In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 27, No. 15_suppl ( 2009-05-20), p. e13004-e13004
Abstract:
e13004 Background: Ras plays a crucial role in the control of cellular proliferation and differentiation. Farnesylation is an essential step in the post-translational processing of Ras. SCH 66336 inhibits farnesyl transferase, the crucial enzyme in this process. We report a phase I trial of TMZ and SCH 66336. Methods: Eligibility included: adult patients with stable or recurrent MG (GBM, anaplastic astrocytoma [AA], anaplastic oligodendroglioma [AO] ) previously treated with radiation therapy (RT) and with or without chemotherapy; interval of at least two weeks between prior RT, or four weeks between prior chemotherapy; Karnofsky ≥ 60%; and adequate hematologic, renal and liver function. Patients were divided in two strata: those receiving enzyme-inducing antiepileptic drugs (EIAED) and those not receiving EIAED. Each patient was treated with TMZ for five days every 28 days, first cycle dosed at 150 mg/m 2 and subsequent cycles at 200 mg/m 2 . SCH 66336 was dosed orally daily and was dose escalated. Responses were assessed after two cycles (8 weeks). The primary endpoints of this study were to determine the maximum tolerated dose (MTD) of SCH 66336 when administered with TMZ, and the toxicity of this combination. Results: Thirty-six patients were enrolled (25 GBM, 6 AA, 3 AO). Fifteen patients have been accrued to the EIAED stratum at SCH 66336 doses of 125, 175, and 250 mg orally BID. Twenty-one patients have been accrued to the non-EIAED stratum at SCH 66336 doses of 75, 100, 150, and 200 mg orally BID. Dose-limiting toxicities were: deep venous thrombosis (1 grade 3); nausea and vomiting (1 grade 3); diarrhea (1 grade 3); elevated ALT (1 grade 3); elevated creatinine (1 grade 3); and fatigue (1 grade 3). Radiographic evaluation reported: 2 partial responses, 14 stable disease for at least 4 cycles, and 11 disease progression after either the first or second cycle. Sixteen patients have completed at least six cycles. One patient is still on treatment, completing cycle 12. The MTD of this combination for the EIAED stratum is 175 mg BID and the non-EIAED stratum is 150 mg BID. Conclusions: SCH 66336 in combination with TMZ is well-tolerated and shows promising response when administered to patient when stable on TMZ alone or after RT and TMZ. No significant financial relationships to disclose.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2009.27.15_suppl.e13004
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2009
detail.hit.zdb_id:
2005181-5
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