Dr. Jonathan Kaufman (Winship Cancer Institute, Emory University, Atlanta, Georgia) discusses a phase I study of the combination of carfilzomib (Kyprolis) and panobinostat in patients with relapsed and refractory myeloma. The results from this phase I Multiple Myeloma Research Consortium (MMRC) clinical trial were presented at the 56th American Society of Hematology (ASH) Annual Meeting. ASH 2014 abstract 32.

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation I
Jonathan L. Kaufman, MD1, Todd Zimmerman, MD2, Cara A Rosenbaum, MD3, Ajay K. Nooka, MD, MPH4, Leonard T Heffner Jr., MD5, R. Donald Harvey, PharmD6, Charise Gleason, MSN, ANP-BC, AOCNP7*, Colleen Lewis, MSN, ANP-BC, AOCNP5*, Cathy Sharp, RN, MN, OCN5*, Kenisha W Barron, B.S, CCRC5* and Sagar Lonial, MD8

1Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
2Department of Medicine, Section Hematology/Oncology, University of Chicago Medicine, Chicago, IL
3Department of Medicine, Hematology/Oncology, University of Chicago, Chicago, IL
4Division of BMT, Winship Cancer Institute - Hematology and Medical Oncology, Emory University, Atlanta, GA
5Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
6Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
7Winship Cancer Institute, Emory University, Atlanta, GA
8Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA

 
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.

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ABOUT JONATHAN L. KAUFMAN, MD

Jonathan L. Kaufman, MD, is Associate Professor and Associate Vice-Chair for Quality and Safety of the Department of Hematology and Medical Oncology at Emory University School of Medicine. Board-certified in hematology and medical oncology, Dr. Kaufman's practice includes treating multiple myeloma and amyloidosis patients at Emory University Hospital. He is also an active clinical and translational researcher in the fields of multiple myeloma, amyloidosis, and bone marrow transplant. Dr. Kaufman is a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute. He also holds memberships with the American Society of Clinical Oncology and American Society of Hematology. Visit Dr. Jonathan Kaufman’s full biography.

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