Novartis told of Gleevec tablet side effects

Life Raft, pharmaceutical giant share information in ongoing war on GIST

Novartis agrees further investigation is warranted into the side effects being experienced by patients as they switch from Gleevec capsules to the new tablets.

That was one of several points made during a Jan. 15 meeting between representatives of the Life Raft Group and Novartis.

Jerry Call, the Life Raft Group’s science coordinator, and Norman Scherzer, executive director, visited Novartis Oncology headquarters in Florham Park, N.J. The meeting marked the continuation of a dialogue that has been going on for more than a year and a half.

Novartis was represented in person and by teleconference from throughout the United States and Novartis corporate headquarters in Basel, Switzerland by Barbara Kennedy , executive director, Oncology Scientific Operations; Dr. Nicholas Shand, Oncology Clinical Research in Basel; Anna Tsyrlova, Ph.D., senior clinical research scientist and global PKC412 clinical trial leader in Basel; Geoffrey Cook , director, U.S. Public Relations; Dr. Laurie Letvak, global brand medical director for Glivec; Dr. Pamela Cohen, executive director, PKC412; Alan Yap, Ph.D., senior clinical research scientist, PKC412; Dr. Bin Peng, Ph.D., senior clinical lead pharmacokineticist, and Ron Linnartz, clinical development, RAD.

The meeting began with a presentation by the Life Raft Group about side effects (nausea, vomiting) GIST patients have encountered when switching from Gleevec capsules to tablets. Novartis noted that they had received a few reports from both GIST and CML patients but have not yet determined any reason for this. Dissolution rates for the capsules and the tablets were checked and found to be the same. Novartis also clarified that there was only one production source for Gleevec, at their facility in Ireland.

Other than suggesting that patients having problems with the 400 mg. tablets switch to four 100 mg. tablets, there were no other clear answers. Novartis volunteered that further investigation was needed. It was suggested that patients could try dissolving the tablets in either apple juice or water - approximately 50 mL (1/4 cup) for each 100 mg. tablet or 200 mL (3/4 cup) for a 400 mg. tablet.

The Life Raft Group then offered the following key points on clinical trials:
— GIST patients join clinical trials to survive: Although that may seem obvious, once stated, it is the principal prism through which patients view the clinical trial landscape.
— Patient enrollment in clinical trials can be facilitated by timely information, geographic accessibility, and financial accessibility.
— Trial coordination needs to be strengthened, particularly with regard to standardizing data designs between trials.

Strategic Suggestion:

The LRG suggested getting patients into Gleevec “combination” trials at an earlier stage. The rational is that for at least one class of drugs, the results of adding the second drug may be enhanced if tumors still retain sensitivity to Gleevec.

Jerry Call submitted that Gleevec resistance paradigms provide a possible window of opportunity. That the lower the resistance to Gleevec, the more likely the addition of a second drug — to which Gleevec is sensitive — will yield synergistic activity.

Some Life Raft Group recommendations: Get patients into Gleevec combination trials early, allow “stable” patients to enter, and to not set the bar for progression too high. Further, to not require progression at higher doses (or to not require progression at all), to drop the use of RECIST criteria and to incorporate resistance testing (when this becomes feasible).

Novartis made a few points for the current standard of requiring progression before allowing patients to enter combination trials, citing that it is easier to gauge the results of the second drug in a tumor that you know is resistant (growing) versus in a stable patient. Further discussions are planned.

Novartis then briefed us on two combination clinical trials for GIST.

PKC412 plus Gleevec:

Phase II trials are underway in Berlin, Germany and at Oregon Health & Sciences University in Portland. Patients must be on 600 mg. (or more) Gleevec for at least two months prior to entry into the trial — although there may be exceptions for patients who demonstrate significant progression prior to two months.

RAD001 (RAD) plus Gleevec:

Phase I trials are ongoing but a change is being made in the dosing schedule from 20 mg. every eight days to a daily dose escalation (from 2.5 mg. to 10 mg.). A strong interaction was noted between Gleevec and RAD. Gleevec inhibits CYP3A4, which causes metabolism of RAD to be inhibited. This typically caused a three-to five-fold increase in RAD concentrations. Thus 2.5 mg. per day would be equivalent to at least 7.5 mg.

There will be four clinical trial locations: Lyon, France; Berlin, Germany; Leuven, Belgium, and Boston, U.S.A.