A phase I study of OSI461 in combination with mit

Authors: Lee P Resta Roberto Pili Mario A Eisenberger Avery Spitz Serina King Jennifer Porter Amy Franke Ramesh Boinpally Michael A Carducci Christopher J Sweeney

Publish Date: 2010/05/06

Volume: 67, Issue: 2, Pages: 431-438

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Abstract

OSI461 dose was escalated to 1000 mg po bid One patient experienced a doselimiting toxicity DLT Three patients discontinued the study due to adverse events AE Two patients 10 had a partial response and ten patients 50 had stable disease as best responseThe combination of OSI461 and mitoxantrone was well tolerated Dose escalation was stopped because of toxicities in a concurrent Phase I trial The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone and further studies of the combination of OSI461 and mitoxantrone were not pursuedOSI461 is a second generation selective apoptotic antineoplastic drug SAAND SAANDs induce apoptosis of tumor cells by inhibiting 3′5′cyclic guanosine monophosphate cGMP phosphodiesterase PDE isoforms PDE2 and PDE5 elevating cGMP activating protein kinase G PKG and decreasing βcatenin 1 OSI461 has approximately 100× more affinity for cGMP PDE than does exisulind a first generation SAAND compoundIn vitro data suggest that OSI461 inhibits angiogenesis and blocks mitotic progression through disruption of microtubule organization and spindle formation 2 OSI461 induces apoptosis in a wide variety of epithelialderived and nonepithelialderived tumor cell lines while sparing normal cells Nude mice with human prostate adenocarcinoma xenografts showed a decrease in tumor size when treated with mitoxantrone and OSI461 when compared to animals treated with either mitoxantrone or OSI461 aloneMitoxantrone is a commercially available synthetic cytotoxic antineoplastic anthracenedione derivative approved by the FDA and used routinely in combination with corticosteroids for the treatment of patients with advanced hormonerefractory prostate cancer It has also been extensively studied in the treatment of breast cancer leukemia and lymphoma Mitoxantrone causes crosslinks and strand breaks in DNA interferes with RNA and inhibits topoisomerase IIOSI461 is a cytostatic agent that has shown modest antitumor activity in a Phase II pilot study involving patients with hormonerefractory prostate cancer The combination of cytostatic agents with standard cytotoxic therapies is under intensive evaluation and the combination of OSI461 and mitoxantrone which showed evidence of efficacy in a preclinical model as described above appeared worthwhile to investigate both from a pharmacologic and from a clinical perspective In addition both agents have demonstrated activity in patients with hormonerefractory prostate cancer Therefore we conducted a Phase I dosefinding study of OSI461 orally twice daily in combination with mitoxantrone dosed on Day 1 of each 21day cycle

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