A Phase I Dose-escalation and Metabolomics Study of Metformin Combined With Chemotherapy and/or Immunotherapy in Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 10
- 主要终点
- Incidence of Dose Limiting Toxicities (DLTs)-Metformin only stage
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •Hemoglobin ≥ 8 g/dL if determined suitable by the investigator for the selected chemotherapy and/or immunotherapy regimen for the particular patient
- •Absolute neutrophil count (ANC) > 1500/mm3
- •Platelets > 75,000/mm3 if determined suitable by the investigator for the selected chemotherapy and /or immunotherapy regimen for the particular patient
- •Estimated Glomerular Filtration Rate (eGFR) > 45 mL/min/1.73 m2 (as described by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 2021 equation)
- •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.
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN. For participants with hepatic metastases, AST and ALT ≤ 5 x ULN.
- •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
排除标准
- •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:
- •New York Heart Association Class III or IV heart failure
- •Myocardial infarction, unstable angina, or stroke ≤ 3 months prior to Cycle 1 Day 1
- •Uncontrolled arrhythmia
- •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
研究组 & 干预措施
Metformin
Metformin will be administered in combination with any standard chemotherapy/immunotherapy. Metformin 1000mg-3000mg day in dose escalation
干预措施: Metformin (Drug)
结局指标
主要结局
Incidence of Dose Limiting Toxicities (DLTs)-Metformin only stage
时间窗: From the start of Metformin run in to the end of Metformin run in. Up to 14 days
Adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).
Incidence of Dose Limiting Toxicities (DLTs)-Chemotherapy or Immunotherapy (IO) plus Metformin Stage
时间窗: From start of Chemotherapy or IO plus Metformin until 30 days after the end of treatment
Adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).
Determine the maximum tolerated dose (MTD) of metformin in combination with chemotherapy/IO
时间窗: Up to 4 months after treatment initiation
The MTD will be defined as the dose level below the dose level at which two or more patients in the same cohort experience a DLT. If none or only one patient experiences a DLT at level 5, then dose level 5 will be defined as the MTD.
Incidence of Dose Limiting Toxicities (DLTs)-Metformin only stage
时间窗: From the start of Metformin run in to the end of Metformin run in. Up to 14 days
Adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).
Incidence of Dose Limiting Toxicities (DLTs)-Chemotherapy or Immunotherapy (IO) plus Metformin Stage
时间窗: From start of Chemotherapy or IO plus Metformin until 30 days after the end of treatment
Adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0).
Determine the maximum tolerated dose (MTD) of metformin in combination with chemotherapy/IO
时间窗: Up to 4 months after treatment initiation
The MTD will be defined as the dose level below the dose level at which two or more patients in the same cohort experience a DLT. If none or only one patient experiences a DLT at level 5, then dose level 5 will be defined as the MTD.
次要结局
- Assessment of overall response rate (ORR)(Up to 4 months after treatment initiation)
- Assessment of Duration of Response (DOR)(Up to 4 months after treatment initiation)
- Assessment of Progression free survival (PFS)(Up to 4 months after treatment initiation)
- Assessment of overall response rate (ORR)(Up to 4 months after treatment initiation)
- Assessment of Duration of Response (DOR)(Up to 4 months after treatment initiation)
- Assessment of Progression free survival (PFS)(Up to 4 months after treatment initiation)
研究者
Wasif Saif
Principal Investigator
Barbara Ann Karmanos Cancer Institute