Treatment > OSI-774 · Temozolomide Clinical Trials

Meeting Abstract

Phase I study of OSI-774 alone or with temozolomide in patients with malignant glioma

M. Prados, S. Chang, E. Burton, A. Kapadia, J. Rabbitt, M. Page, A. Federoff, S. Kelly, G. Fyfe

Univ of California San Francisco, San Francisco, CA; Genentech, Inc., South San Francisco, CA

Purpose. To evaluate the toxicity and PK of OSI-774 in pts with malignant glioma (MG).
Pts were stratified based upon the use of enzyme inducing antiepileptic drugs (EIAED).

Methods. Pts with stable or progressive MG were treated with OSI-774 starting at 100 mg/day.
Pts could also receive temozolomide if not used prior to OSI or they had not progressed with prior exposure.
OSI-774 began 7 days prior to temozolomide (dose: 150 mg/m2/day x 5 q 28, up to 200 mg/m2).
OSI-774 was increased by 50/day by treatment group until DLT occured.
DLT included any non-heme grade-3 or grade 4 heme toxicity during the first 2 wks of OSI-774.
There were 4 pts groups: Group A (no EIAED) on OSI-774 or OSI-774/temozolomide, and Group B (on EIAED) on OSI-774 or OSI-774/temozolomide.
Intra-patient dose escalation was allowed.
Pts treated at progression were evaluated for response with MRI q 2 months.

Results. 47 pts enrolled as of 11/15/02, 26 males/21 females, median age 50.1 yrs; 38 with glioblastoma multiforme, 9 with grade 3 tumors; 37 treated at relapse, 10 treated with stable disease.
Current OSI-774 dose levels are: Group A OSI-774 alone 250 mg/day; OSI-774/temozolomide 200 mg/day; Group B OSI-774 alone 450 mg/day; OSI-774/temozolomide 350 mg/day.
MTD has not been reached.
DLTs have occurred at 150 mg (1 pt with hyponatremia; 1 pt with nausea/dehydration) and 400 mg (1 pt, rash).
Dose escalation continues in all 4 groups.
Preliminary PK results done day 8 cycle 1 suggest that exposure to OSI-774 and its active metabolite are markedly reduced (~50-75%) when given in combination with EIAEDs or EIAEDs + temozolomide.
MRI response was evaluated in 25/37 pts with progressive disease (6 too early, 6 with clinical progression) with 6 partial responses (4 GBM, 1 grade 3 treated with OSI-774 alone, 1 GBM with OSI-774/temozolomide), 2 minor responses, and 3 stable disease.

Conclusion. Accrual continues in all 4 groups.
Toxicity is acceptable at the current doses of OSI-774, and PK results show decreased exposure to OSI-774 and its active metabolite due to EIAED use.
Objective responses are very encouraging.
Prior tumor EGFR status analysis is ongoing.
A phase-2 study will commence after the phase-1 study is complete.

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