Metformin Combined With Chemotherapy and/or Immunotherapy in Solid Malignancies

A Phase I Dose-escalation and Metabolomics Study of Metformin Combined With Chemotherapy and/or Immunotherapy in Solid Malignancies

The goal of this clinical trial is to evaluate the safety of Metformin alone and in combination with chemotherapy or immunotherapy in patients with solid tumor cancers. The main questions it aims to answer are:

• what are the toxicities of metformin at multiple dose levels
• what is the maximum tolerated dose of Metformin in combination with chemotherapy or immunotherapy

Participants enrolled will be treated with standard of care chemotherapy and/or immunotherapy in accordance to their disease/stage. In addition, participants will take Metformin alone for 14 days in between the first cycle of chemotherapy and the second cycle of chemotherapy to determine tolerability to the Metformin. Participants will then take Metformin daily in combination with the standard of care chemotherapy and/or Immunotherapy from cycle 2 onwards.

Inclusion Criteria:

• Have histologically confirmed advanced solid tumor and are considered a suitable candidate for chemotherapy and/or immunotherapy or both

• Are a male or female participant aged ≥ 18 years

• Have provided a signed, written informed consent form

• Have measurable disease per RECIST v1.1

• Have adequate hematologic, renal, liver, and coagulation function as defined by the following:

  1. Hemoglobin ≥ 8 g/dL if determined suitable by the investigator for the selected chemotherapy and/or immunotherapy regimen for the particular patient
  2. Absolute neutrophil count (ANC) > 1500/mm3
  3. Platelets > 75,000/mm3 if determined suitable by the investigator for the selected chemotherapy and /or immunotherapy regimen for the particular patient
  4. Estimated Glomerular Filtration Rate (eGFR) > 45 mL/min/1.73 m2 (as described by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 2021 equation)
  5. Total bilirubin ≤ 1.5 x upper limit of normal (ULN). Participants with known Gilbert's syndrome who have total bilirubin level ≤ 3 x ULN may be enrolled if deemed suitable for a particular patient by the investigator for the selected chemotherapy and/or immunotherapy regimen.
  6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN. For participants with hepatic metastases, AST and ALT ≤ 5 x ULN.
  7. Alkaline phosphatase (ALP) < 2.5 x ULN. For participants with hepatic and/or bone metastases ≤ 5 x ULN

• Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, and suitable for chemotherapy/IO recommended by the investigator.

• Participants who have experienced expected toxicity from Cycle 1 of anticancer therapy which is unlikely to recover to grade 1 or better prior to Cycle 2 (e.g., anemia, alopecia, vitiligo, endocrine dysfunction associated with IO) and may otherwise not impact the eligibility will be allowed.

• Women of child-bearing potential must agree to avoid becoming pregnant and male participants should avoid impregnating a female partner or donating sperm starting at initiation of treatment up until at least 90 days after the last dose of study drug.

• Have an estimated life expectancy of at least 12 weeks

Exclusion Criteria:

• Patients who have or are any of the following exclusion criteria are not eligible for participation in the study.

• Patients with uncontrolled diabetes

• Patients who have received metformin must be at least five half-lives beyond such treatment (four weeks) and must not be taking metformin at the time of enrollment.

• Patients with a known hypersensitivity to metformin, its excipients, its analogs, or any of its components

• Patients on other antidiabetic medicines are eligible as long as adding metformin will not be contraindicated

• Patients with an inability to tolerate oral medications

• Women who are pregnant or lactating

• Patients with clinically significant intercurrent disease including, but not limited to:

  1. New York Heart Association Class III or IV heart failure
  2. Myocardial infarction, unstable angina, or stroke ≤ 3 months prior to Cycle 1 Day 1
  3. Uncontrolled arrhythmia
  4. Clinically significant active infection requiring IV antibiotic, antiviral, or antifungal medications

• Patients with other current medical or other conditions that, in the opinion of the investigator, may confound study interpretation or prevent completion of study procedures and follow-up examinations

• Patients with an unwillingness or inability to comply with the study procedures required in this protocol

• Patients using an investigational agent within four weeks of study entry

• Patients with uncontrolled metabolic disorders or primary or secondary effects of cancer that induce a high medical risk