title: A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma.
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.
authors.affiliation: Oncotherapeutics, Los Angeles, CA, USA, jberenson@imbcr.org.
authors.forename: James R
authors.initials: JR
authors.lastname: Berenson
authors.forename: James D
authors.initials: JD
authors.lastname: Hilger
authors.forename: Ori
authors.initials: O
authors.lastname: Yellin
authors.forename: Ralph V
authors.initials: RV
authors.lastname: Boccia
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Matous
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dressler
authors.forename: Hassan H
authors.initials: HH
authors.lastname: Ghazal
authors.forename: Saad
authors.initials: S
authors.lastname: Jamshed
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Kingsley
authors.forename: Wael A
authors.initials: WA
authors.lastname: Harb
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Noga
authors.forename: Youram
authors.initials: Y
authors.lastname: Nassir
authors.forename: Regina A
authors.initials: RA
authors.lastname: Swift
authors.forename: Robert
authors.initials: R
authors.lastname: Vescio
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D007239:Infections / Q000209:etiology; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D000077767:Panobinostat; D012008:Recurrence; D016879:Salvage Therapy
chemical_list: D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D008558:Melphalan