A Phase I/II Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin’s Lymphoma (HL)
Authors: Christian Beth , Wei Lai , Sexton Jennifer , Jaglowski Samantha M. , Devine Steven M. , Fehniger Todd A. , Wagner-Johnston Nina , Bartlett Nancy L. , Blum Kristie A. 
Published: November 2019

Introduction: Phase 2 single agent trials with lenalidomide and panobinostat in patients with relapsed or refractory HL have demonstrated overall response rates (ORR) of 19% (Fehniger et al., Blood 118:5119-5125, 2011) and 27% (Younes et al., JCO 30:2197-2203, 2012), respectively. We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with combined lenalidomide and panobinostat in patients with relapsed HL.

Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy were eligible. Measurable disease > 1 cm, ejection fraction ≥ 45%, ECOG PS 0-2, QTc ≤ 450 msec, ANC ≥ 1200/mm3, platelets ≥ 100,000/mm3, AST/ALT ≤ 2.5 x the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN, and creatinine clearance 60 ≥ ml/min were also required. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly were combined with lenalidomide 25 mg days 1-21 utilizing a 3+3 standard dose escalation design. DLT was defined during cycle 1 as grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, or other grade 3-4 non-hematologic toxicity. Twenty-eight days defined a cycle and patients could remain on therapy until disease progression. Response was assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 25:579-586, 2007).

Results: From Feb 2012 through June 2014, 22 patients (16 males) with cHL (n=21) and LP HL (n=1) and a median age of 45 (range 22-72) have been enrolled. Patients had received a median of 4 prior therapies (range 2-13), 9 patients were refractory to their most recent therapy, and 91% had stage III-IV disease at study entry. Ten patients had a prior autologous SCT, 1 patient had received prior allogeneic EBV-directed cytotoxic T-cells, 1 patient had a prior syngeneic transplant, and 1 patient had both prior autologous and allogeneic transplants. Eleven patients were enrolled in the phase 1 study at dose level (DL) 1 (25 mg lenalidomide + 15 mg panobinostat, n=6) and at DL 2 (25 mg lenalidomide + 20 mg panobinostat, n=5). Although there were no DLTs observed in cycle 1, 2 patients treated at DL 2 experienced grade 4 neutropenia and thrombocytopenia for > 14 days in cycle 2 and 3 of 5 patients were dose reduced to DL 1 in cycles 2 or 3. Therefore, DL 1 was expanded to 6 patients to ensure patient safety at this dose level and the phase 2 study was conducted at DL 1. Eleven patients have been treated in the phase 2 study. In all 22 patients, the median number of cycles completed on study was 4 (range 1-22). Grade 3-4 toxicities in all patients included neutropenia (59%), thrombocytopenia (41%), lymphopenia (27%), febrile neutropenia (27%), hypophosphatemia (9%), hypocalcemia (5%), QTc prolongation (5%), fatigue (5%), nausea/vomiting (5%), erythema nodosum (5%), transaminitis (5%), and unexplained altered mental status after administration of study medications (5%). Dose reductions were required in 10 patients (45%, 5 in the phase 2 study and 3 patients with multiple dose reductions) for febrile neutropenia, grade 3-4 neutropenia/thrombocytopenia, erythema nodosum, and transaminitis. Twenty-one patients have discontinued protocol therapy for PD (n=15), adverse events (n=5, including grade 4 neutropenia/thrombocytopenia or unexplained altered mental status after drug dosing), and to undergo elective CABG (n=1). ORR is 14% (2 CR and 1 PR) in 21 evaluable patients with complete responses in 1 patient with cHL and 1 patient with LP HL of 6 and 25 months duration, respectively.

Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL. Due to myelosuppression at higher doses, the recommended phase 2 dose of the combination is 25 mg lenalidomide days 1-21 with 15 mg panobinostat days 1, 3, and 5 weekly on a 28-day cycle. Accrual continues to the two-stage phase 2 trial, but based on preliminary data in the first 22 patients, the efficacy of combined lenalidomide and panobinostat appears similar to that previously reported with these drugs as single agents.

Disclosures

Christian: Celgene: Research Funding. Fehniger:Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Bartlett:Celgene: Research Funding; Novartis: Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of Hodgkin's lymphoma.