Abstract
2041 KOS-862 (a mitotic spindle poison causing G2/M arrest) and GEM (a pyrimidine antimetabolite) are anti-cancer agents with different mechanisms of antitumor activity and potentially non-overlapping toxicities. In vitro treatment of 2 human lung cancer cell lines (MV522; SK-MES) with the two agents showed additive antitumor activity without sequence dependence. Methods: To define the MTD, toxicity profile and PK of KOS-862 and GEM when administered weekly for 3 out of every 4 weeks, pts received KOS-862 (50, 60 and 75 mg/m2) and GEM (750 mg/m2) in 3 cohorts. KOS-862 was given IV over 90 min. with appropriate prophylaxis for Cremophor; GEM was given IV over 30 min. PK studies were performed for KOS-862, seco-KOS-862 (metabolite) and GEM. Results: 14 pts (7 F; median age 58; median ECOG PS 1; median prior regimens 2, range 0–4) enrolled in 3 dose levels. The toxicities included mild-to-moderate fatigue, nausea/abdominal pain, diarrhea, vomiting, neurosensory deficits, fever and chills. At KOS-862 (75 mg/m2) and GEM (750 mg/m2), 2 pts (both cholangiocarcinoma) out of 4 pts experienced dose-limiting toxicity (DLT), consisting of severe dehydration, diarrhea and neutropenia. 1 of these had twice the expected Cmax for KOS-862. An intermediate KOS-862 dose level (60 mg/m2) produced no DLT in 6 pts, however the Day 15 dose could not be delivered in 2 of 6 pts due to thrombocytopenia. The study was therefore amended to a 3-week cycle (2 weeks on, 1 week off). No alteration in PK was seen for KOS-862 and its metabolite between weeks 1 & 2. KOS-862 (n=11): t½ 9.2 ± 3.7 h, Vss 117±57 L/m2 and CL 6.67 ± 4.0 L/h/m2; 60mg/m2 Cmax 1806 - 3991 ng/mL; AUCtot 9984 ± 3883 ng/mL*h. Tmax (metabolite) occurs 0.5 h after KOS-862. GEM PK (n=12): t½ 23 ± 7min (range 15 - 36), Vss 62.7 ± 32 L/m2, AUCtot (750 mg/m2) range 3.6 - 16.7 ug/mL*h. There was 1 PR (unknown primary cancer) and 2 pts had SD > 3 months, suggesting evidence of activity. Conclusions: This novel regimen of KOS-862 and GEM has evidence of activity. Accrual is continuing in order to define the optimal dose on the 3-week regimen. There is no PK interaction when both agents are given in combination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Kosan Biosciences, Lilly Eli Lilly, Kosan Biosciences Lilly Oncology
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