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Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer

  • PHASE II STUDIES
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Summary

Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53–82), with pre-treatment PSA of 205.3 (11.1–1801.0), previously treated with a median of 2 (0–5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2–3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (−40–632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368.

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Authorship

All authors were involved in this study. JG, MC, RD: conceptualization, review and editing; PB, RG, JG: formal analysis and writing, review and editing.

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Authors and Affiliations

  1. Tulane University, New Orleans, LA, USA

    Pedro C. Barata

  2. Seidman Cancer Center, Case Comprehensive Cancer Center, University Hospitals, Cleveland, OH, USA

    Matthew Cooney & Prateek Mendiratta

  3. Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA

    Ruby Gupta & Jorge A. Garcia

  4. Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA

    Robert Dreicer

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  1. Pedro C. Barata
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Corresponding author

Correspondence to Jorge A. Garcia.

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Conflict of interest

PB, MC, PM, RG and RD declare no conflict of interest for this study. JG has disclosed to be a consultant or advisor for Genentech, Pfizer; and received research funding from Genentech and Pfizer.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Barata, P.C., Cooney, M., Mendiratta, P. et al. Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer. Invest New Drugs 37, 331–337 (2019). https://doi.org/10.1007/s10637-018-0687-5

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  • DOI: https://doi.org/10.1007/s10637-018-0687-5

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