Author(s): M. Mateos, A. Spencer, K. Taylor, S. Lonial, J. De La Rubia, T. Facon, B. Bengoudifa, K. Hazell, P. M. Bourquelot, J. F. San-Miguel
Background: Panobinostat (PAN; LBH589) is an orally bioavailable pan-deacetylase inhibitor targeting epigenetic and non- epigenetic oncogenic pathways. Combining PAN with the immunomodulatory agent LEN and DEX in vitro and in vivo has shown potent anti-MM activity. This Phase Ib study sought to establish the maximum tolerated dose (MTD) of PAN with LEN + DEX for treatment of Rel or Rel and Ref MM.
Methods: Cohorts of ≥6 pts received PAN (po thrice weekly) + LEN (25 mg po Days [D] 1-21) + DEX (40 mg po D1-4, 9-12, 17-20, Cycles [C] 1-4, and D1-4, C5 onwards), on a 28 D cycle. DLTs, safety, tolerability, PK/PD, and preliminary efficacy were evaluated.
Results: As of Dec 1, 2009, 46 pts had been treated at 4 PAN dose levels: 5 mg (n=8), 10 mg (n=8), 20 mg (n=21), or 25 mg (n=9) after a median 2 prior therapies (range 1-8), including bortezomib (n=28), thalidomide (n= 29), LEN (n=8), and/or SCT (n=36). 25 pts had refractory disease. 12 pts remain on study. DLTs were observed in 9/36 evaluable pts, including 3/7 at PAN 25 mg: hematologic (n=4) (thrombocytopenia [TCP], neutropenia [NP]), QTcF prolongation (n=2), atrial fibrillation (n=1), fatigue (n=1), pneumonia (n=1). In 46 pts evaluable for safety, AEs in ≥20% pts were hematologic (Gr 3/4 TCP or NP in 44% and 37%, respectively), GI, or muscular. Other Gr 3/4 AEs: fatigue/asthenia, reduced appetite, insomnia, muscle weakness/metabolic (DEX-related), respiratory infection, diarrhea, dysgeusia. 2 deaths on study (febrile NP with respiratory infection and ischemic colitis) were suspected as treatment-related. 1 pt had a DVT. Dose adjustment frequency was comparable in lower-dose cohorts, primarily due to DEX-related AEs, but increased in the PAN 25 mg cohort (≥1 reduction in 6 pts). The PAN 20 mg dose level has been expanded to determine MTD. 30 pts were evaluable for response, with responses observed in 17: 1 sCR, 1 CR, 7 VGPRs, 8 PRs. 7 pts had SD; 6 pts had PD.
Conclusions: In this first trial of the oral triple PAN + LEN + DEX combination in pts with advanced MM, no new safety concerns were identified and preliminary efficacy was very encouraging. Further study will incorporate a lower DEX dose and non-continuous PAN dosing schedule.