Proteasome inhibitors (PI) such as bortezomib and carfilzomib (CFZ) have improved the treatment of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Preclinical studies demonstrate synergistic anti-MM activity of the combination of HDACi and PI through dual inhibition of the proteasome and aggresome pathways. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. This Phase I/II trial will determine the maximum tolerated dose (MTD) and evaluate the safety and efficacy of the combination of PAN and CFZ in relapsed/refractory pts with MM. When the MTD has been determined, the trial will continue to enroll pts with relapsed/refractory MM at the recommended dose.
The dose escalation portion of the study will determine the maximum tolerated dose (MTD) of 4 planned dose levels with the combination of CFZ and PAN using a standard 3+3 dose escalation design. Dose modifications are not permitted during cycle 1 unless a pt experiences a dose limiting toxicity (DLT). DLTs are defined as: G4 neutropenia, febrile neutropenia, G4 thrombocytopenia or G3 thrombocytopenia with bleeding, G2 neuropathy with uncontrolled pain, any G3 non-hematologic drug-related toxicity requiring a dose reduction, or pts who are unable to receive 75% of the required dose due to toxicity. PAN is administered orally three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). CFZ is administered IV over 10 min for doses < 27mg/m2 and over 30 min for doses >27 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. AEs are assessed according to CTCAE Version 4 and responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria).
Ten pts have been enrolled to date across 3 dose levels and completed the DLT window. The dose levels explored to date are: level 1, CFZ 20/27 and PAN 20 mg; level 2 CFZ 20/36 and PAN 20 mg; and level 3, CFZ 20/45 and PAN 20 mg. The median age of pts was 65.5 (range 42–75). The median number of prior therapies was 3 (range 1–7); all pts had prior bortezomib (10% bortezomib refractory) and 40% were refractory to their last treatment. Nine pts are currently on study and 1 pt from DL1 discontinued due to progressive disease. No DLTs have been observed to date, there have been no dose reductions and there have been no deaths on study. Treatment related hematologic AEs were G3 thrombocytopenia observed in 40% of pts in dose levels 1–3, followed by neutropenia in 10% of pts from DL 1. No G4 hematologic and only 1 G3 non-hematologic AEs were observed. The most common treatment related non-heme AEs were GI with grade 1/2 nausea and vomiting occurring in 70% of pts (60% G1 & 10% G2), diarrhea in 60% of pts (40% G1, 10% G2 & 10% G3). Other mild to moderate adverse events occurring in >1 pt were; fatigue 50% of pts (30% G1, 20% G2), fever/chills 50% (G1), dry mouth 30% (G1), congestion 20% (G2), dysgusia 20% (10% G1, 10% G2), epitaxis 20% (G2), hypocalcemia 20% (G1), and liver function 20% (G1). Grade 2 peripheral neuropathy was reported in 1 patient. Of the 10 pts treated, 9 are evaluable for response (10% VGPR, 40% PR, 10% MR, and 30% SD). The median number of cycles for the evaluable pts is 5 (range 2–8).
The combination of PAN and CFZ is well tolerated in relapsed/refractory MM patients. There have been no DLTs or dose reductions reported to date. MTD has not been reached at the current dose of CFZ 20/45 and PAN 20. The majority of AEs reported were manageable and expected. Early efficacy results are encouraging, and dose escalation to CFZ 20/45 and PAN 30 is planned.
Off Label Use: Off-label use of the combo Panobinostat and Carfilomib in the treatment of relapsed/refractory Multiple Myeloma.
Asterisk with author names denotes non-ASH members.