LAUSR

Approval of bortezomib revolutionized the treatment of multiple myeloma (MM). Since then, second-generation proteasome inhibitors (PI) (carfilzomib and oral ixazomib) have been developed and approved. Panobinostat, a pan-deacetylase inhibitor (HDACi) has been approved in combination with bortezomib and dexamethasone to treat relapsed MM patients who have received ≥ 2 prior lines of therapy including bortezomib and an immunomodulatory drug (IMiD). Two early phase clinical trials evaluating combination of carfilzomib and panobinostat without dexamethasone have shown similar overall response rates (ORR) of more than 60% and progression-free survival (PFS) of eight months, despite using different panobinostat schedules. We conducted an open label, single-center, single-arm trial of panobinostat and carfilzomib in patients with relapsed/refractory MM (RRMM). The primary objective of this Phase I study was to determine the maximum recommended dose from the four pre-planned dose levels (Table 1). The primary objective in Phase Ib was to determine the overall response rate of the combination per International Myeloma Working Group (IMWG) Uniform Response Criteria for MM. Secondary end points were PFS and overall survival (OS). To be eligible, patients needed to have RRMM and ≥ 2 lines of prior therapy including at least one IMiD and PI. Detailed eligibility criteria are provided in the Online Supplementary Appendix. The protocol was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. The trial was registered at clinicaltrials.gov: identifier NCT01301807. The Phase Ia used a 3+3 design to evaluate four doses to determine the combination’s maximum recommended dose without dexamethasone (Table 1). After eight cycles of therapy, patients could continue with carfilzomib dosing on days 1, 2, 15, 16 and panobinostat as tolerated. Dexamethasone 40 mg weekly could be added at the investigator’s discretion during Phase Ib, and 4 mg weekly could be used in patients intolerant to steroids. Responses were evaluated at each cycle in patients that completed at least one cycle of therapy. Patients who received at least one dose of study drugs were evaluable for toxicity, graded in severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE ver. 4). Time-to-event outcomes, including PFS/OS, were estimated using the Kaplan-Meier method. A total of 47 patients were enrolled and treated at MD Anderson between August 2 2011 and April 29 2016 (Figure 1). The median age of enrolled patients was 63 years (range 41-76). Patients received a median of four prior lines of therapy (range 2-16) including prior bortezomib (96%), carfilzomib (28%), IMiD (100%), and autologous stem cell transplantation (87%). All patients (100%) were refractory to either bortezomib or IMiD. Ten (10) patients (21%) were high risk by fluorescence in situ hybridization (FISH) (Online Supplementary Table S1). Twenty-four patients were treated on Phase Ia and dose-limiting toxicities (DLT) were evaluated after the first cycle of therapy. None of the patients at dose levels 1 and 2 (3 patients each) encountered DLT. One of three patients at dose level 3 encountered DLT (grade 4 thrombocytopenia with bleeding); three additional patients were treated at dose level 3 and, per protocol, dose level 1 was backfilled with three patients. None of these additional patients treated at dose levels 1 and 3 experienced DLT. Three patients were then treated at dose level 4, and dose level 2 was backfilled with three patients; none of the patients at dose level 4 or level 2 experienced DLT. Three patients were added to dose level 4, and of these only one patient experienced a DLT (grade 4 thrombocytopenia with bleeding, grade 4 creatinine increase, grade 3 myalgia). Per protocol, the maximum tolerated dose (MTD) of panobinostat and carfilzomib was not reached. The maximum recommended dose was determined to be dose level 4 (Table 1). Twenty-three patients were treated at the maximum recommended dose on the Phase Ib expansion for a total of 29 patients (panobinostat 20mg, carfilzomib