Phase I trial of combination nab-paclitaxel and pemetrexed in advanced solid tumors

Abstract

13530 Background: nab-paclitaxel (ABI 007) is a 130 nm nanoparticle composed of paclitaxel and non-modified human serum albumin designed to increase intra-tumoral delivery and concentration. Pemetrexed (P) is a multitargeted antifolate that inhibits several key enzymes in cell proliferation including thymidylate synthase (TS), dihydrofolate reductase and glycinamide ribonucleotide formyl transferase (GARFT). Pre-clinical investigations combining paclitaxel and pemetrexed resulted in additive to greater than additive tumor responses. We hypothesized that the combination of ABI-007 and pemetrexed will have at least an additive anti-tumor effect and will be well-tolerated with manageable side effects. Methods: Three dose levels were tested: P 500 mg/m2 day 1 in all cohorts and ABI 007 on day 1 at doses of 180, 220, 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) using the CTCAE V 3.0 was defined as: grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding, febrile neutropenia, neutropenia with documented infection, or any other grade ≥ 3 non hematologic toxicity. A grade 3 hypersensitivity infusion reaction was not considered a DLT. Results: Planned dose escalation has been completed without reaching the MTD. 9 patients were treated including 5 NSCLC, 2 H&N, 1 ovary and 1 prostate cancer. Patient characteristics: age range 51–76, median 71; gender M:F 6:3; KPS <80/≥80: 1/8; median cycles 3. There were no DLTs, and the final cohort is being expanded to include 6 patients. Grade ≥ 3 toxicities were syncope (1) and fatigue (1). In 7 patients assessable for response: 1 PR and 2 stable disease. Correlative science studies are ongoing evaluating the expression of markers of folate homeostasis including TS, GARFT, reduced folate carrier and alpha-folate receptor; taxane associated markers p27, bcl2, Tub III, Tau, SPARC, CAV1. Shed tumor DNA in plasma will be assessed for KRAS mutations, p16 and APC gene promoter methylation. Conclusions: Pemetrexed 500 mg/m2 day 1 with ABI 007 260 mg/m2 is feasible and well tolerated. Phase II trials are planned in NSCLC and breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Abraxis Oncology