Panorama 2: A Phase Ii Study Of Panobinostat (Lbh589) In Combination With Bortezomib (Btz) And Dexamethasone (Dex) In Patients With Relapsed And Btz-Refractory Multiple Myeloma (Mm)

TPS308 Background: BTZ, a backbone of novel therapy for patients (pts) with MM, is an effective agent but pts will relapse and ultimately become refractory to BTZ-based therapy as well as other novel agents, thereby constituting a high unmet medical need. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) that targets HDAC6, disrupts aggresome and HSP90 activity, and promotes MM cell death. Combination with BTZ has shown synergistic cytotoxicity in preclinical studies. In a phase Ib MM study, combination of oral PAN with iv BTZ displayed a predictable and manageable safety profile with limited neurotoxicity and clinical efficacy seen with CR + PR + MR in 68% of pts, including 8 of 13 (62%) BTZ-refractory pts. Hence this combination is to be further evaluated in the PANORAMA program (PANobinostat ORAl in Multiple myelomA) Phase III (PANORAMA 1) and Phase II (PANORAMA 2) studies. PANORAMA 2is a U.S.-based, multicenter, single-arm study to evaluate the efficacy of PAN + BTZ + DEX in pts with relapsed and BTZ- refractory MM to assess if the combination with PAN can resensitize pts to BTZ+DEX. Methods: Adult pts with relapsed BTZ- refractory MM (≥2 prior lines of therapy, including an IMiD [thalidomide/lenalidomide], who had progressed on/within 60 days [D] of last BTZ-based therapy) are eligible. Pts receive maximum 8 21-D cycles of PAN (po 20 mg D1, 3, 5, 8, 10, 12) + BTZ (iv 1.3 mg/m2 D1, 4, 8, 11) + DEX (po 20 mg D1, 2, 4, 5, 8, 9, 11, 12). This provides a 1-wk treatment break to maximize tolerability and therapy duration. Per Simon's 2-stage design (H1: ORR >10% vs H0: ORR ≤10%, powered for ORR=25%), Stage 1 will enroll 24 pts. If PR or better in ≥4 pts is seen, 23 additional pts will be enrolled to stage 2. Study endpoint will be met upon ≥8 responses total. Treatment is continued until PD, unacceptable toxicity, or consent withdrawal. Pt follow-up is for 28 D post last dose for safety and up to 2 years for tumor assessment and survival. Primary endpoint is ORR (PR or better); secondary endpoints include MR rate, time to response, DoR, PFS, TTP, OS, and safety, including PN graded by FACT GOG/NTX. Exploratory endpoints include VGPR rate and biomarker studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Celgene, Facet Biotech, Millennium, Novartis Novartis Novartis Bristol-Myers Squibb, Celgene, Facet Biotech, Gloucester Pharmaceuticals, Millennium, Novartis