Abstract P5-19-23: A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer
Authors: Jhaveri Komal , Cadoo Karen , Chandarlapaty Sarat , Teplinsky Eleonora , Speyer James , D' Andrea Gabriella , Patil Sujata , Haque Sofia , Friedman Kent , Heese Scott , Neville Deirdre , Esteva Francisco , Hudis Clifford , Modi Shanu 
Published: May 2015

Abstract
Introduction: Targeted therapies in HER2+ metastatic breast cancer (MBC) have significantly improved survival, however efficacy is limited by development of therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Ganetespib is a novel, synthetic HSP90 inhibitor with increased potency and tolerability compared with earlier agents. Our group has conducted a single agent ganetespib trial in unselected patients which showed anti-tumor activity in HER2+ and triple negative breast cancer. In addition, preclinical data suggests HSP90 inhibition is synergistic with taxanes with potential for significant clinical activity. Ganetespib has been combined with docetaxel in non-small cell lung cancer, it has not previously been combined with paclitaxel and trastuzumab. This study will define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ganetespib when given with paclitaxel and trastuzumab for patients with HER2+ MBC.
Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab resistant HER2+ MBC receive trastuzumab (4mg/kg loading dose, then 2mg/kg) and paclitaxel weekly (80mg/m2) with ganetespib day 1, 8 ,15 of 28 day cycle. Patients are required to have prior pertuzumab and T-DM1 (prior pertuzumab and T-DM1 are not mandated if heavily pretreated prior to their respective FDA approvals). Hormone receptor positive patients are required to have at least one prior line of endocrine therapy. The single agent dose limiting toxicity (DLT) of ganetespib is diarrhea and therefore patients receive prophylactic anti-motility agents. The anticipated MTD of ganetespib in this combination has been informed by experience with docetaxel and based on this only three dose levels of ganetespib are being explored 100mg/m2, 150mg/m2 and a third intermediate cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics of paclitaxel and preliminary assessment of efficacy of the combination (scans at 8 weeks and every 12 weeks thereafter, RECIST 1.1).
Results: The first dosing cohort has fully enrolled and there were no significant toxicities or DLTs reported. Median age was 48 years (range 39-49), median prior lines of chemotherapy were 4 (range 3-7) and included prior pertuzumab and T-DM1 in all 3 patients. 5 adverse events have been defined as possibly/probably related to ganetespib – grade 2 anemia and leukopenia, grade 1 diarrhea (2 patients), fatigue, and rash. Enrollment to the second and potentially final cohort is underway.
Conclusion: This study will define the RP2D of ganetespib in combination with paclitaxel and trastuzumab. Final safety, pharmacokinetic and preliminary response data for all patients will be presented. This combination, with a novel anti-HER2 agent, has encouraging potential for activity in HER2+ breast cancer which is refractory to other HER2 targeting agents.
Citation Format: Komal Jhaveri, Karen Cadoo, Sarat Chandarlapaty, Eleonora Teplinsky, James Speyer, Gabriella D' Andrea, Sujata Patil, Sofia Haque, Kent Friedman, Scott Heese, Deirdre Neville, Francisco Esteva, Clifford Hudis, Shanu Modi. A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-23.