Summary
This research project addresses the urgent need for novel therapeutic strategies to overcome chemotherapy resistance and mitigate chemotherapy-induced peripheral neuropathy (CIPN) in patients with recurrent ovarian and endometrial cancers, which are among the most lethal gynecologic malignancies worldwide. The study focuses on BMX-001, a redox-active manganese metalloporphyrin compound that uniquely combines the ability to enhance anti-tumor efficacy and protect normal tissues from the toxic effects of chemotherapy, specifically paclitaxel (PTX). PTX, despite being a cornerstone of treatment, is associated with significant dose-limiting neurotoxicity, which severely impacts patients quality of life and limits the use of subsequent therapies. BMX-001 has demonstrated potential in preclinical models to not only augment the anti-tumor effects of PTX but also reduce PTX-induced neuropathy. The research will be conducted through a single-site, Phase 1/2 clinical trial led by the Duke Cancer Institute. The trial aims to determine the recommended Phase 2 dose of BMX-001 when combined with weekly PTX and to evaluate the clinical activity of this combination therapy. Specifically, the trial will assess the safety, tolerability, and potential to double the dose of BMX-001, which is hypothesized to further enhance the efficacy of PTX without increasing toxicity. The study\'s specific aims include establishing the recommended dose for expansion, assessing objective response rates (ORR), and quantifying the reduction in PTX-induced neurotoxicity using validated questionnaires and monofilament testing. The project also incorporates the analysis of circulating tumor DNA (ctDNA) as a biomarker for treatment response, adding a layer of precision to the evaluation of the therapy response impact on tumor burden. The outcomes of this research have the potential to significantly improve treatment protocols for patients with chemo-resistant gynecologic cancers by offering a therapy that enhances tumor control while protecting against debilitating side effects. Successful completion of this trial will lay the groundwork for larger, definitive trials and may extend the benefits of BMX-001 to other solid tumors, ultimately contributing to better survival outcomes and quality of life for a broader patient population.
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Inclusion Criteria: 1. Recurrent advanced metastatic ovarian or endometrial cancer that progressed during or following prior SOC therapy 2. Aged 18 years or older 3. Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 to 1 4. Ability to understand and willingness to give written informed consent 5. Measurable disease according to RECIST v1.1 or assessable disease based on presence of malignancy pleural effusion or ascites, or disease that does not meet measurable criteria. 6. Negative serum pregnancy test within 48 hours of dosing if indicated. 7. Adequate bone marrow function 8. Adequate hepatic function 9. Adequate renal function as determined by calculated or measured creatinine clearance ≥30 mL/min (using Cockcroft- Gault equation) or serum creatinine \< 1.5 X institutional ULN 10. Full recovery from all recent surgery on start date of treatment; at least 1 week must have elapsed from the time of a minor surgery (port placement at any time is acceptable); from the date of treatment at least 21 days must have elapsed from the time of a major surgery. Must have fully recovered from all surgery-related toxicities to Grade 1 or less 11. At least 28 days between termination of prior anticancer or hormonal therapy and first administration of BMX-001 Exclusion Criteria: 1. Residual Grade 2 peripheral neuropathy 2. Untreated central nervous system (CNS) metastases (surgery and/or radiotherapy), Subjects requiring corticosteroid therapy for the management of CNS metastases may not be on \>10 mg/day prednisone or equivalent. Subjects that have demonstrated signs or symptoms of neurologic instability for 28 days or less prior to enrollment. 3. Is being treated with concurrent anticancer therapy or other interventional treatments administered for their underlying cancer 4. Subjects who have received prior therapy with weekly PTX in the recurrent setting. 5. Clinically significant cardiac disease. 6. History of or present CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (eg, uncontrolled seizures) 7. Nonhealing wound, ulcer, or bone fracture 8. Serious active infection requiring IV antibiotics and/or hospitalization within 7 days of enrollment 9. Known severe hypersensitivity to any of the study drugs or excipients, including history of allergic, anaphylactic, or other severe hypersensitivity reactions to fusion proteins, products containing Cremophor EL (eg, cyclosporin for injection concentrate and teniposide for injection concentrate) 10. Require regular blood transfusions, platelet transfusions, or granulocyte colony stimulating factor. 11. For female patients of childbearing potential, the following are exclusion criteria, as applicable: 12. Refusal to use highly effective method of contraception or to practice true abstinence during treatment and for 6 months after the last dose of study drug 13. Pregnant or breast feeding; 14. Presence of any other condition that may increase the risk associated with enrollment on the study, interfere with data interpretation, or make the patient inappropriate for study enrollment in the opinion of the treating investigator 15. Prior treatment with or participation in a study with BMX-001 16. A history of additional risk factors for Torsades de Pointes (e.g., congestive heart failure, hypokalemia, known family history of Long QT Syndrome). 17. Severe, active co-morbidity, as defined in protocol.