MLN9708, a Novel, Investigational Proteasome Inhibitor, in Patients with Relapsed/Refractory Lymphoma: Results of a Phase 1 Dose-Escalation Study

Abstract

Abstract 2672 Background:MLN9708 is an investigational, potent, reversible, and specific 20S proteasome inhibitor. It is immediately hydrolyzed in vivo to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 showed faster proteasome dissociation and greater tissue penetration than bortezomib. In OCI-Ly10 and PHTX22L mouse models of lymphoma, prolonged tumor proteasome inhibition and enhanced antitumor activity was seen with MLN2238 compared with bortezomib. Both intravenous (IV) and oral formulations are in clinical development. Here we report data from the first phase 1 study of IV MLN9708 in patients with lymphoma (ClinicalTrials.gov: NCT00893464). Methods:The primary objectives were to determine the maximum tolerated dose (MTD) and safety of MLN9708. Other objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile, and assessment of antitumor activity and tumor biomarkers. Adults with lymphoma who had failed at least 2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles for up to 12 cycles or until disease progression or unacceptable toxicity occurred. Patients had ECOG PS 0–2, adequate renal, hepatic, and hematologic function, and no grade ≥2 peripheral neuropathy. One patient was enrolled at the starting dose of 0.125 mg/m2; dose doubling proceeded with 1 patient at each dose level up to 1.0 mg/m2. Dose escalation then proceeded in ≤40% increments via a standard 3+3 scheme based on DLT occurrence in cycle 1. The MTD was defined as the highest dose resulting in DLT during cycle 1 in 0/3 or 1/6 patients. Adverse events (AEs) were graded using NCI-CTCAE v3.0. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analysis. PK and PD parameters were calculated using noncompartmental methods (WinNonlin v5.3). Archived tumor specimens were used for biomarker analysis. Response was assessed using International Working Group criteria for lymphoma. Results:At data cut-off (July 8, 2011), 17 patients had been enrolled and treated: 1 each at 0.125, 0.25, 0.5, and 1.0 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 2 at 2.34 mg/m2. The median age was 53 years (range 23–78). Histologies were follicular lymphoma (n=6), diffuse large B-cell lymphoma (n=3), Hodgkin lymphoma (n=3), T-cell lymphoma (n=3), and other (n=2). The median number of prior therapies was 5, including radiation and stem cell transplant in 29% of patients each; 47% had received ≥6. Patients received a median of 2 cycles (range 1–16); treatment is ongoing in 3 patients. Two DLTs were seen (1.76 mg/m2, grade 4 neutropenia; 2.34 mg/m2, grade 3 neutropenia delaying cycle 2 by >1 week); the MTD has not yet been reached. Drug-related AEs included fatigue (n=8), diarrhea (n=5), nausea (n=5) and vomiting, pyrexia, neutropenia, thrombocytopenia, and headache (n=4 each). Drug-related peripheral neuropathy was reported in 3 patients (one grade 1, two grade 2 in patients with peripheral neuropathy at baseline). Grade ≥3 drug-related AEs were seen in 8 patients, including neutropenia (n=4) and thrombocytopenia (n=3). Two patients treated at 1.4 mg/m2 had SAEs (grade 3 increased creatinine, grade 2 pyrexia). There were no on-study deaths. One patient treated at 2.34 mg/m2 discontinued due to drug-related grade 3 neutropenia. Three patients treated at 1.76 mg/m2 required dose reductions. Of 16 response-evaluable patients, 3 achieved partial response and continue to respond (2/6 with follicular lymphoma at 1.4 and 1.76 mg/m2, 1/3 with T-cell lymphoma at 2.34 mg/m2); duration of response is >9 months in a patient with follicular lymphoma. Stable disease, durable for up to 3.7 months, occurred in 4 patients. MLN2238 plasma concentration decreased by 90% within 4 hours post dose. After multiple dosing, the terminal half-life ranged from 4–8 days. Plasma exposure appeared to increase proportionally with increasing dose from 0.5–2.34 mg/m2. Whole blood 20S proteasome inhibition was immediate, and maximal inhibition correlated with maximum plasma concentration. Conclusions:These data suggest that once-weekly MLN9708 is generally well tolerated and has early signs of clinical activity in some patients with heavily treated lymphoma. Dose escalation continues to determine the MTD; a total of 16 patients will be evaluated at the MTD. Updated data and analyses of patient stratification biomarkers will be presented. Disclosures:Off Label Use: Use of investigational agent MLN9708 for the treatment of relapsed/refractory lymphoma. Rifkin:Amgen: Speakers Bureau; Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Xi:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Martin:Millennium Pharmaceuticals, Inc.: Research Funding, Speakers Bureau.