Burnett, Christine

Abstract Background: Engineered toxin bodies (ETBs), composed of an engineered Shiga-like Toxin A subunit genetically fused to an antibody-binding domain, can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other targeted agents. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, also binds to an epitope distinct from trastuzumab and pertuzumab, which may permit combination strategies with other HER2 targeting agents. Methods: The primary objective is to determine maximum tolerated dose (MTD) of MT-5111 monotherapy in adult patients (pts) with advanced HER2+ solid tumors. Secondary objectives are PK, efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study includes the following 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and any other HER2+ tumors. All pts will receive MT-5111 weekly as a 30-min IV infusion in each 21-d treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: As of the data cut in December 2020, 16 pts were treated; cancer types included breast (n=6), gastric (n=1), colon (n=1), gallbladder (n=5), and other solid tumors (n=3). Mean age was 64 years (range, 34-78); 37.5% were male. Pts received a median of 4 prior lines of systemic therapies (range, 1-8). No G4 or G5 TEAEs occurred. Six pts had 11 G3 TEAEs; the most common were increased AST and dyspnea (both n=2). Three pts had tx-emergent serious adverse events (abdominal distension [n=1]; dyspnea [n=2]). Tx-related TEAEs occurred in 8 (50%) pts; the most common was fatigue (n=5, 31.3%) and all were ≤ grade 2 in nature, except for one grade 3 event of dyspnea. No cardiac TEAEs, clinically significant changes in cardiac biomarkers (troponin, electrocardiogram, left ventricular ejection fraction), or cases of capillary leak syndrome were observed. Fifteen pts discontinued with PD; 1 pt in cohort 5 (4.5 µg/kg) is on tx with stable disease. To date, no DLTs have been observed and the MTD has not been reached. One pt in cohort 2 (1 µg/kg) had resolution of all hepatic lesions (sub-centimeter lesions pre-tx) at the end of C8; however, the pt came off study due to clinical progression at the end of C10. PK data for the first 5 cohorts matched simulations based on non-human primate studies. Conclusions: MT-5111 was well tolerated with no clinically significant cardiotoxicity. Continued dose escalations are ongoing. Citation Format: Zev A. Wainberg, Monica M. Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Christine Burnett, Joshua Pelham, Eric T. Williams, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Brian A. Van Tine. Phase 1 study of the novel immunotoxin MT-5111 in patients with HER-2+tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT130.

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action & are capable of forcing internalization, self-routing through intracellular compartments to the cytosol & inducing potent cell-kill via the enzymatic & permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein & may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, & maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation & expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response & immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, & 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) & other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.