A Phase I Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL)
Authors: Christian Beth , Kopko Anne , Fehniger Todd A. , Bartlett Nancy L. , Blum Kristie A. 
Published: October 2019

Abstract 1644

Introduction:

Previous phase 2 single agent trials with the immunomodulatory agent, lenalidomide, in patients with relapsed or refractory HL demonstrated overall response rates (ORR) of 14–29%, with a median duration of response of 6 months. Likewise, a single agent trial utilizing the orally available HDAC inhibitor, panobinostat, in 127 patients with relapsed/refractory HL after prior autologous stem cell transplant (ASCT) demonstrated an ORR of 27% with a median duration of response of 6.9 months. Based on the encouraging single agent activity of these agents and in vitro synergy of combined panobinostat and lenalidomide in myeloma cell lines, we are conducting a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with this combination and results of the phase I study are presented.

Methods:

Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy are eligibile. Measurable disease ≥1 cm in at least one dimension, ejection fraction ≥45%, ECOG PS 0–2, QTc on ECG ≤ 450 msec, ANC ≥1200/mm3, platelets ≥100,000/mm3, AST/ALT ≤ 2.5 × the upper limit of normal (ULN), bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥60 ml/min are required at study entry. Prior ASCT, lenalidomide, and panobinostat are permitted. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly are combined with lenalidomide 25 mg days 1–21 utilizing a cohorts of 3 design. DLT is defined during cycle 1 and includes grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, and other grade 3–4 non-hematologic toxicity. Six patients will be enrolled at the MTD to ensure patient safety prior to phase 2 enrollment. Twenty-eight days defines a cycle and patients may remain on therapy until disease progression or unacceptable toxicity. Response is assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 2007).

Results:

Seven patients (6 males) with cHL (n=6) and LP HL (n=1) and a median age of 31 (range 24–72) have been enrolled. Patients received a median of 3 prior therapies (range 3–5), 1 patient received prior radiotherapy, 3 patients were refractory to their most recent therapy, 3 patients had prior ASCT, 6 patients had received prior brentuximab vedotin, and no patients had prior lenalidomide or panobinostat. Other characteristics included stage III-IV disease in 100% (57% stage IV), bulky adenopathy ≥5 cm in 14%, and bone marrow involvement in 14%. Seven patients have completed one or more cycles of therapy (median 3, range 1–4) with either 15 mg (n=3) or 20 mg (n=4) of panobinostat + 25 mg lenalidomide. Four patients discontinued therapy for progressive disease (PD) after 4 cycles (n=3) and 1 cycle (n=1), respectively. Three patients continue to receive protocol treatment, all receiving panobinostat 20 mg days 1, 3, and 5 weekly. No DLTs have been observed. Grade 3–4 events included neutropenia (43%), lymphopenia (29%), thrombocytopenia (29%), and hypophosphatemia (29%). No QTc prolongation has been observed. Dose reductions from 15 mg panobinostat days 1, 3, and 5 weekly + lenalidomide 25 mg to 15 mg panobinostat days 1, 3, and 5 weeks 1 and 3 only + 20 mg lenalidomide were required in 2 patients for grade 3–4 neutropenia during cycles 3 and 4. ORR is 33% in 6 evaluable patients with a complete response in 1 patient with cHL and partial response in 1 patient with LP HL. One patient has not yet undergone restaging scans.

Conclusions:

Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL without dose limiting myelosuppression, cardiac toxicity, QTc prolongation, or other grade 3–4 non-hematologic toxicity. Study accrual continues, 2 additional patients will be added to the highest dose level (panobinostat 20 mg days 1, 3, and 5 weekly for 4 weeks + lenalidomide 25 mg days 1–21) to complete the phase I trial and will be followed by anticipated enrollment of a maximum of 25 patients to a two-stage phase 2 trial targeting an ORR of 30% or higher.

Disclosures:

Blum: Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of HL.