Metformin Combined With Chemotherapy and/or Immunotherapy in Solid Malignancies
ConditionAdvanced Solid Tumor
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorBarbara Ann Karmanos Cancer Institute
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
Disqualifiers
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
Trial design
Design model
Single group
Treatments tested in this trial
Metformin
DrugMetformin will be given for 14 days alone as a run in and then added to any standard of care chemotherapy or immunotherapy for solid tumors.
Treatment groups
60 Participants
are divided into 1 treatment groupGroup A: MetforminExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Incidence of Dose Limiting Toxicities (DLTs)-Metformin only stage
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).
Time frame
From the start of Metformin run in to the end of Metformin run in. Up to 14 days2
Incidence of Dose Limiting Toxicities (DLTs)-Chemotherapy or Immunotherapy (IO) plus Metformin Stage
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).
Time frame
From start of Chemotherapy or IO plus Metformin until 30 days after the end of treatment3
Determine the maximum tolerated dose (MTD) of metformin in combination with chemotherapy/IO
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.
Time frame
Up to 4 months after treatment initiationSecondary outcomes
1
Assessment of overall response rate (ORR)
Tumor response will be determined according to RECIST v1.1. Treatment responses will be summarized by count and percentage, and their rates will be computed along with their associated two-sided 95% confidence intervals (CIs).
Time frame
Up to 4 months after treatment initiation2
Assessment of Duration of Response (DOR)
Tumor response will be determined according to RECIST v1.1. The DOR is measured from the time measurement criteria are met for complete response (CR) or a partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started). Treatment responses will be summarized by count and percentage, and their rates will be computed along with their associated two-sided 95% confidence intervals (CIs). The distributions of time-to-event data, such as DOR and PFS will be graphically summarized using Kaplan-Meier (KM) curves, and their median and 95% CIs will be estimated using KM estimates.
Time frame
Up to 4 months after treatment initiation3
Assessment of Progression free survival (PFS)
Tumor response will be determined according to RECIST v1.1. Progression-free survival (PFS) is defined as the time duration from treatment start to progression time or death, whichever occurs first. Treatment responses will be summarized by count and percentage, and their rates will be computed along with their associated two-sided 95% confidence intervals (CIs). The distributions of time-to-event data, such as DOR and PFS will be graphically summarized using Kaplan-Meier (KM) curves, and their median and 95% CIs will be estimated using KM estimates.
Time frame
Up to 4 months after treatment initiationOther outcomes
1
Evaluate extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a surrogate marker for nicotinamide adenine dinucleotide (NAD) signaling inhibition
Serum NAD+ and eNAMPT will be measured at baseline and every 8 weeks after the start of metformin. Enzyme linked immunosorbent assays (ELISAs) will be used to determine levels. Summary statistics (numerical and/or graphical) for changes of NAD+ and eNAMPT levels between baseline and after treatment will be evaluated, along with their summaries at the baseline and at after treatment. Correlations between NAD+ and eNAMPT to the ORR, DOR, and PFS will be calculated from patients who have a partial (at least a 30%) complete response to treatment.
Time frame
Up to 4 months after treatment initiation2
Assess metabolic parameters
Glycated hemoglobin, glucose, insulin, Insulin like growth factor-1, and C-peptide levels will be measured at baseline and every 8 weeks after the start of metformin. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) will be calculated at the same timepoints. Summary statistics (numerical and/or graphical) of the metabolic parameters will be evaluated at baseline and every 8 weeks. Comparing the pretreatment biomarker levels with the post treatment levels to determine the effect of the drug using Wilcoxon signed rank test. The differences between the responding and non-responding groups using Wilcoxon-Mann-Whitney test for statistical significance will also be compared. The correlation of the metabolic parameters with tumor markers and efficacy (ORR, DOR, and PFS) will be assessed using Pearson correlation and scatter plots.
Time frame
Up to 4 months after treatment initiation3
Perform metabolomics analysis
Blood will be drawn at baseline and every 8 weeks after the start of treatment. Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and MetaboAnalyst, a panel of over 200 polar metabolites will be investigated and their correlation with metformin responsiveness and PFS will be evaluated.
Time frame
Up to 4 months after treatment initiationSponsors and contacts
Click on the lead sponsor to view all of their trials.
Source ClinicalTrials.gov