Phase I dosage-finding and pharmacokinetic (PK) study of intravenous topotecan and oral erlotinib in patients (pts) with refractory solid tumors.

L. S. SCHWARTZBERG; C. F. STEWART; P. SCHAIQUEVICH; P. LEGENNE; K. BHATT; A. JOHNS; MS WALKER

Chicago, USA

Congreso; American Society of Clinical Oncology; 2008

American Society of Clinical Oncology

Background: Topotecan (TPT) is a substrate for efflux transporters of the ABC family. Erlotnib (E), a 4-aniloquinazole, inhibits ABCG2 at clinically achievable plasma concentrations. This phase I study was designed to determine the maximum tolerated dose (MTD) of this combination of two active anticancer drugs with ABC transporter modulation capability and assess PK interactions. Methods: Escalating dose levels (DL) of 3 pt cohorts each of TPT IV at 0.75 mg/m2 (DL 1); 1.0 mg/m2 (DL 2); and 1.25 mg/m2 (DL 3); day 1 -5 q 21 day cycle. E was added on cycle 1, day 2 at 150 mg po daily continuously. Serial plasma samples were obtained pre and post TPT day 1, cycle 1 and day 1, cycle 2 or 3 and 24 hr urine samples were obtained after cycle 1 and cycle 2. Dose-limiting toxicity (DLT) was defined as G4 hematologic and/or G3/4 nonhematologic toxicities. Results: 23 enrolled pts included 4 ovarian, 4 colorectal, 4 sarcoma, 4 small cell lung, and 7 other tumors; 16 were Caucasian and 7 African American. Median (range) prior treatment regimens was 3 (1-5). At DL 1, 0/3 pts had DLT and at DL 2 1/6 pts had DLT of febrile neutropenia (FN). At DL 3, 2/6 pts had DLTs (neutropenia and thrombocytopenia). MTD was determined at DL 2, TPT 1.0 mg/m2 + E 150 mg. Six additional pts were enrolled at DL 2 to assess PK on cycles 1 and 3. 2/6 had G4 neutropenia and thrombocytopenia. Across the total cycles delivered of 68, G4 hematologic toxicities were neutropenia 22%, FN 1%, anemia 1%, thrombocytopenia 6%. In cohort 3, G4 neutropenia occurred in 6/22 cycles (27%). No G4 nonhematologic toxicity was noted in > 5% of patients. 18 pts were evaluable for response: 7 pts had stable disease > 12 weeks, and 2 pts had a partial response. The median (range) TPT systemic clearance measured on day 1 of course 1 (without E) was 8.1 L/h/m2 (3.6 to 14.9) compared with 7.9 L/h/m2 (4.5 to 12.2) measured on day 1 of course 2 or 3 (with E). Initial analysis revealed no obvious relationship between TPT systemic exposure and toxicity. Conclusions: TPT and E can be given together at clinically effective doses with acceptable hematologic and nonhematologic toxicity. The addition of E has minimal effect on systemic TPT clearance. Further studies are needed to establish efficacy of this combination.