A Single-Arm, Open-Label, Multi-Center Phase I/II Study Of The Combination Of Panobinostat and Carfilzomib In Patients (pts) With Relapsed Or Relapse/Refractory Multiple Myeloma (MM)
Authors: Berdeja Jesus , Savona Michael , Mace Joseph R , Hart Lowell , Essell James , Owera Rami , Arrowsmith Edward , Flinn Ian 
Published: October 2019

Abstract

Background
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 with PI through dual inhibition of the proteasome and aggresome pathways. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs in clinical studies. In this study, we evaluate the safety and efficacy of the PAN/CFZ combination in pts with relapsed and relapsed/refractory MM. Here we present the updated results of this ongoing trial.

Methods
Patients with MM who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of 4 planned dose levels with the combination of CFZ and PAN. PAN was administered orally three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). CFZ was administered IV over 30 min on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The 4 dose levels tested were DL 1, defined as 20 mg PAN and 20/27 mg/m2 CFZ; DL 2, defined as 20 mg PAN and 20/36 mg/m2 CFZ; DL 3, defined as 20 mg PAN and 20/45 mg/m2 CFZ; and DL 4, defined as 30 mg PAN and 20/45 mg/m2 CFZ. Treatment was continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. Adverse Events (AEs) were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). The MPD (maximum planned dose) was further explored in the expansion phase.

Results
10 patients were treated in the dose escalation portion of the study. No DLTs were observed. DL 4 was further explored and 31 patients were enrolled in the expansion phase of the study. As of the data cutoff of 5/31/2013, 44 pts were accrued to the trial, including 34 pts on the eventual expanded DL 4. The median age of pts was 66 (41-83); most patients were ISS stages 2 and 3; 38% of pts had adverse prognostic cytogenetics or FISH, including 23% with del 17p. The median number of prior therapies was 3 (1-6) including 89% with prior bortezomib, 89% with prior immune modulating drugs (IMiDs), 34% with prior stem cell transplants. Thirty six percent of pts were refractory to bortezomib, 30% were refractory to IMiDs, 14% were refractory to both bortezomib and IMiDs, and 43% were refractory to their last treatment regimen. Twenty seven (61%) pts remain on active treatment. Forty five percent of pts experienced ≥ grade 3 hematologic-related AEs, the most common being G3 thrombocytopenia (30%) and neutropenia (20% G3 and 2% G4). Thirty four percent of pts experienced ≥ grade 3 non-hematologic AEs, the most common being fatigue (11% G3) and nausea/vomiting (9% G3). The most salient of all grade AEs were nausea/vomiting (39% G1, 20% G2, 9% G3, 0 G4) and thrombocytopenia (14% G1, 27% G2, 30% G3, 0 G4). Peripheral neuropathy was rare (5% G1, 2% G2, 0 G3/4). In pts treated on DL 4 (30 mg PAN and 20/45 mg/m2 CFZ), late cycle dose reductions for PAN were common (59% of pts) and the median PAN dose delivered was 23.4 mg. CFZ dose reductions were rare (18% of pts) and the median CFZ dose was 40.8 mg/m2. The ORR was 64% with 31% ≥VGPR and 30% PR. In addition, there were 5% MR, 26% SD and 5% PD. The ORR for bortezomib exposed pts, bortezomib refractory pts and dual bortezomib and IMiD refractory pts was 60%, 67% and 66%, respectively. With a median follow up of 6.3 months, the PFS at 6 and 12 months was 63% and 41% respectively. The OS was 83% at both 6 and 12 months and the median TTP was 8.6 months.

Conclusions
The combination of PAN and CFZ is feasible and effective in this relapsed/refractory MM population. Due to dose reductions required for PAN and no MTD reached, 2 further dose levels will be explored with plans to do a parallel dose expansion if tolerated.

Disclosures:
Off Label Use: Off-label use of the combo Panobinostat and Carfilomib in the treatment of relapsed/refractory Multiple Myeloma.