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Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors

  • Clinical Trial Report
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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens.

Methods

Five therapies each co-administered with amuvatinib 100–800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth.

Results

Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies.

Conclusion

Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.

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Acknowledgments

The authors would like to acknowledge the contributions of Richard Mamelok, M.D., Gil Fine, Ph.D., Stefan Dyla, Ph.D., Harold Keer, M.D., Ph.D., Joseph Iovino, and Toniann Derion, Ph.D., ELS, Astex Pharmaceuticals, Inc. The authors would like to thank Carla Coackley from Ontario Cancer Institute/Princess Margaret Cancer Centre and Departments of Radiation Oncology and Medical Biophysics, University of Toronto, for her assistance with RAD51 laboratory data. This study was sponsored, monitored, and funded by Astex Pharmaceuticals, Inc. (formerly SuperGen, Inc.).

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Authors and Affiliations

  1. Cancer Therapy and Research Center (CTRC), University of Texas (UT) Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX, 78229, USA

    Monica Mita

  2. Pinnacle Oncology Hematology, 9055 E. Del Camino Drive, Suite 100, Scottsdale, AZ, 85258, USA

    Michael Gordon

  3. UCLA Department of Hematology and Oncology, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA

    Lee Rosen

  4. Departments of Radiation Oncology and Medical Biophysics, Ontario Cancer Institute, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, ON, M5G2M9, Canada

    Nirmal Kapoor & Robert Bristow

  5. Astex Pharmaceuticals, Inc., 4140 Dublin Blvd., Suite 200, Dublin, CA, 94568, USA

    Gavin Choy, Sanjeev Redkar, Pietro Taverna, Aram Oganesian, Amarpal Sahai & Mohammad Azab

  6. South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, Suite 4021, San Antonio, TX, 78229, USA

    Anthony W. Tolcher

  7. Cedars-Sinai Medical Center, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA

    Monica Mita

Authors
  1. Monica Mita
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  2. Michael Gordon
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  3. Lee Rosen
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  4. Nirmal Kapoor
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  5. Gavin Choy
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  6. Sanjeev Redkar
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  7. Pietro Taverna
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  8. Aram Oganesian
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  9. Amarpal Sahai
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  10. Mohammad Azab
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  11. Robert Bristow
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  12. Anthony W. Tolcher
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Correspondence to Monica Mita.

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Mita, M., Gordon, M., Rosen, L. et al. Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors. Cancer Chemother Pharmacol 74, 195–204 (2014). https://doi.org/10.1007/s00280-014-2481-1

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  • DOI: https://doi.org/10.1007/s00280-014-2481-1

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