Phase I Study of Lorvotuzumab Mertansine (IMGN901) In Combination with Lenalidomide and Dexamethasone In Patients with CD56-Positive Relapsed or Relapsed/Refractory Mulitple Myeloma - A Preliminary Safety and Efficacy Analysis of the Combination
Authors: Berdeja Jesus G , Ailawadhi Sikander , Niesvizky Ruben , Wolf Jeffrey L , Zildjian Sybil H , O'Leary James , Chanan-Khan Asher 
Published: October 2019

Abstract
Abstract 1934

Background:
Lorvotuzumab mertansine, also known as IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, lorvotuzumab, using an engineered disulfide linker. Once bound to CD56 on a cancer cell and internalized, the conjugate releases DM1. About 78% of multiple myeloma (MM) cases have strong surface expression of CD56. In preclinical settings, IMGN901 showed significant in vitro and in vivo anti-myeloma activity as a single agent and in combination with approved drugs such as lenalidomide. IMGN901 has also been shown to be active and well tolerated as a single agent in a separate phase I study in patients with relapsed or relapsed/refractory MM.

Objectives:
To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetics (PK), and activity of IMGN901 in combination with lenalidomide and dexamethasone in patients with MM.

Methods:
Patients with CD56+ relapsed or relapsed/refractory MM receive IMGN901once weekly for 3 consecutive weeks every 4 weeks (Days 1, 8, 15 every 28 days). Lenalidomide (25mg) is taken orally once daily on Days 1 to 21 every 28 days and dexamethasone (40mg) is taken orally once weekly for 4 weeks (Days 1, 8, 15, and 22 every 28 days). The doses of lenalidomide and dexamethasone will remain fixed while escalating dose levels of IMGN901 are assessed. Patients are enrolled into each dose level in cohorts of 3, with DLTs triggering cohort expansion. Pharmacokinetics of IMGN901 and lenalidomide at the MTD will be collected, with exploratory pharmacodynamic studies planned.

Results:
The first dose cohort (75mg/m2 IMGN901) has been fully enrolled and accrual to the second dose cohort (90mg/m2) has commenced. There has been no DLT, no serious adverse events, and no drug-related grade 3 or 4 toxicities. Among the three patients enrolled in the 75mg/m2 dose cohort, by the end of cycle 2, one withdrew secondary to progressive disease (PD) and the other two had achieved a partial response (PR) based on the International Uniform Response Criteria for MM; the two patients with PRs remain on study. One of these patients had received 3 prior lines of therapy plus a transplant. This patient's PR has since improved to a very good partial response (as of end of Cycle 3). The other responding patient had received 4 prior treatment regimens plus 2 transplants.

Conclusions:
In this assessment of IMGN901 used in combination with lenalidomide and dexamethasone in patients with CD56+ relapsed or relapsed/refractory MM, objective evidence of clinical activity has been observed in two of the three patients who received the first dose level of IMGN901 evaluated. The combination has been well tolerated to date, MTD has not been defined and dose escalation continues. This very early experience is encouraging and supports the continued assessment of IMGN901 used in combination with lenalidomide and dexamethasone for patients with CD56+ relapsed or relapsed/refractory MM.

Disclosures:
Ailawadhi: Celgene: Speakers Bureau. Zildjian:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.