ALBERT

Description: Background: Proteasome inhibitors (PIs) are a highly active drug class in multiple myeloma (MM), but development of resistance is commonly observed. Although all clinical-stage PIs are effective inhibitors of chymotrypsin-like (CT-L) proteasome subunit activity, a possible mechanism of resistance is compensatory hyperactivation of the caspase-like (C-L) and trypsin-like (T-L) subunits. Marizomib (MRZ) is a novel, irreversible, second-generation PI under development for the treatment of MM and malignant glioma. MRZ potently inhibits the 3 subunits of the 20S proteasome with a specificity and activity distinct from that of bortezomib and carfilzomib and their oral analogs ixazomib and oprozomib. Methods: In the clinical study NPI-0052-102, we evaluated the pharmacodynamic (PD) activity of MRZ against all three proteasome subunits in whole blood after single, or repeated administration, via two schedules in patients (pts) with previously treated advanced malignancies (solid tumors or hematologic). Pts received MRZ via Schedule A - weekly dosing for 3 doses in 4-week cycles by IV infusion over 1 to 10 min, or Schedule B - twice-weekly dosing for 4 doses in 3-week cycles by IV infusion over 10 min to 2 hr. Blood samples were collected on Days 1 and 15 (Schedule A) or 1 and 11 (Schedule B), pelleted by centrifugation and frozen within 48 hrs. Pellets were lysed and the activity of all 3 proteasomal subunits was assayed using specific fluorogenic substrates. Results: Partial or complete inhibition of all three proteasome subunits was achieved with both once-weekly and twice-weekly MRZ dosing. The rank order of sensitivity, CT-L 〉 T-L 〉 C-L, was as expected from the biochemical and cellular potencies of the drug. For CT-L activity, proteasome inhibition was dose dependent, with both the initial effect (on Cycle 1, Day 1 - C1D1) and the peak effect of proteasome inhibition increasing in a dose-dependent manner. CT-L inhibition was modest at the lowest dose levels (≤ 0.15 mg/m2), reaching moderate levels after repeat dosing. At intermediate dose levels of 0.3 to 0.55 mg/m2, CT-L inhibition was 31% to 75% on C1D1, rising to 70% to 93% after repeat dosing. At doses of 0.7 mg/m2 and above, inhibition of CT-L activity was usually complete within the first cycle. By contrast, C-L and T-L activities were unchanged or increased in the first cycle, suggesting compensatory hyperactivation in response to effective blockade of CT-L activity. Importantly, however, this response was overcome by repeat dosing with MRZ, and inhibition of T-L and C-L activity was noted across all dose levels. For C-L activity, treatment with MRZ at the recommended Phase 2 dose (RP2D) of 0.5 mg/m2 with twice-weekly dosing resulted in inhibition of up to 39% by Cycle 2 and was maintained, when tested, through Cycles 4 and 6. Treatment at the RP2D of 0.7 mg/m2 for once-weekly dosing resulted in C-L inhibition of 14% to 37% by the end of the first cycle, rising to 31% to 50% by the end of Cycle 2. Blockade of T-L activity was more robust after multiple cycles of MRZ therapy. Although inhibition of the T-L subunit was absent on C1D1 in patients receiving 0.5 to 0.55 mg/m2, inhibition of up to 80% was achieved by Cycle 2 and maintained for the duration of treatment. At the once-weekly RP2D of 0.7 mg/m2, T-L inhibition of 29% to 56% was achieved by the end of the first cycle, rising to 64% to 78% by the end of Cycle 2. Conclusions: The PD activity of MRZ against all three proteolytic subunits was assessed in patients with MM, solid tumors, and advanced lymphomas. At the twice-weekly and once-weekly RP2Ds, complete inhibition of CT-L activity was observed within 1-2 cycles of therapy, but accompanied by compensatory hyperactivation of the C-L and T-L subunits. This phenomenon in red cells suggests that it may be due to allosteric interactions within the catalytic core of the 20S proteasome rather than de novo synthesis of additional proteasomes. Ongoing MRZ therapy was able to overcome this adaptive response, resulting in robust pan-subunit proteasome inhibition within 2-6 cycles, most probably due to the cumulative effect of multiple exposures to MRZ. Due to their reversible binding mode (bortezomib, ixazomib) or monospecificity for the CT-L site (carfilzomib, oprozomib), other clinical PIs are predicted to lack this capability. This unique property of MRZ may explain in part its clinical activity in patients with MM resistant to both bortezomib and carfilzomib. Disclosures Off Label Use: marizomib treatment for multiple myeloma and solid tumours.. Harrison:AbbVie: Research Funding; Janssen: Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Burrows:Triphase Accelerator Corporation: Consultancy. Reich:Triphase Accelerator Corporation: Consultancy. Trikha:Triphase Accelerator Corporation: Employment.

Description: Introduction: MRZ is a novel, irreversible, proteasome inhibitor (PI) under clinical development for the treatment of relapsed and refractory multiple myeloma (RRMM). MRZ potently inhibits the 3 proteolytic activities of the 20S proteasome with specificity and activity distinct from that of bortezomib (BZ) and carfilzomib (CFZ). The combination of MRZ and POM has demonstrated promising synergy in in vitro and in vivo models of MM. Methods: As of July 22, 2015, 22 of 36 planned patients (pts) were enrolled with 14 pts in the 3+3 dose-escalation stage and 8 pts into the Recommended Phase 2 Dose (RP2D) stage. All pts received ≥2 prior therapies that must have included both lenalidomide (LEN) and BZ, and have been refractory to their last therapy. Intravenous MRZ (0.3 to 0.5 mg/m2) was administered over 120 minutes on Days (D) 1, 4, 8, and 11; POM (3 or 4 mg) once daily on D1 through 21; and Lo-DEX (5 or 10 mg) once daily on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, and 23 of every 28-D cycle. Safety, pharmacokinetics (PK), cytogenetics, proteasome inhibition, and clinical response were assessed. Results: Pts were 68% male, median (range) age 62 yrs (31 - 76), and with a median of 5 (2 - 15) prior lines of therapy. All pts received prior BZ and LEN; 41% and 55% had also received prior CFZ and thalidomide (THAL), respectively. There were no DLTs during dose-escalation and the most common (〉10% incidence) adverse events (AEs) related to any study treatment in the 22 pts included fatigue (41%), neutropenia (41%), anemia (27%), thrombocytopenia (23%), nausea (18%), diarrhea, dyspnea, insomnia, edema peripheral, and white blood cell count decreased (14%). The grade 3 AEs related to any study treatment in more than one pt included neutropenia (27%) and anemia (9%), pneumonia (9%), and thrombocytopenia (9%). The only grade 4 AE related to any study treatment was neutropenia in one pt. Tumor lysis syndrome (grade 2) related to study treatment was observed in 1 pt; 2 pts had grade 1 peripheral neuropathy (1 considered related to POM alone and 1 related to possibly MRZ and POM); 2 pts came off study and subsequently died from progressive disease (61 and 102 days after last dose); and 1 pt died suddenly during Cycle 1 due to cardiopulmonary arrest, considered possibly related to POM. Since no DLTs were observed the maximum tolerated dose was not exceeded, the highest dose cohort studied, MRZ 0.5 mg/m2, POM 4 mg, and Lo-DEX 10 mg, was determined to be the RP2D. All 17 pts with pre and post dose measurements demonstrated a rapid decrease in their myeloma proteins by C2D1. Preliminary IMWG response assessments provided for the 14 pts with response data through C3D1 included 9 (64%) with partial response (PR); 2 (14%) with minimal response (MR); and 3 (21%) with stable disease (SD). The overall response rate (PR) was 64% and the clinical benefit rate (MR + PR) was 79%. Subset analyses of these 14 pts included high risk cytogenetics (17p deletion and/or 4:14 chromosome translocation) and prior CFZ treatment. In the high risk cytogenetics there were 4/5 PRs and 1/5 MR. Of the 7 pts with prior CFZ treatment there were 5 with PR and 2 with SD, and all 4 pts who had CFZ in their last regimen achieved PR. There was ~100% inhibition of the chymotrypsin-like subunit as early as C1D11, with robust inhibition of the trypsin-like and caspase-like subunits evolving over time in whole blood assays. MRZ, POM, and Lo-DEX PK are in process and will be presented. Conclusions: MRZ in combination with POM and Lo-DEX was generally well tolerated and demonstrated promising activity in heavily pre-treated pts with RRMM including those with high risk cytogenetics and who were refractory to prior treatment with CFZ. The trial will enroll up to 22 pts at the RP2D (36 pts total) to provide additional safety and efficacy data. Disclosures Off Label Use: marizomib for relapsed multiple myeloma. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Zonder:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Harrison:Celgene: Honoraria, Research Funding. Khot:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Honoraria. Chauhan:Triphase: Consultancy. Anderson:Celgene: Consultancy; Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership. Reich:Triphase Accelerator Corporation: Consultancy. Trikha:Triphase Accelerator Corporation: Employment. Richardson:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.