A Phase I/II Study of the Combination of Panobinostat (PAN) and Carfilzomib (CFZ) in Patients (pts) with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Comparison of Two Expansion Cohorts

Background: Proteasome inhibitors (PI) such as bortezomib (BTZ) and carfilzomib (CFZ) have improved the treatment (tx) 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. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs through inhibition of the proteasome and aggresome pathways. It was recently approved by the FDA in combination with BTZ and dexamethasone based on the results of the PANORAMA1 study demonstrating efficacy, but significant G3 diarrhea (Lancet Oncol 2014;15:1195-206). We have previously reported the combination of CFZ and PAN in pts with relapsed and relapsed/refractory MM with encouraging results (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present a comparison of the initial dose expansion (DL 4) and the subsequent dose expansion (DL 6).

Methods: Ps with MM who had relapsed after ≥ 1 prior tx were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. In the initial dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. The 4 dose levels tested were DL 1 (20 mg PAN and 20/27 mg/m² CFZ); DL 2 (20 mg PAN and 20/36 mg/m² CFZ); DL 3 (20 mg PAN and 20/45 mg/m² CFZ), and DL 4 (30 mg PAN and 20/45 mg/m² CFZ). MTD was not reached and the maximum planned dose DL 4 was expanded. We then revised the study in order to escalate to DL 5 (30 mg PAN plus 20/56 mg/m² CFZ). Due to numerous PAN dose reductions resulting in a delivered PAN dose closer to 20 mg, we explored DL 6 (PAN 20 mg and CFZ 20/56 mg/m²). Tx 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. AEs were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria).

Results: 80 pts were enrolled (50% male, median age 65 (range 41-91), 58% poor risk, and median of 4.5 prior therapies (1-9)). Prior PI or IMiD exposure and refractory status for all pts and expansion cohorts are shown in Table 1. 34 pts were in the 1^st dose expansion (DL 4) and 33 in the 2^nd (DL6). 13 (16%) pts remain on active tx overall, 6% of pts on DL 4 and 30% of pts on DL6. The most common all grade toxicities were thrombocytopenia (73%), nausea (69%), diarrhea (64%), and fatigue (51%). There were no significant differences in types or grades of toxicities between the 2 expansion cohorts except for decreased all grade diarrhea favoring DL 6 (71% v 49%).  There was 1 tx related death due to heart failure in a pt with a prior history of hypertension and hyperlipidemia.  The ORR was 75% (32% ≥ VGPR, 43% PR) for all pts, 72% (37% ≥ VGPR, 34% PR) for DL4 and 84% (34% ≥ VGPR, 50% PR) for DL 6 pts. With a median follow up (FU) of 14.5 mos for all pts, median PFS and TTP were 13.5 and 18.7 mos, respectively. Median OS was not reached. DL4 pts had a median FU of 24.3 mos, median PFS of 17.8 mo, median TTP of 19.5 mo, and median OS of 28.2 mo. The PFS and OS data of DL 6 pts is immature.

Conclusions: The PAN/CFZ combination is effective with an acceptable safety profile in this heavily pretreated and highly refractory population. The results of this study compare favorably with the results of the PANORAMA-1 study in both efficacy and toxicity. An increase in CFZ from 45 to 56 mg/m² did not appear to increase cardiopulmonary toxicity while a decrease in PAN from 30 to 20 mg appeared to have decreased the incidence of diarrhea.  Both expansion dose levels tested were highly efficacious and well tolerated.  Further evaluation of this combination in this schedule is warranted.

Table 1

	DL 4 (n=34)	DL 6 (n=33)	All Pts (n=80)
Median # prior therapies, (range)	5 (1-9)	4 (1-9)	4.5 (1-9)
Prior PIs	33 (97%)	33 (100%)	79 (99%)
Prior IMiDs	31 (91%)	26 (79%)	69 (86%)
Refractory to prior PIs	15 (44%)	19 (58%)	37 (46%)
Refractory to prior IMiDs	17 (50%)	16 (48%)	42 (53%)
Refractory to both prior IMiDs and PIs	8 (24%)	8 (24%)	20 (25%)
Refractory to Last Therapy	23 (68%)	27 (81%)	57 (71%)