BMX-001 + Paclitaxel in Adult Patients With Advanced, Recurrent, Metastatic Ovarian or Endometrial Cancer

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\&#39;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.

This clinical trial is a proof-of-concept Phase 1/2 study aimed at establishing the recommended Phase 2 dose (RP2D) of BMX-001 when administered in combination with weekly paclitaxel (PTX) in patients with advanced, metastatic ovarian or endometrial cancer. The rationale for this open-label trial is twofold: (1) response rates to weekly PTX in patients with platinum-resistant ovarian cancer (PROC) are generally low, and when a response is achieved, its duration is often short, necessitating novel therapeutic approaches to improve outcomes; (2) weekly PTX is associated with dose-limiting side effects, particularly chemotherapy-induced peripheral neuropathy (CIPN), which significantly impacts patients quality of life.

The trial includes a dose-finding stage designed to assess the safety and dose-limiting toxicities (DLTs) of the combination treatment. The study will use a Bayesian Optimal Interval (BOIN) design to test the safety of weekly BMX-001 injections in combination with weekly PTX. The goal is to determine if BMX-001 can be safely administered at increasing doses while enhancing both the efficacy of treatment as well as diminishing chemotherapy side effects in patients with recurrent, advanced ovarian and endometrial cancers.

Patients in the dose-escalation phase will receive up to 16 doses over an 8-week period. All participants will receive PTX at a dose of 80 mg/m² on the first day of each weekly cycle. The starting dose of BMX-001 will be 28 mg subcutaneously on the first day of each weekly cycle. Cohorts of three patients will be treated and evaluated for DLTs sequentially. If the starting dose is well-tolerated, subsequent cohorts will escalate to higher doses, with a maximum of 28 mg followed by 28 mg BMX-001 given 4-6 hours apart on the same day each week. Should any patients at Dose Level 1 experience DLTs, the dose will be de-escalated according to the BOIN design to Dose Level -1 (14 mg/week), and if necessary, further to Dose Level -2 (7 mg/week), which is the final de-escalation dose group.

Upon completion of the dose-finding phase, an expansion cohort will be enrolled at the RP2D. The study will enroll up to 27 patients in this trial. The primary outcome measure is to establish the RP2D of BMX-001 in combination with PTX. Secondary outcomes include evaluation of preliminary efficacy based on objective response rate (ORR) using RECIST v 1.1 per investigator assessment endpoints and obtaining a description of patient-reported outcomes of health related quality of life (HRQoL) quality of life (QoL) using FACT/GOG-NTX Questionnaire and monofilament testing.

Other outcome measures to be assessed in all patients include characterization of the pharmacokinetic profile of BMX-001 when delivered in combination with PTX in recurrent ovarian or endometrial cancer and also to assess correlations between B cell lymphoma/leukemia 2 (BCL2), Nrf2, TNF-alpha, and NFkB RNA and protein expression and activation, ctDNA, and clinical responses. This initial single arm trial is limited to 27 subjects based on the funds available in this SBIR. In spite of the small sample size, the study expects to obtain sufficient data to enable design a subsequent randomized trial that would meet registration requirements

Eligibility Criteria:
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 \&lt; 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 \&gt;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.