A Phase I Study of Ixazomib in Combination with Panobinostat and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Background: In a pivotal trial addition of panobinostat at 20mg three times a week, two weeks on, one week off, to bortezomib and dexamethasone increased progression-free survival of relapsed or relapsed and refractory multiple myeloma (MM) but clinically significant adverse events, including severe diarrhea and unexpected cardiac events limited enthusiasm. Here we describe safety and preliminary efficacy data for an all-oral regimen that uses ixazomib as proteasome inhibitor and every other week dosing of panobinostat.

Methods: Two dose levels (DL) of ixazomib (3mg, 4mg) given on day 1, 8, 15 every 28 days  were evaluated in combination with panobinostat 20mg on day 1, 3, 5, 15, 17, 19 and dexamethasone 20mg day 1, 2, 8, 9, 15, 16 using a classical 3 x 3 design. Inclusion criteria included at least two prior regimens, previous therapy with a proteasome inhibitor and IMiD, measurable disease according to uniform response criteria, and adequate organ function with QTcF < 450msec and estimated creatinine clearance of at least 30ml/min. 

Results: Eleven patients (pts) of median age 65 (range 50-73), all with MM refractory to their last regimen, were enrolled after a median of 5 prior regimens (range 2-10). Their disease was refractory to lennalidomide (n=11), bortezomib (n=10), proteasome inhibititor with IMiD (n=9), carfilzomib (n=7), and alkylating chemotherapy (n=7). The target dose level 2 was reached without dose limiting toxicity (DLT). Median time on therapy as of July 21, 2015 is 54 days (range 21-183) including three pts who remain on study. No serious adverse event was observed and no dose reductions of panobinostat or ixazomib were required. No non-hematologic CTCAE v. 4.03 grade 3/4 toxicities were seen but 3 pts developed grade 3 hematologic toxicities (2 neutropenia, 1 thrombocytopenia). Worst diarrhea was grade 1 (n=6), worst nausea grade 2 (n=1) and 4 additional pts developed transient grade 1 nausea. Other possibly panobinostat or ixazomib related grade 1/2 adverse events included thrombocytopenia (n=5), neutropenia (n=3), fatigue (n=2), anemia (n=2), anorexia (n=1) and arthralgia (n=1). Median QTcF before treatment start was 405 msec (range 378-430) and increased on average by 4.3% (maximally by 13%). One patient developed transient grade 1 QTcF prolongation to 552 msec. No other cardiac adverse events were observed.  Best response according to uniform response criteria with adapted EBMT criteria for minor response (MR) was MR in 3 pts, of whom two had disease progressive on proteasome/IMiD combinations at study entry. One MR is ongoing; the other two each lasted 6 months. One additional patient had stable disease for 6 months.

Conclusions: Addition of panobinostat at 20mg three times a week every other week to ixazomib at target 4mg weekly, three weeks on, one week off, with dexamethasone 20mg on the day of and after ixazomib was very well tolerated and demonstrated activity in extensively pretreated multiple myeloma patients with progressive disease on proteasome/IMiD combinations. We therefore propose this regimen for phase 2 evaluation.