Phase Ib study of oral panobinostat (LBH589) plus lenalidomide (LEN) plus dexamethasone (DEX) in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM).
Authors: 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
Journal: Journal of Clinical Oncology (2010)

8030^ 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. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Celgene, Janssen-Cilag, Millennium, Novartis Novartis Celgene, Janssen-Cilag, Novartis Gloucester Pharmaceuticals, Millennium, Novartis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.