Clinical trials target resistant GIST

By Jerry Call

SUTENT

Study of SU011248 Administered In A Daily Regimen In Patients With Gastrointestinal Stromal Tumor

As previously reported, Pfizer has submitted a new drug application for Sutent (sunitinib malate) to the Food and Drug Administration. Pfizer is seeking FDA approval for Sutent in the treatment of GISTs and renal cell carcinoma among patients whose tumors do not respond to or do not tolerate standard treatment.

Sutent belongs to the new class of cancer drugs known as signal transduction inhibitors. More specifically, it is a “tyrosine kinase inhibitor”. There are a number of tyrosine kinase inhibitors that have been approved for use or are in clinical trials. Gleevec was the first to be approved and is the most widely recognized drug in this class.

Most tyrosine kinase inhibitors, such as Gleevec, are oral drugs that are given daily on a continuous basis. In contrast, the new drug application for Sutent for GIST patients was based on phase III trials where patients took Sutent for four weeks, then stopped the drug for two weeks and repeated this cycle as long as they received benefit from the drug. The dose for the phase III trials was 50 mg/day as long as the patient tolerated that dose.

Some doctors and researchers have wondered whether Sutent might be more effective if given on a continuous basis instead of the four week on drug/two week off drug cycle. A new phase II trial for GIST patients is now open at Dana-Farber Cancer Institute to begin to examine this question. The trial will also examine the feasibility of giving Sutent on a continuous basis. Our understanding is that the dose chosen for evaluation will be 37.5 mg/ day.

This trial is for patients that have failed Gleevec therapy, or are intolerant to Gleevec, and who have not previously tried Sutent. Patients can contact EmergingMed at 1-800-620-6104 (U.S.) or 1-877-416-6248 (international number) for more information.

BAY 43-9006

A Phase II trial of BAY 43-9006 for GIST patients that have failed Gleevec

The University of Chicago has opened a phase II trial of BAY 43- 9006 for GIST patients that have failed Gleevec. We understand that several other centers will also participate in this trial. As we go to press, we are aware of Memorial Sloan-Kettering and Duke. For further information check our website: www.liferaftgroup.org.

BAY 43-9006 is a tyrosine kinase inhibitor that is being produced by Bayer Pharmaceuticals Corporation in a partnership with Onyx Pharmaceuticals Inc. BAY 43-9006 is perhaps best known as a potent inhibitor of RAF kinases. RAF is an important kinase in the MAPK pathway. BAY 43-9006 also inhibits several other kinases including KIT, VEGFR-2, VEGFR-3, PDGRF-β, FLT3, and RET. Inhibition of KIT signaling provides a direct antitumor effect in most GIST tumors inhibition of VEGF receptors and PDGFR-β provide antiangiogenesis effects (similar to Sutent). Since RAF is downstream of KIT, inhibition of RAF might also contribute an antitumor effect.

Many tyrosine kinase inhibitors are being evaluated in more than one cancer. Bay 43-9006 and Sutent have both been evaluated in Phase III trials for patients with advanced renal cell carcinoma (kidney cancer). In July, 2005, Bayer and Onyx submitted a New Drug Application (NDA) for sorafenib (BAY 43-9006) for patients with advanced renal cell carcinoma (kidney cancer). This was followed by a September announcement that it had been accepted for review and granted Priority Review status by the U.S. Food and Drug Administration. Our understanding is that the drug will be called Nexavar.

Dr. Hedy Kindler is in charge of GIST research at the University of Chicago. She is the Director of Gastrointestinal Oncology at the university. Those interested in an appointment at the University of Chicago can call the intake coordinator at 773-834-7424. Those interested in information about the trial can contact Pam Lofton at 773-702-2036.

AMN107 + Gleevec

Phase I Study of AMN107 with Imatinib in Gastrointestinal Stromal Tumors (GIST)

We have previously reported the opening of a phase I/II trial combining AMN107 and Gleevec. Our understanding is that this trial is moving along well.

This is a dose escalation trial to determine the maximum tolerated dose of the combination. Below is our understanding of the intended dose escalation cohorts. This is subject to change/modification as information about the combination is obtained.

The first 6 patients will in fact receive 800mg of AMN107 (400mg twice a day)

The next group will receive 200mg of AMN107 plus 800mg of Gleevec

The next group will receive 400mg of AMN107 plus 800mg of Gleevec

The next group will receive 800mg of AMN107 plus 800mg of Gleevec

The first cohort (800mg of AMN107) of this trial has filled and patients are now being placed into the second cohort (200mgAMN107 plus 800mg Gleevec).

This trial is an early phase trial with a limited number of slots (currently 35 slots). We understand that there is a waiting list at trial centers.

Dana-Farber and Fox Chase are working together to provide the best possible access to U.S. Patients. In Europe, the trial sites are:
• Peter Reichardt, Berlin, Germany
• Paolo Giovanni Casali, Milan Italy
• J.Y. Blay, Lyon France
• P. Schöffski, Leuven Belgium

U.S. patients wanting more information can contact Travis Quigley at Dana Farber at 617-632-5117 or Monica Davey at Fox Chase at 215- 728-5534.