A Phase I Study Of Panobinostat In Combination With ICE (Ifosfamide, Carboplatin and Etoposide) In Patients With Relapsed Or Refractory Classical Hodgkin Lymphoma (cHL)

The standard approach to patients with refractory or recurrent cHL is treatment with an effective salvage chemotherapy followed by stem cell transplantation. The best outcome from the transplant is expected in patients who achieve complete response (CR) after the salvage chemotherapy. The commonly used regimen, ICE produces CR rate ranging from 26% (response evaluation by CT, Moskowitz CH et al. Blood 2001) to 61% (by augmented ICE, response evaluation by PET, Moskowitz CH et al. Blood 2012). Panobinostat is a potent oral pan-deacetylase inhibitor that has shown activity against refractory or recurrent cHL after transplant with acceptable toxicity profile with a dose limiting toxicity of reversible thrombocytopenia (Younes A et al. JCO 2012). We conducted a phase I study of oral panobinostat in combination with standard ICE for patients who had recurrent or refractory disease after ABVD based chemotherapy. The treatment consisted of oral panobinostat on Monday/Wednesday/Friday starting from 1 week before first ICE, and to be continued during ICE through the second cycle. Third cycle was administered without panobinostat concerning the potential adverse impact on stem cell collection. The starting dose of panobinostat was 20mg, and the target dose was 30mg based on 3+3 design, with planned expansion at the highest dose. As the time of data cut off (July 2013), a total of 23 patients were registered and 21 were assessable for toxicity and response. The median age of patients were 31 (range 19-60), male/female 14/7 patients, primary refractory disease in 9 patients. At 20mg, dose limiting toxicity (DLT, febrile neutropenia) was observed in one of the 6 patients. At 30mg, 3 patients were enrolled without DLT. Thus, we expanded the cohort at 30mg in two different schedules (A: panobinostat to be started one week before first ICE, then 1st and 2nd week of ICE [n=10], B: panobinostat to be started one week before ICE, then only 1st week of ICE of each cycle [n=2, ongoing]). Overall, there was no grade 3/4 non-hematologic toxicity observed. The common non-hematologic toxicity of grade 1/2 (>10%) was fatigue (43%), nausea (43%), and vomit (29%). Hematologic toxicity included anemia (grade 1/2 in 24%, grade 3 in 5%), neutropenia (grade 1/2 in 5%, grade 3 in 10%, grade 4 in 57%), thrombocytopenia (grade 1/2 in 5%, grade 2 in 10%, grade 4 in 81%) and febrile neutropenia (grade 3 in 10%). All 21 patients were assessed for response and overall response rate was 86%, with complete response rate of 71%. All responding patients (86%) proceeded to autologous stem cell transplant after this regimen. Patients who did not have a stem cell collection after 3rd cycle of ICE received stem cell mobilizing chemotherapy. There were no issues with stem cell harvest and engraftment in any of patients. In conclusion, panobinostat plus ICE is an effective first salvage regimen for recurrent or refractory cHL. We are currently evaluating schedule B, which is with shorter treatment with panobinostat, in an expansion cohort in this phase I study.