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A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma

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Abstract

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373–379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1–16) and two prior bortezomib-containing regimens (range, 0–9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

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Acknowledgments

The authors would like to acknowledge Shellie Rothstein for assistance throughout the trial and Fritz Costa and Melissa Kalbarczyk for invaluable assistance with data management and entry.

Conflict of interest disclosure

JRB is a member of the speakers bureau for Norvatis and acknowledges consulting and research funds from Novartis. RVB is a member of the speakers bureau for Novartis. RAS is a member of speakers bureau and advisory board for Novartis. The rest of the authors declare no conflict of interest.

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Authors and Affiliations

  1. Oncotherapeutics, Los Angeles, CA, USA

    James R. Berenson, James D. Hilger & Ori Yellin

  2. James R. Berenson, MD, Inc, Los Angeles, CA, USA

    James R. Berenson, Youram Nassir & Regina A. Swift

  3. Institute for Myeloma and Bone Cancer Research, 9201 W. Sunset Blvd., Suite 300, West Hollywood, 90069, CA, USA

    James R. Berenson

  4. Center for Cancer and Blood Disorders, Bethesda, MD, USA

    Ralph V. Boccia

  5. Colorado Blood Cancer Institute, Denver, CO, USA

    Jeffrey Matous

  6. St. Vincent’s Medical Center, Bridgeport, CT, USA

    Kenneth Dressler

  7. Kentucky Cancer Clinic, Hazard, KY, USA

    Hassan H. Ghazal

  8. Linden Oaks-Lipson Cancer Center, Rochester, NY, USA

    Saad Jamshed

  9. Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA

    Edwin C. Kingsley

  10. Horizon Oncology Research, Inc, Lafayette, IN, USA

    Wael A. Harb

  11. Harry and Jeanette Weinberg Cancer Institute, Baltimore, MD, USA

    Stephen J. Noga

  12. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Robert Vescio

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  1. James R. Berenson
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  2. James D. Hilger
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  3. Ori Yellin
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Correspondence to James R. Berenson.

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Berenson, J.R., Hilger, J.D., Yellin, O. et al. A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma. Ann Hematol 93, 89–98 (2014). https://doi.org/10.1007/s00277-013-1910-2

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  • DOI: https://doi.org/10.1007/s00277-013-1910-2

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