Phase I Study of the Combination of Carfilzomib and Panobinostat for Patients with Relapsed and Refractory Myeloma: A Multiple Myeloma Research Consortium (MMRC) Clinical Trial

Introduction:

Patients with myeloma ultimately become refractory to current therapies, requiring new approaches to treatment. Carfilzomib is a second generation proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory disease. Panobinostat is a pan-deacetylase inhibitor that has been shown to be effective and overcome resistance in combination with bortezomib in refractory patients. In addition, patients treated with a combination of bortezomib/dexamethasone/panobinostat had a significant improvement in progression free survival (PFS) compared to bortezomib/dexamethasone alone. Based on preclinical data supporting combined HDAC and proteasome inhibition, we hypothesized that carfilzomib and panobinostat would be safe and effective in relapsed/refractory myeloma patients. Herein we report the initial findings of the MMRC multicenter phase I study of the combination.

Methods:

The primary objective is to determine the maximum tolerated dose (MTD) of the combination of panobinostat and carfilzomib using a standard 3+3 alternate dose escalation design with 4 cohorts. An additional 12 patient expansion group will be treated at the MTD to further assess the activity and safety of the combination. Secondary objectives are to evaluate the extended safety of this combination and to assess response, response duration and progression free survival (PFS). Panobinostat is administered orally three times weekly for three of four weeks, ranging from 15 to 20 mg. Carfilzomib is administered IV days 1, 2, 8, 9, 15, and 16, ranging from 20/27 mg/m2 to 20/45mg/m2. Cycles are repeated every 4 weeks. Dose limiting toxicities (DLT) are determined in the first cycle, and all adverse events are assessed according to CTCAE V4. Responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria).

Results:

To date, 20 patients in four cohorts have been enrolled and all have completed the first cycle. Median age is 64.5 years (48-75). All patients had refractory and progressive disease; with a median number of 4) prior treatment lines. Three DLTs occurred. One patient had grade 4 thrombocytopenia with grade 3 acute kidney injury, one patient developed persistent grade 4 thrombocytopenia without bleeding and one patient had grade 3 diarrhea uncontrolled by maximal medical therapy. The MTD is panobinostat 20 mg and carfilzomib 20/36 mg/m². The most common grade 3 toxicities were hematologic. Regardless of causality, grade 3 or higher anemia, thrombocytopenia and neutropenia occurred in 35%, 35%, and 20% of patients, respectively. The most common grade 3/4 or higher nonhematologic toxicities were fatigue (15%), anorexia (10%), hyponatremia (10%) and nausea (10%). The overall response rate is 50% with 30% PRs and 20% VGPR or better. The median PFS is 14.3 months.

Conclusion:

The combination of carfilzomib and panobinostat is well tolerated with no unexpected toxicities. Response, durability of response, and PFS are encouraging and warrant further study.