been advised that there are still some slots for the phase I AMG706 trial at M.D. Anderson. This phase I trial was recently amended to add four to eight weeks. Sugen-resistant GIST patients are eligible for the phase l trial.

Note: Although Sugen-resistant GIST patients will not be eligible for the phase II Amgen trial, there is no data to support the assumption that patients won’t respond to AMG706 because of similarities between the two drugs.

SU11248 is administered in a cycle of four weeks on and two weeks off. AMG706 is administered daily. While the targets of AMG706 may be similar to SU11248, the drugs may have entirely different activity profiles. One drug may work better on one type of mutation while the other might work better on another type. At this point, which type AMG706 might work on is unknown.

PKC412: Novartis’ phase l trial for PKC412 plus Gleevec has begun at Oregon Health & Sciences University and in Berlin.

PKC412: Inhibits more targets than Gleevec; inhibits PKC (which isoforms of PKC is unknown), KIT, VEGFR, FLT3; requires a higher dose of Gleevec due to interactions between Gleevec and PKC412; may be a choice for some PDGFRA mutations.

BMS354825: A phase I trial for Bristol-Myers Squibb’s BMS354825 has begun at Dana-Farber Cancer Institute in Boston and at Glasgow University in Glasgow, Scotland. Very few slots are available for GIST patients. Incredible results have been reported for Gleevec-resistant chronic myelogenous leukemia patients (see Page 1) and this drug is very high on the Life Raft’s radar. This drug inhibits KIT, PDGFRA, Src, and Bcr-Abl.

AP23573: ARIAD’s AP23573 continues in phase I clinical trials at University of Texas in San Antonio and University of Chicago Medical Center. Life Raft representatives will meet with ARIAD officials in a few days to discuss expanded trials for GIST. Also of interest is a second ARIAD drug, AP23464.

17DMAG: In this newsletter the Life Raft adds a new drug to the list. It is 17DMAG, made by InvivoGen. A phase I trial for prostate cancer patients at Memorial Sloan-Kettering is expected, but the Life Raft is seeing if GIST patients can be included.

17DMAG: Is an improved version of 17AAG; has improved bioavailability; inhibits HSP90and multiple proteins that might be involved in cancer including AKT, and possibly some types of KIT mutations that are resistant to Gleevec.

G3139: Genta’s long-awaited phase II trial of G3139 (Gentasense) plus Gleevec has been put on hold. It is expected to take place at M.D. Anderson, Dana-Farber, University of Michigan, Memorial Sloan-Kettering, and the Mayo Clinic.

Gentasense: Is an antisense drug that targets mRNA for bcl-2. This reduces the production of bcl-2 protein, which acts to prevent apoptosis (cell death).

The Life Raft aims to monitor other potential drugs, including Novartis’ RAD001 plus Gleevec, Gleevec plus Avastin (Bevacizumab), Abbot’s ABT869, Bayer’s BAY439006, AB Science’s new drug in France, and Kirin’s KRN951.