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Updated: Aug 14, 2026
Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver
Published on: July 31, 2016
A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple
James R Berenson1, James D Hilger, Ori Yellin
1Oncotherapeutics, Los Angeles, CA, USA, jberenson@imbcr.org.
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.
Insights
This study evaluated panobinostat plus melphalan for relapsed/refractory multiple myeloma. The combination showed tolerability issues, with limited responses observed, highlighting the need to balance efficacy and safety.
Area of Science:
- Oncology
- Hematology
- Clinical Pharmacology
Background:
- Panobinostat, a histone deacetylase inhibitor, demonstrates preclinical synergy with melphalan in multiple myeloma.
- Relapsed/refractory multiple myeloma presents a significant unmet need for effective treatment strategies.
Purpose of the Study:
- To assess the safety and efficacy of combining panobinostat with melphalan in patients with relapsed/refractory multiple myeloma.
- To determine the maximum-tolerated dose and optimal dosing schedule for this combination therapy.
Main Methods:
- A phase 1/2 clinical trial involving 40 patients with relapsed/refractory multiple myeloma.
- Investigated four different treatment schedules of panobinostat and melphalan due to tolerability concerns.
- Established maximum-tolerated dose at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D.
Main Results:
- Overall response rate was 7.5% (3/40 patients achieved partial response).
- All responders were in a specific cohort of treatment schedule B.
- Common toxicities included Grade 3 neutropenia (30.8%) and thrombocytopenia (23.1%).
Conclusions:
- The combination of panobinostat and melphalan exhibits tolerability challenges in regimens that show some response.
- Careful consideration is required to balance the efficacy and tolerability of this combination therapy.
- Further optimization of dosing and scheduling may be necessary to improve the therapeutic index.
