Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma
Authors: Papadopoulos Kyriakos , diCapua Siegel David Samuel , Singhal Seema B. , Infante Jeffrey R. , Sausville Edward A. , Gordon Michael S. , Kauffman Michael , Woo Tina , Lee Susan , Bui Lynne , Hannah Alison L. , Lee Peter 
Published: October 2019

Abstract
Abstract 3024

Background:
Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters.

Methods:
This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts).

Results:
To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table.
Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity.

Conclusions:
In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial.

Disclosures:
Papadopoulos: Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.