Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation

Phase II study of first-line sagopilone combined with prednisone in patients with metastatic castration-resistant prostate cancer (CRPC)

5059 Background: Epothilones comprise a new class of microtubule stabilizing agents, and sagopilone is a novel, fully synthetic epothilone that has shown significant activity against a broad range of tumor models. Methods: Chemotherapy-naïve metastatic CRPC patients received sagopilone 16 mg/m2 IV over 3 hours every 21 days and prednisone 5 mg PO BID. The primary efficacy evaluation was based on PSA decline (≥50% PSA reduction confirmed at least 28 days apart). The Simon 2-Stage design required 3 responders among the first 13 evaluable patients and 13 responders among the first 46 evaluable patients to declare the agent of interest for further investigation. Results: Between August 2006 and May 2008, 53 patients were enrolled and treated. Sites of metastases were: bones, lymph nodes, and viscera in 72%, 68%, and 25% patients, respectively. Median PSA was 107.5 (6.2–1727) ng/ml. A median of 5 (2–12) cycles were delivered. The median dose delivered per cycle was 13.3 mg/m2. Two patients did not meet all eligibility criteria and were excluded from efficacy analyses; 3 additional patients were excluded from PSA decline and progression-free survival analyses due to missing baseline PSA assessment. Twenty of 48 patients (42%; 80% CI: 32%-52%) had a confirmed PSA decline in excess of 50% and 30 (63%; 95% CI: 47%-76%) had a 30% reduction in PSA within 3 months of enrollment. Of 39 patients with measurable disease by RECIST, 1 had a complete, 9 had a partial confirmed response (26%; 95% CI: 13%-42%). The median PFS was 6.4 months (95% CI: 4.7 to 10.2). All 53 patients are evaluable for safety. Toxicities occurring in ≥ 20% patients included peripheral neuropathy 74% (19% grade 3), fatigue 40% (6% grade 3, 2% grade 4), extremity pain 36% (6% grade 3), arthralgia 23% (no grade 3, 4), and constipation 21% (no grade 3, 4). Conclusions: Sagopilone is active in metastatic chemotherapy-naïve CRPC patients, with probability of PSA decline, measurable disease responses, and PFS approximating the current standard of docetaxel + prednisone. Neuropathy and fatigue are the most common toxicities, while hematologic toxicity is rare. Further evaluation of this agent in prostate cancer is warranted. [Table: see text] </jats:p