Treatment with an investigational mitochondrial inhibitor and bevacizumab has started in a phase 1b clinical trial of patients with previously-treated metastatic colorectal cancer.
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The first patient has been dosed with ME-344 in combination with bevacizumab (Avastin) as part of a phase 1b study (NCT05824559) of patients with previously-treated metastatic colorectal cancer (mCRC).1
ME-344 targets the oxidative phosphorylation pathway, which can shrink or kill cancer cells. The agent has shown anti-tumor activity in both preclinical and clinical studies.
Previously, in patients with refractory solid tumors, treatment with ME-344, administered once-weekly, demonstrated preliminary activity and tolerable safety. Thirty patients were included in the study. Of those included, 70% received a minimum of 3 cycles of treatment. There was 1 partial response to ME-344 in a patient with small cell lung cancer, and 10 patients had stable disease (SD). Of those with SD, 4 responded for a prolonged period including 1 patient with urothelial carcinoma, 1 with cervical leiomyosarcoma, and 1 with cervical cancer. Notably, duration of response (DOR) to ME-344 in this study exceeded DOR to prior treatment regimens.2
Trial Name: A Phase 1b Study of the OxPhos Inhibitor ME-344 Combined With Bevacizumab in Previously Treated Metastatic Colorectal Cancer
ClinicalTrials.gov Identifier: NCT05824559
Sponsor: MEI Pharma, Inc
Recruitment Contact: Sylwia Sobolewska, 347-522-0549, ssobolewska@criterium.com
Completion Date: June 30, 2024
In terms of survival, ME-344 showed a median progression-free survival (PFS) of 6.9 weeks (95% CI, 1.6-7.1)
All patients in the study experienced an adverse event (AE), including 63% that were treatment related. Treatment-related AEs were predominantly grade 1 and 2. The most frequently observed AEs in the study were peripheral neuropathy (20%), nausea (20%), dizziness (20%), fatigue (17%), vomiting (13%), diarrhea (10%), and asthenia (10%).
Serious AEs occurred in 6 patients, leading to discontinuation of treatment. There were 2 deaths during the study that occurred within a month of treatment discontinuation, but no deaths occurred while patients were actively receiving treatment.
In the phase 1b, open-label, sequential study, multiple doses and dose schedules will be evaluated in patients with previously-treated mCRC. Patients in cohort 1 will be treated with ME-344 on days 1, 8, and 15, plus bevacizumab given on days 1 and 15 of each 28-day cycle. Patients in cohort 2 will receive ME-344 on days 1 and 15 in combination with bevacizumab dosed on days 1 and 15 of every 28-day cycle.3
The primary end point to be investigated in the study is PFS, and the secondary end points are ORR and safety/tolerability.
Recruitment for this study is underway at locations across the United States. Patients eligible to be enrolled are those aged 18 year or older with histologically or cytologically confirmed CRC that progressed or became intolerant to any of the FDA-approved therapies in the metastatic setting. Patients are also required to have adequate bone marrow, liver, and renal function. Any patients who received an investigational drug or anticancer therapy previously must have completed therapy more than 28 days before the first dose of ME-344 is administered in the study.
Patients are excluded from the study if they present with untreated brain metastases, spinal cord compression, or primary brain tumor. In addition, patients cannot have symptomatic brain metastases, leptomeningeal disease, spinal cord compression, or primary brain tumor. Those with evidence of uncontrolled cardiovascular disease or cardiac condition, history of central nervous system disease, uncontrolled hypertension, or other serious illnesses, known hepatitis B of C virus, symptomatic or uncontrolled infection with human t-cell leukemia virus, venous thromboembolism, or peripheral neuropathy that is grade 2 or higher are ineligible to enroll in the study. Prior treatment with bevacizumab or aflibercept therapy ≤ 3 weeks of starting ME-344 disqualifies patients from enrolling in the study.
“We are excited to continue to pioneer the evaluation of mitochondrial inhibition as a promising approach to treat solid tumors with the initiation of this innovative study evaluating ME-344, our mitochondrial inhibitor, in combination with bevacizumab in patients with colorectal cancer who progressed after standard therapies,” said Richard Ghalie, MD, chief medical officer, MEI Pharma, in a press release.1 “With the current study, we look forward to the opportunity to build on both mechanistic and efficacy data from earlier pre-clinical and clinical studies demonstrating the anti-tumor activity of ME-344 in combination with bevacizumab.”
REFERENCES:
1. MEI Pharma announces first patient dosed in clinical study evaluating ME-344 plus bevacizumab (Avastin®) in patients with previously treated metastatic colorectal cancer. August 16, 2023. Accessed: August 18, 2023. https://tinyurl.com/mcndfjf
2. Bendell JC, Patel MR Infante JR, et al. Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors. Cancer. 2015;121(7):1056-1063. doi:10.1002/cncr.29155
3. ME-344 and bevacizumab in previously treated metastatic colorectal cancer. ClinicalTrials.gov. Updated: August 14, 2023. Accessed: August 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05824559?term=NCT05824559&draw=2&rank=1
