Novartis Scientists Review Status of Drugs in Pipeline

On November 8th Life Raft Group Executive Director Norman Scherzer sat down with 15 key officials and scientists at Novartis Worldwide Oncology headquarters in New Jersey to discuss the status of Novartis drugs that might have applicability to the treatment of GIST patients. Present at this meeting were:

Pamela Barckett, LRG Med. Rsch. Asst.; Sarah Boyce, Gleevec Brand Director U.S.; Pamela Cohen, Global Leader PKC412; Heather Duncan, Director New Product Commercialization; Leslie Fields, Patient Advocacy Relations; Sushant Harkiker, Assoc. Director RAD Clinical Research; Barbara Kennedy, Exec. Director Oncology Scientific Operations; Kalvin Kochhar, Assoc. Director Glivec Global Marketing; Mildred Kowalski, Assoc. Director Patient Advocacy Relations; Tracey Lawhon, Intern. Proj. Team Leader AMN107; Laurie Letvak Glivec, Global Medical Affairs; Karen McDougal, Clinical Research Mgr. Gleevec; Hugh O’Dowd, Global Brand Leader Gleevic; Inga Sams, Assoc. Dir Gleevec Phase 1V; Norman Scherzer, LRG Exec. Director; Johanna Shulman, Sr. Product Mgr Gleevec; Gloria Stone, Global Communications; Lei Zhang, Assoc. Director PKC Team.

This level of openness and trust on the part of a pharmaceutical company is quite something extraordinary. Discussions went on for two hours and covered five Novartis drugs, including four adjuvant Gleevec trials. This summary will cover only the four non FDA approved Novartis drugs. We will cover the ongoing adjuvant and neo-adjuvant Gleevec trials in a future edition of this Newsletter.

RAD001 (Everlolimus) Protocol number CRAD001C2206

RAD is an oral mTOR-inhibitor. It is given in combination with Gleevec to GIST patients resistant to Gleevec. This study is currently in phase l with patients at 5mg per day of RAD plus 600 mg of Gleevec. There are 4 centers in Europe (Germany-2 sites; France and Belgium) and 1 in the U.S. (Dana- Farber). There have been two phase l cohorts: Each group was given 600 mg of Gleevec. In addition, one group of 13 was given a weekly dose of 20 mg-all 13 progressed and 0 are ongoing. A second group of 13 was given a daily dosage of 5mg-1 has responded, 7 have progressed, and 6 are ongoing.

PKC412 Protocol number CPKC412A2211

PKC412 is an inhibitor of protein kinase C (PKC). The PKC family consists of at least 12 isoforms of serine/ threonine kinases that play a major role in signal transduction. It has been shown that PKC inhibitors can also reduce tumor angiogenesis. PKC412 is a very active and more selective derivative of the PKC inhibitor staurosporine. It is given in combination with Gleevec to GIST patients resistant to Gleevec. There are two sites, one in Berlin, Germany and one in Portland Oregon.

The first part of this phase l trial had daily doses of 100 mg PKC412 plus 600 mg Gleevec-this part is closed-all 12 patients are off the study. 8 of the 12 patients had partial progression due at least in part to Gleevec levels being lowered by the interaction with PKC412. The study was then amended.

The amended part of this phase l trial has 3 cohorts: Patients need to be stable on 800 mg of Gleevec for at least 2 months before starting combination treatment. This is a dose escalation trial starting at 200mg of PKC412 per day plus three dose levels of Gleevec, 1000mg per day, 1200 mg per day and 1500mg per day. Planned enrollment is up to 18 patients. There is no wash out period (that is, do not have to stop Gleevec prior to starting the trial). The dosage of PKC412 was initially decreased to 50mg per day and the dosage of Gleevec was then increased from 800 to 1000 per day. 7 patients were enrolled-at cycle four, 2 have dropped out, 2 have stable disease and 3 have partial progression.

This combination drug trial has been quite an ordeal with unexpected and striking interactions between PKC412 and Gleevec. This is demonstrated by the intent to put patients on up to 1500mg of Gleevec per day along with PKC412 because the expected “actual” level of Gleevec will be far below that amount. The interaction of these drugs is good reason to be particularly cautious about early phase l trials.

AMN107

This new drug has been high on the rumor circuit and has aroused great interest. It is currently in a phase l trial for chronic myelogenous leukemia (cml) with promising results. It is planned to be in a combination trial with Gleevec for Gleevec resistant GIST patients in 2005.

PTK787:

We briefly discussed PTK787 but no new information was learned. This drug is not yet in trial for GIST patients.

By Norman Scherzer