ME-344 and Bevacizumab in Previously Treated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the oxidative phosphorylation (OxPhos) pathway inhibitor ME-344 in combination with bevacizumab in subjects with recurrent mCRC.

Detailed Description
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This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the oxidative phosphorylation (OxPhos) pathway inhibitor ME-344 in combination with bevacizumab in subjects with recurrent mCRC. This study will enroll subjects with metastatic CRC, including but not limited to subjects with RAS wild-type or mutant tumors, MSI-H/pMMR, and BRAF V600E, who have progressed or demonstrated intolerability to standard approved therapies which include fluoropyrimidine, oxaliplatin, irinotecan-based chemotherapies, cetuximab/panitumumab, PD-1 inhibitors, or BRAF inhibitors (if clinically indicated), and/or other checkpoint inhibitors. Approximately 40 subjects will be enrolled in the study, in 2 cohorts of 20 subjects each. Subjects will continue treatment with ME-344 and bevacizumab until radiological progressive disease, unacceptable AEs, withdrawal of consent, start of new anticancer therapy, or death.

Official Title
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A Phase 1b Study of the OxPhos Inhibitor ME-344 Combined With Bevacizumab in Previously Treated Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: ME-344
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Histological or cytological documentation of adenocarcinoma of the colon or rectum that is metastatic (all other histological types are excluded) Subjects who progressed or demonstrated intolerability to prior standard approved therapies which include fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapies, cetuximab/panitumumab (if clinically indicated e.g., RAS wild-type tumors) PD-1 or BRAF inhibitors (if clinically indicated), and/or other checkpoint inhibitors in the metastatic setting. Previous treatment with any investigational drug or anticancer treatment must be completed >28 days or 5 half-lives, whichever is longer, before the first dose of study treatment. Adequate bone marrow, liver, and renal function Exclusion Criteria: Untreated brain metastases, spinal cord compression, or primary brain tumor Symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or primary brain tumor Evidence of uncontrolled or unstable cardiovascular disease, myocardial infarction (within 6 months), unstable angina pectoris, congestive heart failure, serious arrhythmias requiring drug therapy History of CNS disease Bevacizumab or aflibercept therapy ≤ 3 weeks prior to starting study treatment Peripheral neuropathy Grade ≥ 2 Uncontrolled hypertension or diabetes mellitus, active peptic ulcers, unhealed wounds, clinically significant disease or systemic infections Known seropositive for, or active infection with hepatitis B or C virus Symptomatic or uncontrolled infection with human T-cell leukemia virus Venous thromboembolism (unless appropriately treated and stable on anticoagulant for at least 2 weeks).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the oxidative phosphorylation (OxPhos) pathway inhibitor ME-344 in combination with bevacizumab in subjects with recurrent mCRC. Subjects in Cohort 1 will receive ME-344 (IV) on Days 1, 8 and 15 combined with bevacizumab (IV) on Days 1 and 15 of each 28-day cycle. Subjects in Cohort 2 will receive ME 344 (IV) on Days 1 and 15 combined with bevacizumab (IV) on Days 1 and 15 of each 28-day cycle.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ME-344 and Bevacizumab<br>ME-344 (IV) Cohort 1: Days 1, 8, and 15 of each 28-day cycle. Cohort 2: Days 1 and 15 of each 28-day cycle. Bevacizumab (IV) Cohorts 1 and 2: Days 1 and 15 of each 28-day cycle. | Drug: ME-344<br>* ME-344 will be administered intravenously (IV)<br>Drug: Bevacizumab<br>* Bevacizumab will be administered intravenously (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) rate at 16 weeks | This will be measured using the Kaplan Meir (KM) method, and calculated from day of first study drug until observation of disease progression. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | This will be measure by the proportion of patients achieving complete response [CR] or partial response [PR] per RECIST v.1.1). | 6 months | 
| Safety and tolerability of ME-344 administered in combination with bevacizumab | This will be measured by the number of participants with treatment emergent Adverse Events, with abnormal physical examination findings, abnormal vital signs, abnormal ECG QT interval and abnormal clinical laboratory results | 1 year |