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Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer

  • Nicole O. Williams
  • , Dionisia Quiroga
  • , Courtney Johnson
  • , Adam Brufsky
  • , Mara Chambers
  • , Saveri Bhattacharya
  • , Maria Patterson
  • , Sagar D. Sardesai
  • , Daniel Stover
  • , Maryam Lustberg
  • , Anne M. Noonan
  • , Mathew Cherian
  • , Darlene M. Bystry
  • , Kasey L. Hill
  • , Min Chen
  • , Mitch A. Phelps
  • , Michael Grever
  • , Julie A. Stephens
  • , Bhuvaneswari Ramaswamy
  • , William E. Carson
    • Robert Wesolowski

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Original languageEnglish
JournalTherapeutic Advances in Medical Oncology
Volume15
DOIs
StatePublished - Jan 1 2023

Bibliographical note

Publisher Copyright:
© The Author(s), 2023.

Funding

This multicenter phase Ib study evaluated the combination of onalespib and paclitaxel in patients with advanced (defined as inoperable or metastatic) TNBC. TNBC was defined in this study as being hormone receptor negative (ER < 1%, PR < 1%) or low (ER < 10%, PR < 10%) and HER2-negative. Patients were recruited to this study from four academic institutions (The Ohio State University, University of Pittsburgh, University of Kentucky, and Thomas Jefferson University) beginning in April 2016 and ending in September 2019. The primary objectives were to determine the recommended phase II dose (RP2D) of this combination therapy and its toxicity profile based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. Secondary objectives included determination of the pharmacokinetic (PK) effects of each agent on the other, overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) based on the Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1. The study protocol was approved by the Institutional Review Board (IRB) at each of the participating institutions as well as the NCI Central IRB under common study number NCI9876. This study protocol followed the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines and complied with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist ( Supplemental Figure 1 ). Written informed consent was obtained from all patients. The study was sponsored by the NCI and registered at ClinicalTrials.gov (NCT02474173). Astex Pharmaceuticals, Inc. provided onalespib for this study. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by the National Cancer Institute (NCI) which provided financial support for the research described in this manuscript. It was conducted through the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) and supported by the UM1CA186712 grant to Dr WC. Dr DQ was supported by the NIH T32 grant CA247815. This study is registered at ClinicalTrials.gov (NCT02474173). The authors would like to thank the patients and their families, the investigators, research nurses, study coordinators, and operations staff who contributed to this study. The authors would like to thank the Shared Resources Core at The Ohio State University James Comprehensive Cancer Center. The authors would also like to recognize Mahmoud Kassem for his assistance with manuscript preparation. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by the National Cancer Institute (NCI) which provided financial support for the research described in this manuscript. It was conducted through the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) and supported by the UM1CA186712 grant to Dr WC. Dr DQ was supported by the NIH T32 grant CA247815. This study is registered at ClinicalTrials.gov (NCT02474173).

FundersFunder number
Ohio State University James Comprehensive Cancer Center
National Institutes of Health (NIH)CA247815
National Childhood Cancer Registry – National Cancer InstituteNCT02474173, UM1CA186712

    UN SDGs

    This output contributes to the following UN Sustainable Development Goals (SDGs)

    1. SDG 3 - Good Health and Well-being
      SDG 3 Good Health and Well-being

    Keywords

    • AT13387
    • HSP90 inhibitor
    • heat shock protein
    • onalespib
    • paclitaxel
    • phase I clinical trial
    • triple-negative breast cancer

    ASJC Scopus subject areas

    • Oncology

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