Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023)

Abstract

Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable/refractory MPNSTs. Patients and Methods. In this multi-institutional, open-label, phase 1/2 study of ganetespib and sirolimus, patients ≥16 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3 + 3 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain.

Results: Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200 mg/m2 intravenously on days 1, 8, and 15 with sirolimus 4 mg orally once daily with day 1 loading dose of 12 mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1-4). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable.

Conclusion: Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (NCT02008877).

Conflict of interest statement

D. Reinke reports grant from Department of Defense and other support from Synta Pharmaceuticals. P. Wolters reports holdings from Bristol-Meyers Squibb, Inc., and a grant from the Neurofibromatosis Therapeutic Acceleration Program outside the submitted work. S. Chawla reports other support from Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC, and Janssen outside the submitted work. R. Chugh reports grants from AADi, Novartis, Lilly, Medivation, Plexiconn, Pfizer, Advenchen, Morphotek, and Mabvax; grants and personal fees from Epizyme; and personal fees from Janssen and Immune Design outside the submitted work. Brian Van Tine reports grants from Pfizer and Merck and other support from Janssen, Epizyme Daiichi Sankyo, Blueprint Medicine, Immune Design, Janssen, Caris, and Lilly outside this work. No potential conflicts of interest were disclosed by the other authors.

Copyright © 2020 AeRang Kim et al.

Figures

Figure 1

Aggregate pharmacodynamic responses to ganetespib and sirolimus therapy.