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Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma
Jesús F San-Miguel1, Paul G Richardson, Andreas Günther
1Jesús F. San-Miguel and María Victoria Mateos, Servicio e Hematologia, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Institut de Bilogia Molecular de Barcelona (Universidad de Salamanca-Spanish National Research Council), Salamanca; Joan Bladé, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Paul G. Richardson and Kenneth C. Anderson, Dana-Farber Cancer Institute, Boston, MA; David Siegel, Hackensack University Medical Center, Hackensack; Kaushal K. Mishra and Song Mu, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Andreas Günther, University of Kiel, Kiel; Orhan Sezer, Charité Universitätsmedizin Berlin, Berlin, Germany; Richard LeBlanc, Maisonneuve-Rosemont Hospital, Montreal, Quebec; Heather Sutherland, Vancouver General Hospital, Vancouver, British Columbia, Canada; and Monika Sopala and Priscille M. Bourquelot, Novartis Pharma AG, Basel, Switzerland.
Purpose:
Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM.
Patients And Methods:
In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria.
Results:
The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ≥ minimal response.
Conclusion:
The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.
Insights
Panobinostat combined with bortezomib shows activity in relapsed/refractory multiple myeloma (MM). This combination therapy, including for bortezomib-refractory patients, established a maximum-tolerated dose (MTD) and warrants further clinical trials.
Area of Science:
- Oncology
- Pharmacology
Background:
- Relapsed/refractory multiple myeloma (MM) has a poor prognosis, necessitating novel therapeutic strategies.
- Panobinostat, a deacetylase inhibitor, exhibits synergistic effects with bortezomib against MM cells.
Purpose of the Study:
- To determine the maximum-tolerated dose (MTD) of panobinostat in combination with bortezomib for patients with relapsed or relapsed and refractory multiple myeloma.
- To evaluate the safety and efficacy of this combination therapy.
Main Methods:
- A phase Ib dose-escalation study administered oral panobinostat thrice weekly with bortezomib in 21-day cycles.
- An expansion phase incorporated a panobinostat treatment holiday and added dexamethasone, with safety, pharmacokinetics, and efficacy assessed.
Main Results:
- The MTD was established at panobinostat 20 mg and bortezomib 1.3 mg/m(2).
- Common grade 3/4 adverse events included thrombocytopenia and neutropenia.
- Overall response rates were 52.9% at the MTD escalation phase and 73.3% in the expansion phase, including responses in bortezomib-refractory patients.
Conclusions:
- The combination of panobinostat and bortezomib is active in relapsed/refractory multiple myeloma, including in patients refractory to bortezomib.
- The established MTD provides a basis for further investigation in a phase II/III clinical trial program (PANORAMA).
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