Many drugs coming for Gleevec-resistant GIST

Pharma scientists open doors to Life Raft Group

By Norman Scherzer LRG executive director

During the past month the Life Raft Group has had discussions with several pharmaceutical companies in an ongoing effort to monitor the progress of new and potential treatments for GIST.

Recognition is due Amgen, Ariad, Bristol- Myers Squibb and Novartis for making their key scientists available, for displaying courtesy and respect to Life Raft inquiries, and for continuing their efforts to find new drugs to overcome Gleevec resistance. Thanks is also due to many GIST specialists who spoke both on and off the record.

AMGEN

Amgen continues to recruit patients for its phase II trial of AMG706 for patients with Gleevec-resistant GIST.Although the Life Raft Group is monitoring the efficacy of this trial drug, there has not been enough time to responsibly report on this. AMG706 targets three known GIST receptors: c-kit, PDGFRA and VEGFR. One question was whether the six-hour half-life of a 125 mg. daily dose of AMG706 is sufficient to inhibit kit. LRG representatives were assured that it was, both at a March 2 meeting with Dr. Daniel Stepan and Tuomo Patsi at the LRG office, and in a follow-up meeting with PK expert Dr. Shekman Wang. LRG science coordinator Jerry Call in Colorado participated in both meetings via teleconference. Our understanding is that the minimum AMG706 concentration is expected to be about 1.5 to 3 times the amount needed to inhibit kit.

The short half-life is said to be able to reach its concentration level more quickly and provide a safety margin if a patient must stop the medication due to toxicity. It is important to take the drug at the same time each day — on an empty stomach — and to be vigilant in not skipping doses.

As VEGF inhibitors are known to increase the possibility of hypertension, Amgen made frequent blood pressure checks part of its protocol. In response to patient concerns about having to travel back and forth to the trial site to have this done, Amgen is arranging for a visiting nurse to do this at the patient’s home if they live far from the trial site.

Also discussed were such possibilities as testing AMG706 at a greater dosage, such as 150 mg., and comparing AMG706 to SU11248 in a headto- head trial.

ARIAD

We recently spoke to Dr. Camille Bedrosian, ARIAD chief medical officer, about the clinical trial status of a drug called AP23573. We expressed our concern that a phase II trial for sarcoma had been started but that it excluded GIST patients. This trial is enrolling 170 patients from four cohorts: leiomyosarcoma, liposarcoma, bone sarcoma and other sarcomas. AP23573 is an I.V. drug that is given for five days followed by a nine-day break.

We were told that ARIAD believes GIST should have a separate trial and that they were still considering this. ARIAD has also committed to having an oral version of AP23573 by June 30, 2005. Therefore, if there is a trial for GIST, it would likely include this oral drug.

BRISTOL-MYERS SQUIBB

I traveled to the Bristol-Myers Squibb’s pharmaceutical headquarters in Princeton, New Jersey, to meet several officials. Participating via teleconference was the LRG’s Jerry Call, and Dr. Claude Nicaise Bristol-Myer Squibb’s vice-president for oncology global marketing, Worldwide Medicines Group. Nicaise is the clinical lead person for BMS354825.

BMS354825 is in phase I clinical trial for sarcoma at Dana-Farber Cancer Institute in Boston, and in Scotland. Most of the Dana-Farber patients have Gleevec- and SU11248-resistant GIST; most of the Scotland patients do not have GIST at all. This is a dose escalation trial. The current dose is 120 mg. twice a day for five days followed by a two-day break. Compared to the experience of chronic myelogenous leukemia patients in earlier trials, some speculated that GIST patients might require a higher dose because of different sensitivity of the target proteins. The current phase II trial for CML uses a dose of 140 mg. per day.

Plans are underway for a phase II GIST trial and consideration is also being given to administering this drug on a continuous basis as opposed to the five-day-on, two-day-off schedule.

The costs of travel and lodging for patients that do not live in the Boston area were discussed. BMS officials said they’re working with Cancer Care to try to provide some assistance. Also discussed was the frequency of EKG tests and, particularly, that these tests must be done in Boston. We asked BMS to consider allowing such tests to be done near the patient’s home. As was the case with Amgen, we brainstormed other trial possibilities, including combining it with Gleevec.

NOVARTIS

March 14, I traveled to Novartis Oncology in Florham Park, New Jersey to meet with several officials; Jerry Call again joined from Colorado via teleconference. There were also several follow-up discussions over the next several days to address issues regarding AMN107. More than 15 different Novartis officials participated in these discussions.

Adjuvant Gleevec: Dr. Laurie Letvak, Novartis Global Medical Affairs, reviewed the status of four adjuvant clinical trials. These trials range from one to three years and address different risk groups, but all patients take 400 mg. of Gleevec. We expressed concern that these trials do not address higher dosage levels and briefly discussed plans of the Life Raft Group to conduct its own study — retrospective rather than randomized — of preventive treatment that considers higher dosage levels.

PKC412: Dr. Pamela Cohen, PKC clinical team lead, reviewed this trial. As previously reported, this combination Gleevec+PKC412 trial has taken some time to work out due to the interaction of the two drugs. Basically, higher doses of Gleevec are needed to offset this interaction. Although it’s still too early to draw solid conclusions, there are reports of stable disease. Jerry Call explores PKC412 in this newsletter.

RAD: Dr. David Lebwohl, RAD clinical team lead, reviewed this trial, which seems to be progressing very slowly. RAD, an mtor inhibitor, is given along with 600 mg. of Gleevec. There are three trial sites, in Boston, Berlin and Belgium.

AMN107: Dr. M. Luisa Veronese, AMN107-GIST clinical team lead based in Basel, Switzerland, reported on this trial in a series of communications following the meeting. The protocol had been delayed but at last report had received all internal scientific approvals and is expected to be at trial sites very soon.

The protocol calls for a phase I trial. The first part will have just six patients taking 400 mg. of AMN107 twice a day. The second part will combine AMN107 and Gleevec. This will be a dose escalation trial combining 800 mg. of Gleevec with 200 mg. of AMN107 in the first cohort, with 400 mg. of AMN107 in the second cohort, and with 800 mg. of AMN107 in the third. All three cohorts will have three patients.

There may be a simultaneous cohort of six patients who had disease progression on 600 mg. Gleevec and were intolerant of 800 mg. Gleevec. These patients would take 400 mg. AMN107 twice a day.

Gleevec-resistant patients will be accepted regardless of whether they have tried other drugs.

The Life Raft Group has learned this trial may be available at Dana-Farber and Fox Chase Cancer Center in Philadelphia, and in Belgium, France, Germany, Italy, and the Netherlands. These sites are subject to change.