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.

Sagopilone (ZK-EPO): from a natural product to a fully synthetic clinical development candidate.

BACKGROUND: Tubulin is among the most established and clinically validated targets in oncology. The taxanes, paclitaxel and docetaxel, stabilize microtubules and have shown significant clinical activity, but factors such as the development of resistance can limit their clinical use. The epothilones are a novel class of natural microtubule-stabilizing products with potential activity in an expanded spectrum of tumour indications. OBJECTIVE: In an extensive lead optimization programme, we selected sagopilone from 350 compounds produced by total synthesis because of its combination of potent activity and good tolerability in tumour models. It is the first fully synthetic epothilone in clinical development. METHODS: Here we review the directed optimization of the natural product epothilone B to produce sagopilone, along with its mechanism of action, preclinical data and emerging clinical results. RESULTS/CONCLUSIONS: We show how this optimization process translated into superior preclinical activity, coupled with a favourable tolerability profile. Activity has been determined in a number of animal models, including those from tumours resistant to other systemic treatments. The approach used to develop sagopilone may become more common as structure-driven research is increasingly employed to exploit the enormous potential of natural products, in parallel with other targeted approaches, heralding a new era of anticancer therapy.