Title: Ganetespib in Combination with Pemetrexed-Platinum Chemotherapy in Patients with Pleural Mesothelioma (MESO-02): A Phase Ib Trial

down-regulating Hsp90 client protein levels with acceptable in single-agent phase II solid studies. Furthermore, Hsp90 inhibition with ganetespib can enhance T-cell-mediated anti-tumor immune response. We present the MESO-02 trial of ganetespib plus pemetrexed and cisplatin/carboplatin in chemotherapy-naïve MPM patients. This novel combination was well-tolerated. We observed promising anti-tumor activity including partial responses, particularly in patients with epithelioid histology, and Loss of Heterozygosity was associated with shorter time to progression. Response rates of ganetespib are comparable or better than those observed in other novel-agent MPM trials. This study supports further investigation of ganetespib combination therapy to treat MPM in a large randomized controlled trial. ABSTRACT Purpose Ganetespib, a highly potent, small molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the Maximum Tolerated Dose (MTD) of ganetespib in chemotherapy-naïve MPM patients. was a phase Ib trial of (100 , , ; and with pemetrexed ; and ; or carboplatin (area under concentration-time curve day in MPM patients. Dose-escalation was performed using the 3+3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS) and pharmacogenomic analyses. Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies.