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Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors

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Summary

Purpose To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design This was a standard “3 + 3” dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort −1 and −1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m2 BID days 1–14; oxaliplatin 100 mg/m2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

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Acknowledgments

We gratefully acknowledge the invaluable contributions of the patients and their families. We would also like to acknowledge the Duke University GI Oncology clinical trials team.

Role of the funding source

This was an investigator-initiated study supported by Novartis Pharmaceuticals and Genentech, Inc. The study was independently managed and analyzed. The final responsibility for the manuscript and the decision to submit for publication was made by the investigators. This work was also supported by National Institute of Health Grant 5K24-CA113755-05 (H.I. Hurwitz).

Conflict of interest

Dr. Andrew Nixon serves as a consultant for GlaxoSmithKline, Novartis and obtains research support from Amgen, F. Hoffman-La Roche, Pfizer, and Tracon Pharmaceuticals. Dr. Michael Morse has received honoraria from Genentech and Novartis. Dr. Herbert Hurwitz serves as a consultant for Genentech, Roche, Sanofi, Regeneron, Bristol Meyer Squibb, Lilly, Amgen, Incyte, Novartis, Tracon Pharmaceuticals, and Pfizer. Dr. Yousuf Zafar serves as a consultant for Genentech. Dr. Hope Uronis has research funding from Genentech. Dr. John Strickler serves as a consultant for Amgen. The remaining authors have no conflicts of interest. Dr. Mark Kozloff serves on the speaking bureau and as a consultant for Novartis. All other authors declare no conflict of interest.

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Authors and Affiliations

  1. Duke University Medical Center, Seeley G. Mudd Bldg 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA

    Fatima Rangwala, Christy C. Arrowood, Jennifer Meadows, Sandra Tourt-Uhlig, Jennifer Murphy, Kellen L. Meadows, Samuel Broderick, John C. Brady, Stephanie M. Cushman, Michael A. Morse, Hope E. Uronis, S. David Hsu, S. Yousuf Zafar, Alexander N. Starodub, John H. Strickler, Andrew B. Nixon & Herbert I. Hurwitz

  2. Sarah Cannon Research Institute, Nashville, TN, USA

    Johanna C. Bendell

  3. Ingalls Memorial Hospital/Cancer Research Center, Harvey, IL, USA

    Mark F. Kozloff & James Wallace

  4. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    Andrew Dellinger & Herbert Pang

  5. Goshen Center for Cancer Care, Goshen, IN, 46526, USA

    Alexander N. Starodub

  6. Duke Clinical Research Institute, Durham, NC, 27705, USA

    Sandra Tourt-Uhlig, Jennifer Murphy, Aijing Starr & Samuel Broderick

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  1. Fatima Rangwala
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  2. Johanna C. Bendell
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  10. Aijing Starr
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  18. James Wallace
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  21. Herbert Pang
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Correspondence to Herbert I. Hurwitz.

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Rangwala, F., Bendell, J.C., Kozloff, M.F. et al. Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors. Invest New Drugs 32, 700–709 (2014). https://doi.org/10.1007/s10637-014-0089-2

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