A phase I study of the novel immunotoxin, MT-5111, in subjects (subj) with HER-2 positive tumors: Interim results.

Abstract

e15567 Background: Engineered toxin bodies (ETBs), composed of a Shiga-like Toxin A subunit genetically fused to antibody-like binding domains, can force receptor internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, binds to an epitope distinct from and non-competitive with trastuzumab and pertuzumab. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adults with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics, efficacy, and immunogenicity. Part 1 will identify the MTD via MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10 µg/kg/dose) according to a modified 3+3 design. Part 2 will further evaluate the safety of MT-5111 at the recommended phase 2 dose (RP2D) in 3 separate cohorts of subjs with a HER2 immunohistochemistry score ≥2 in a metastatic lesion of primary breast, gastroesophageal, or other cancers. All subjs receive MT-5111 as a 30-minute IV infusion on Days 1, 8, and 15 of each 21-day treatment (tx) cycle (C) until disease progression, unacceptable toxicity, death, or withdrawn consent. Details can be found on clinicaltrials.gov (NCT04029922). Results: The first cohort (0.5 µg/kg/dose) enrolled 4 subjs (metastatic breast cancer, n = 2; metastatic cholangiocarcinoma, n = 2). Three subjs were female and the mean age was 69 years (median 65, range 64-78). Subjs received a mean of 5 prior lines of therapy (median 4.5, range 3-8). Three subjs completed C1 of tx without dose-limiting toxicities; 1 subj was inevaluable. Two subjs had progressive disease in C2. A total of 23 AEs occurred in 4 subjs; all were grade (G) 1-2 except one G3 event of hypertension in a subj with a history of hypertension. There were 2 tx-related AEs (G1 chills; G2 aspartate aminotransferase increased in the setting of progressive liver metastases). There was 1 serious, non-tx-related AE (G2 dyspnea) that occurred in the inevaluable subj. No cardiac AEs were noted, nor clinically significant changes in cardiac biomarkers, an important safety parameter given non-human primate toxicity. Conclusions: MT-5111 appears to be well tolerated at the lowest dose with no apparent cardiotoxicity to date. Drug concentrations are expected to be below the level required for in vitro tumor cell killing. Safety and efficacy data from subsequent dose escalation cohorts are expected by May 2020. Clinical trial information: NCT04029922.