Results of a Phase 1 Dose-Escalation Study of Once-Weekly MLN9708, an Investigational Proteasome Inhibitor, in Patients with Relapsed/Refractory Lymphoma
Authors: Assouline Sarit , Chang Julie E. , Cheson Bruce D. , Rifkin Robert , Hamburg Solomon , Reyes Ruben , Hui Ai-Min , Yu Jiang , Gupta Neeraj , Di Bacco Alessandra , Shou Yaping , Martin Peter 
Published: October 2019

Abstract 3646

Background:

The validity of proteasome inhibition as an effective therapeutic approach in lymphoma has been demonstrated by the first-in-class proteasome inhibitor bortezomib. MLN9708 is a reversible, orally bioavailable, specific investigational 20S proteasome inhibitor that immediately hydrolyzes in vivo to MLN2238, the biologically active form. In mouse models of lymphoma, MLN2238 was associated with greater tumor proteasome inhibition and enhanced antitumor activity versus bortezomib (Lee et al., Clin Cancer Res 2011). The primary objectives of this study of intravenous (IV) MLN9708 in patients with relapsed/refractory lymphoma (NCT00893464) were to determine the safety and maximum tolerated dose (MTD) of once-weekly MLN9708; secondary objectives included characterization of pharmacokinetics (PK) and pharmacodynamics, and assessment of preliminary antitumor activity.

Methods:

Patients aged ≥18 years with measurable relapsed/refractory lymphoma who had failed ≥2 prior lines of therapies received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Dose doubling proceeded from a starting dose of 0.125 mg/m2 with 1 patient per dose up to 1.0 mg/m2. Dose escalation then occurred in 26–40% increments using a standard 3+3 scheme based on occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were graded using NCI CTCAE v3.0. Blood samples were collected at multiple time points on days 1 and 15 of cycle 1, and day 1 of cycle 2 for PK analyses. Response was assessed using IWG criteria.

Results:

At data cut-off (June 29, 2012), 26 patients (16 male) had been enrolled: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, 6 at 2.34 mg/m2, and 5 at 3.11 mg/m2. Median age was 56.5 years (range 23–78). Median number of prior therapies was 5 (range 1–12); 31% had prior radiation therapy, 23% had a prior stem cell transplant. Eight patients had Ann Arbor stage IV, 3 had stage III, 6 had stage II, and 2 had stage I; staging was unknown in 4 patients and not applicable in 3. Histologies included follicular lymphoma (FL; n=8), diffuse large B-cell lymphoma (n=6), peripheral T-cell lymphoma (PTCL; n=4), mycosis fungoides (n=2), Hodgkin lymphoma (n=3), and others (n=3). Patients have received a median of 2 cycles of MLN9708 (range 1–29). Four DLTs were reported: 1 grade 4 neutropenia at 1.76 mg/m2, 1 grade 3 neutropenia at 2.34 mg/m2, and 2 grade 3 acute pre-renal failure due to GI toxicities and dehydration at 3.11 mg/m2. The MTD has been determined as 2.34 mg/m2. All patients experienced drug-related AEs, including fatigue (n=12), diarrhea (n=10), nausea, vomiting (each n=8), thrombocytopenia (n=6), pyrexia, neutropenia, decreased appetite, and headache (each n=5). Twelve patients (46%) had drug-related grade ≥3 AEs, including neutropenia (n=4), thrombocytopenia, and diarrhea (each n=3). Three patients discontinued due to AEs of drug-related grade 3 neutropenia (2.34 mg/m2), drug-related grade 3 asthenia and grade 3 acute pre-renal failure, and unrelated grade 3 thrombocytopenia (both 3.11 mg/m2). Three patients reported drug-related serious AEs. Four patients reported drug-related peripheral neuropathy, all were grade 1 or 2. There was 1 on-study death due to respiratory failure, considered unrelated to MLN9708. PK analyses showed a dose-proportional increase in plasma exposure with increasing dose from 0.5 to 2.34 mg/m2 and a terminal half-life of 5.5–9 days after multiple dosing. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Of 22 response-evaluable patients (as of August 7, 2012), one achieved a complete response (CR; FL at 1.76 mg/m2, initial partial response [PR] at cycle 4, improved to CR at cycle 20, ongoing at cycle 24), and 3 achieved a PR (1 FL at 1.4 mg/m2, achieved at cycle 10, ongoing at cycle 30; 1 FL at 3.11 mg/m2, recently achieved at cycle 2 and ongoing at cycle 3; 1 PTCL at 2.34 mg/m2, achieved at cycle 4 but progressed at cycle 8). A further 4 patients had stable disease of ≥ 4 cycles.

Conclusions:

These phase 1 data suggest that once-weekly IV MLN9708 is generally well tolerated, with infrequent peripheral neuropathy, and shows signs of clinical activity in heavily pretreated relapsed/refractory lymphoma patients, particularly FL patients. Enrollment continues at the MTD; phase 2 studies with oral MLN9708 are planned.

Disclosures:

Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory lymphoma. Chang:Genentech: Research Funding; Celgene: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc./Takeda: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; INCYTE: Speakers Bureau; Amgen: Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Yu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc: Employment. Shou:Millennium Pharmaceuticals, Inc: Employment. Martin:Millennium Pharmaceuticals, Inc.: Speakers Bureau.