Abstract P4-14-21: A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC)
Authors: Jhaveri K , Teplinsky E , Chandarlapaty S , Solit D , Cadoo K , Speyer J , D'Andrea G , Adams S , Patil S , Haque S , Friedman K , Neville D , Esteva F , Hudis C , Modi S 
Published: May 2016

Abstract
Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by 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. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of ganetespib plus paclitaxel and trastuzumab in HER2+ MBC.
Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m2) with ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with ganetespib plus docetaxel in NSCLC, only 3 dose levels of ganetespib were explored: 100mg/m2, 150mg/m2 and a 3rd cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment.
Results: The dosing cohorts (100 mg/m2 (n=3) and 150 mg/m2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to ganetespib. Most common AEs related to ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD&gt;24 weeks) was 50% (4/8). 3 patients remain on study.
Conclusion: The RP2D of ganetespib is 150mg/m2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting.
Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D'Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.