Efficacy of Panobinostat in Phase II Study in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with Autologous Stem Cell Transplant.

Panobinostat (LBH589) is a pan-deacetylase inhibitor (pan-DACi), targeting epigenetic and non-epigenetic oncogenic pathways. In vitro, panobinostat decreases proliferation and induces apoptosis in Hodgkin lymphoma (HL) cell lines at low nanomolar concentrations. Encouraging clinical activity (objective response rate ∼40%) has been demonstrated in patients with HL who are enrolled in an ongoing Phase I study in hematologic malignancies (DeAngelo et al. EHA 2009, Abstract #1064).

Utilizing a Simon two-stage design, the study will determine the efficacy of panobinostat in patients with HL with refractory/relapsed disease following high-dose chemotherapy and autologous hematopoietic stem cell transplant (AHSCT). Oral panobinostat is administered at a dose of 40 mg three times per week, every week in 21-day cycles. Treatment is continued until disease progression or intolerance. Dose delay and modification for toxicity is allowed. CT/MRI scans are conducted after every 2 cycles. Modified Cheson criteria are used to determine overall response.

As of July 10, 2009, 61 patients have been enrolled and treated: median age 31 years [range 18–70]; 29 male, 32 female; 48% Stage III/IV at initial diagnosis; 41% had ≥5 prior lines of therapy; median number of prior regimens is 4 (range 2–6). Of 61 patients, 53 have completed ≥2 cycles of therapy and have had ≥1 post baseline CT/MRI. Responses include one complete response (CR) and 10 partial responses (PR), with up to 92% decrease in tumor burden. Thirty-one patients had SD, of which 25 had reduction in tumor burden (up to 48%). The disease control rate (CR+PR+SD) is 79%. The CR was achieved after 4 cycles of therapy. The patient required dose reduction but continues on the study (>12 cycles) and has maintained CR with no signs of active disease on CT and PET. Another responder with mixed cellularity HL was refractory to prior systemic treatments but has maintained PR on panobinostat and continues on the study (>14 cycles). Median treatment duration is 89+ days (range 5–300+ days), and 27 of the 61 treated patients still continue on study. Common Grade 3/4 adverse events, which were suspected to be related, are thrombocytopenia (77%), anemia (20%), and neutropenia (16%). Thrombocytopenia was observed to be reversible with platelet recovery 7–8 days after drug hold (panobinostat T_1/2 ∼16 hours).

Panobinostat has demonstrated encouraging clinical activity in heavily pretreated patients with post-transplant, refractory/relapsed, classical HL. Panobinostat is generally well tolerated with reversible thrombocytopenia as the primary toxicity managed by dose delay/reduction. Stage 1 has been successfully completed with positive results. Enrollment to Stage 2 continues. Updated efficacy and safety data will be presented at the meeting.

Younes:Novartis: Honoraria. Off Label Use: The data presented is related to investigational unapproved drug.. Ribrag:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy, Research Funding; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Research Funding; J&J: Membership on an entity's Board of Directors or advisory committees; Biogene Idec: Membership on an entity's Board of Directors or advisory committees. McCabe:Novartis: Employment. Shen:Novartis: Employment. Le Corre:Novartis: Employment. Hirawat:Novartis: Employment. Sureda:Novartis: Consultancy, Honoraria.