Abstract A6: Pazopanib combination with paclitaxel and carboplatin in patients with advanced solid tumors and gynecological cancers: Results of two phase I studies

Abstract

Abstract Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit with w/ a recommended dose of 800 mg/day as monotherapy. Preclinical activity supports combining PAZ with paclitaxel (P) and carboplatin (C). Safety, PK, and and clinical activity of PAZ with P and and C were evaluated in two Phase I studies. Methods: Two Phase I studies were conducted using a once daily QD regimen of PAZ (200–800 mg), and once every Q21 days of C (AUC 4–6 mg·min/mL) and P (175 mg/m2) to determine the optimally tolerated regimen (OTR) MTD defined as a dose limiting toxicity (DLT) frequency of <33% in Cycle 1. Study 1 (S1) was a 3 + 3 design expanded at the OTR in patients (pts) with w/ metastatic disease treated with w/ no more than 3 prior lines of therapy. Study 2 (S2) enrolled subjects with w/ gynecological cancer in 2 cohorts of 6 pts each as first-1st line treatment. Results: In Study 1S1, 34 pts (mean age 54; M/F: 17/17; ECOG 0/1: 19/15) were enrolled. Breast (29%) and esophagus (12%) were the most common primary tumor sites. In Study 2S2, 12 pts (mean age 53.754, M/F: 0/12; ECOG 0/1: 8/4) were enrolled. Ovary (50%) and endometrium/uterus (25%) were the most common primary tumor sites. The frequency of adverse events (AEs), regardless of causality, in the 2 studies (1 vs 2), were similar for neutropenia (82% vs 75%) and fatigue (68% vs 75%) and different for nausea (71% vs 50%), thrombocytopenia (68% vs 33%), anemia (65% vs 25%), and abdominal pain (24% vs 50%). The OTR MTD in Study 1S1 was P 175, C AUC 5, and PAZ 200; an OTR MTD was not determined for Study 2S2 due to poor tolerability. In Study 1S1, in the presence of PAZ 200 mg and 400, mg, the AUC (0–23) of C increased by 41 and 31%, respectively and while the Cmax for P increased by 43 and 40%, respectively. Best response in Study 1S1 at the OTRMTD (n=13) was CR [2 pts (15%); 406 and 446 days] and PR [3 pts (23%); 42–208 days]. Conclusions: Full doses of PAZ and C were not tolerated in combination with w/ P due predominantly to hematologicale toxicities in Study 1S1 and to non-hemeatological toxicities in Study 2S2. A drug interaction between PAZ and P and C along with more extensive prior therapy may explain increased myelotoxicity with this triplet in Study 1S1. Based on this PK interaction, lower doses of P and C may still provide adequate therapeutic exposure and better safety profile when combined with a higher dose of PAZ relative to the OTR MTD in study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A6.