Overview

This is a first-in-human, open-label, non-randomized, three-part phase 1 trial of INBRX-109, which is a recombinant humanized tetravalent antibody targeting the human death receptor 5 (DR5).

Eligibility

Inclusion Criteria:

• Males or females aged ≥12 to <85 years for Ewing sarcoma and 18 to <85 years of age for GIST.
• Escalation: Histologically or cytologically-confirmed advanced/metastatic or non-resectable solid tumors, including sarcoma, that are refractory or intolerant to standard therapy, or for which no standard therapy exists that is likely to confer any clinical benefit.
• Expansion Cohorts: Malignant pleural mesothelioma, gastric adenocarcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma and certain sarcoma subtypes (e.g., chondrosarcoma, Ewing sarcoma), GIST, and SDH-def solid tumors with locally advanced or metastatic, non-resectable disease, that are refractory or intolerant to standard therapy, or for which no standard therapy exists that is likely to confer any clinical benefit.
• Measurable disease as defined by RECISTv1.1 (or modified RECIST for mesothelioma) criteria.
• Adequate hematologic, coagulation, hepatic and renal function as defined per protocol.
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 for Part 1 and ECOG PS of 0, 1 or 2 for Parts 2 and 3.

Exclusion Criteria:

• Prior treatment with or exposure to DR5 agonists.
• Receipt of any anticancer therapy (including investigational agents) within 4 weeks or within 5 half-lives prior to the first dose of study treatment. Exceptions per protocol.
• Receipt of radiotherapy within 4 weeks prior to the first dose of study treatment, and liver-directed within 12 months prior to the first dose of study drug.
• Subject has undergone allogeneic hematopoietic stem cell or bone marrow transplantation within the last 5 years. Exception: Participants who have had a stem cell or bone marrow transplant > 5 years ago are eligible for enrollment, as long as there are no symptoms of graft-versus-host disease (GVHD).
• Prior or concurrent malignancies. Exception: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of INBRX-109.
• Hematologic malignancies.
• Symptomatic active primary CNS tumors, leptomeningeal disease, and CNS metastases. Exceptions per protocol.
• Chronic liver disease including but not limited to cirrhosis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), alcohol-related liver disease, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, multiple liver hemangioma (except incidental finding of clinically nonsignificant liver hemangioma), hepatic or biliary autoimmune disorders (ie, primary biliary cholangitis, autoimmune hepatitis), history of portal or hepatic vein thrombosis, and sinusoidal occlusion syndrome. Exceptions per protocol.
• Acute viral or toxic liver disease within 12 months prior to the first dose of study drug.
• Evidence or history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
• Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, cerebrovascular accident, or other acute uncontrolled heart disease < 3 months;
• Sensitivity or contraindications to INBRX-109, irinotecan, or temozolomide.
• Major surgery within 4 weeks prior to enrollment on this trial.
• Systemic infection requiring antibiotics within 2 weeks prior to the first dose of study drug.
• Pregnant or nursing females.
• Patients who are receiving strong cytochrome P450 (CYP) 3A inhibitors and/or inducers, and/or UGT1A1 inhibitors within 14 days of Cycle 1 Day 1.