A Phase IB, Multicenter, Open-Label, Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with Relapsed Multiple Myeloma

Panobinostat (LBH589) is a pan-deacetylase inhibitor (pan-DACi), targeting epigenetic and multiple oncogenic pathways. Beyond numerous hematological cell lines being highly sensitive in vitro, panobinostat has shown to induce cytotoxicity at low nanomolar concentrations in multiple myeloma (MM) cell lines resistant to dexamethasone, melphalan, and doxorubicin. Additional in vitro and in vivo experiments have demonstrated potent synergistic MM cytotoxicity of panobinostat and bortezomib associated with blocking of aggresome and proteosome degradation of ubiquinated protein. Collectively, these data provide a strong rationale for the first clinical trial of this combination in MM patients. The primary objective of this Phase I study is to establish the maximum-tolerated dose (MTD) of panobinostat with bortezomib in a second-line setting. Safety, tolerability, pharmacokinetic/pharmacodynamic profiles, and preliminary efficacy of the combination will be assessed as secondary endpoints.. Patients with relapsed MM, who have received at least 1 prior line of therapy, are to be enrolled, if they are suitable for bortezomib therapy and have no primary refractory MM prior exposure to an HDACi, impaired cardiac function, or QTc prolongation. Dose-escalation started at 10 mg of panobinostat (po thrice weekly) in combination with 1 mg/m² of bortezomib (i.v on Days 1, 4, 8 and 11) over a 21 day cycle. In any cohort, dexamethasone can be added after Cycle 1, in case of worsening disease. A 6-parameter, adaptive Bayesian logistic regression model guides the escalation to MTD with each dose-combination being studied in cohorts of at least 6 patients. At the confirmed MTD, additional patients will be enrolled to obtain further safety and tolerability information. As of 21 July 2008, a total of 14 patients have been enrolled in 2 cohorts: Cohort 1 (10 mg panobinostat + 1.0 mg/m² bortezomib, n=7,), and Cohort 2 (20 mg panobinostat + 1.0 mg/m² bortezomib, n=7). Patients are 10 males and 4 females, with median age of 57 (range 46–78). Median number of prior therapies is 3 (range 1–7). All patients had at least one prior auto-SCT, and bortezomib was listed among prior therapies in 8 pts. Disease status included 9/14 pts refractory at entry, defined as progressing within 60 days of last therapy. 1 patient (Cohort 2) with a borderline entry ANC value experienced an early Grade 4 afebrile neutropenia, which met DLT criteria. Grade 3/4 hematological AEs were the most frequent and included anemia in 2 pts, thrombocytopenia in 11 pts, and neutropenia in 3 pts. G-CSF treatment was required by 2 patients. Non-hematological AEs have included lower grade diarrhea and fatigue. To date, with a total of 44 complete cycles received by 14 patients, 1 immunofixation negative (IF-) CR, 1 VGPR, and 3 PR were seen with dexamethasone added at 2nd cycle in 3 of these 5 pts (CR + 2 PR). The IF-CR response in a patient of Cohort 2, in relapse after Auto-SCT and observed after 3 cycles, was determined by negative IF and normalized serum-free light chain ratio (bone marrow evaluation refused by the patient). VGPR was observed in 1 patient in relapse after auto-SCT, after 7 cycles (Cohort 1); therapy was discontinued in Cycle 10 due to Grade 2 weight loss. PR was observed in 3 patients (1 in Cohort 1; 2 in Cohort 2), occurring early on after one to two cycles. 2 of these patients had received prior bortezomib, 1 had been treated with 4 prior lines of therapy, and the other received 6 prior lines of therapy, including autologous and allogeneic SCT, donor lymphocyte infusion, cyclophosphamide/thalidomide, and lenalidomide. These responses, observed at early/low dose levels of the trial drugs, show a potential activity of panobinostat in combination to bortezomib in patients who had not responded to bortezomib. The combination of panobinostat and bortezomib shows promising activity and a good safety profile. Enrollment into Cohort 3 (20 mg panobinostat + 1.3mg/mg/m² bortezomib) is currently underway. Updated follow-up, as well as new patient data, will be presented.