S. Mu,1 T. Tajima,2 C. Corrado,3 K. Sunami,4 K. Suzuki,5 M. Hino,6 Y. Kuroda,7 H. Shibayama,8 R. Lin,1 E. Waldron,1 F. Binlich9; 1Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2Novartis Pharmaceuticals Corporation, Tokyo, Japan, 3Novartis Pharmaceuticals Corporation, Basel, Switzerland, 4National Hospital Organization, Okayama, Japan, 5Japanese Red Cross Medical Center, Tokyo, Japan, 6Osaka City University Hospital, Okayama, Japan, 7Hiroshima University Hospital, Hiroshima, Japan, 8Osaka University, Osaka, Japan, 9Novartis Pharma S.A.S, Rueil-Malmaison, France
BACKGROUND: Panobinostat (PAN), a potent pan-deacetylase inhibitor, significantly increased progression-free survival (PFS) in patients with RRMM when combined with bortezomib (BTZ) and dexamethasone (Dex) in a phase III trial, PANORAMA-1. Exposure-response correlation (efficacy and safety) was explored for PAN in this combination in a phase I trial B2207 and contrasted with other single-agent trials.
METHODS: Oral PAN (given thrice weekly, 2 weeks on, 1 week off) plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n=13) and B2207 (n=12) trials, with 1.3 mg/m2 BTZ and 20 mg Dex. Overall response rate (ORR) and major adverse events (AE) were tabulated and contrasted based on escalating PAN dose. PAN exposures from these two combination studies were compared against historical single-agent trials.
RESULTS: At MTD of 20 mg PAN, 1.3 mg/m2 BTZ and 20 mg Dex identified in B2207, geometric mean of PAN AUC0-24h was 47.5 (77%) ng∙hr/mL and Cmax was 8.1 (90%) ng/mL. These values were consistent with exposure obtained from PANORAMA-1, but were 20-50% lower than those from single-agent trials of PAN, likely due to CYP3A induction by Dex. ORR (≥ partial response) increased with increase in PAN dose and/or exposure in the escalation phase without Dex. Best ORR of 73% was observed when Dex was added to the combination. Grade 3/4 AEs included thrombocytopenia (TCP), neutropenia, fatigue and diarrhea.
CONCLUSION: Combination of PAN with BTZ and Dex demonstrated promising clinical benefit in RRMM. Apparent exposure-ORR relationship was observed for PAN when combined with BTZ. The addition of Dex achieved best ORR suggesting synergy though plasma exposure of PAN was reduced. Combination with a strong CYP3A inducer should be avoided to prevent further reduction of PAN exposure.