Table 1 Clinical trials of MET application in cancers
From: Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing
Study design | Study population | Dosing regimen | Results | Ref. |
|---|---|---|---|---|
Phase 2, single group assignment, open label, for basic science | • Breast cancer • 41 participants enrolled | Arm: MET (extended release MET 1500 mg once daily for 14–21 days) | Mitochondrial response to MET may define anti-tumor effect MET reduces fatty acid oxidation with a subsequent accumulation of intracellular triglycerides, independent of AMPK activation | |
Phase 2, randomized, parallel assignment, double blinded, for prevention | • Premenopausal, overweight or obese women with metabolic disturbances • 151 participants enrolled | Arm: MET (850 mg QD * 4 weeks, 850 mg BID * 12 months) Arm: placebo | MET did not change percent breast density and dense breast volume but led to a numerical but not significant decrease in non-dense breast volume | [151] |
Randomized, factorial assignment, quadruple blinded, for prevention | • Breast cancer • 333 participants enrolled | Arm: MET (500 mg * week 1; 1000 mg * weeks 2–4 + 1500 mg * weeks 5+) + lifestyle intervention Arm: placebo + lifestyle intervention | In non-cancer patients, 6 months of MET therapy may be inadequate to observe expected epigenetic age deceleration | [152] |
Single group assignment, open label, for treatment | • Breast cancer • 39 participants enrolled | Arm: MET (500 mg TID * 2–3 weeks after diagnostic biopsy until surgery | MET reduced PKB/Akt and ERK1/2 phosphorylation, coupled with a decrease in insulin and IR levels, suggesting insulin-dependent effects are important in the clinical setting | [188] |
Phase 2, randomized, parallel assignment, quadruple blinded, for treatment | • Non-diabetic metastatic breast cancer • 40 participants enrolled | Arm: placebo + chemotherapy Arm: MET (850 mg BID) + chemotherapy | The addition of MET to standard chemotherapy showed no significant effect on response rate, PFS, or OS but was associated with increased grade I and II adverse events and decreased global quality of life | [153] |
Phase 2, single group assignment, open label, for treatment | • HER-2-positive breast cancer • 49 participants enrolled | Arm: liposomal doxorubicin + docetaxel + trastuzumab + MET (single agent day − 13 to day 0; 1000 mg QD day − 13 to − 11; 1000 mg BID from day − 10) | The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and MET was safe and showed good activity, but did not appear to improve activity over conventional sequential regimens | [154] |
Phase 2, randomized, parallel assignment, open label, for treatment | • HER2 negative metastatic breast cancer • 126 participants enrolled | Arm: MET (1000 mg QD * day 1–3; 1000 mg BID after) + Myocet + cyclophosphamide Arm: Myocet + cyclophosphamide | The results excluded any beneficial effect of MET in combination with chemotherapy either in terms of PFS or OS | [155] |
Phase 3, randomized, parallel assignment, triple blinded, for treatment | • Breast cancer • 3649 participants enrolled | Arm: MET hydrochloride (QD * week 1–4, BID * 5 years) Arm: placebo | MET statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin Among patients with high-risk operable breast cancer without diabetes, the addition of MET did not significantly improve invasive disease-free survival | |
Phase 2, randomized, parallel assignment, open label, for treatment | • Stage III NSCLC • 170 participants enrolled | Arm: radiation therapy + carboplatin + paclitaxel Radiation therapy + carboplatin + paclitaxel + MET (500 mg BID * days 1–7, 500 mg TID * days 8–14, 500 mg, 1000 mg, and 500 mg TID * days 15–126) | The addition of MET to chemoradiation was well-tolerated but did not improve OS or PFS | [176] |
Phase 2, randomized, parallel assignment, double blinded, for treatment | • EGFR-mutation-positive NSCLC • 224 participants enrolled | Arm: gefitinib + MET (500 mg BID * 1 week, 1000 mg, 500 mg BID * 1 week, then 1000 mg BID) Arm: gefitinib + placebo | Addition of MET did not show enhanced gefitinib efficacy and hence this study does not support the concurrent use of MET with first-line EGFR-TKI therapy in non-diabetic EGFRm NSCLC patients | [158] |
Phase 3, randomized, crossover assignment, quadruple blinded, for treatment | • Brain tumor treated with cranial or cranial-spinal radiation • 24 participants enrolled | Arm: MET (500 mg/m2 daily given in 2 doses * 1 week, 1000 mg/m2 daily given in 2 doses * 12 weeks) Arm: placebo | MET was linked to better performance on tests of declarative and working memory The effects of MET on cognition and brain structure are feasible and MET is safe and tolerable | [149] |
Early phase 1, single group assignment, open label, for basic science | • Head and neck squamous cell cancer • 50 participants enrolled | Arm: MET (2000 mg per day * ≥ 9 days prior to surgery | MET increases markers of reduced catabolism and increases senescence in stromal cells and cancer cell apoptosis MET may favorably alter the immune TME independent of HPV status MET mediates immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 | |
Phase 1, single group assignment, open label, for treatment | • Head and neck cancer • 20 participants enrolled | Arm: MET (including 2000 mg, 2550 mg, and 3000 mg daily in divided doses) + drug: cisplatin + radiation therapy | Rates of OS and PFS were encouraging in this limited patient population | [15] |
Phase 2, randomized, parallel assignment, double blinded, for prevention | • Barrett esophagus esophageal cancer • 93 participants enrolled | Arm: MET hydrochloride (extended-release tablet PO QD * week 1, BID * weeks 2–12) Other: placebo | MET did not cause major reductions in esophageal levels of pS6K1 and did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues | [159] |
Phase 2, parallel assignment, quadruple blinded, for treatment | • Familial adenomatous polyposis • 34 participants enrolled | Arm: MET (500 mg QD) Arm: MET (1500 mg QD) Arm: placebo | Seven months of treatment with 500 mg or 1500 mg metformin did not reduce the mean number or size of polyps in the colorectum or duodenum in familial adenomatous polyposis patients | [160] |
Phase 2, single group assignment, open label, for prevention | • Colorectal adenomas and obesity • 45 participants enrolled | Arm: MET hydrochloride (500 mg extended release tablets QD * week 1, with a dose escalation of 500 mg each week until the final dose of 1000 mg BID week 4–12) | MET showed no significant change in activated S6serine235 | [161] |
Phase 1, randomized, parallel assignment, open label, for treatment | • Metastatic pancreatic adenocarcinoma • 22 participants enrolled | Arm: MET (850 mg BID on a 28 day cycle) Arm: MET + rapamycin | MET ± rapamycin maintenance for mPDA was well-tolerated and several patients achieved stable disease associated with exceptionally long survival | [162] |
Phase 2, single group assignment, open label, for treatment | • Gemcitabine-refractory advanced pancreatic adenocarcinoma • 41 participants enrolled | Arm: paclitaxel + MET (850 mg Q8H) | Despite the encouraging pre-clinical evidence of antitumor activity of MET, the primary endpoint disease control rate was not met The combination was poorly tolerated | [163] |
Phase 2, randomized, parallel assignment, quadruple blinded, for treatment | • Locally advanced pancreatic cancer, metastatic pancreatic cancer • 120 participants enrolled | Arm: gemcitabine + erlotinib + MET (increased from 500 mg BID in week 1 to 1000 mg BID in week 2) Arm: gemcitabine + erlotinib + placebo | Addition of MET did not improve outcomes in patients with advanced pancreatic cancer treated with gemcitabine and erlotinib | [164] |
Early phase 1, single group assignment, open label, for treatment | • Endometrial cancer • 21 participants enrolled | Arm: MET (850 mg QD * ≥ 7 days, up to 30 days before surgery) | MET decreased serum levels of IGF-1, omentin, insulin, C-peptide, and leptin between pre- and post-treatment samples, as well as decreased phosphorylation of AKT and MAPK | [165] |
Early phase 1, single group assignment, open label, for treatment | • Endometrial cancer • 28 participants enrolled | Arm: MET (850 mg QD) | JPT1 represents a predictive and pharmacodynamic biomarker of MET response | [166] |
Randomized, parallel assignment, double blinded, for treatment | • Endometrial cancer • 50 participants enrolled | Arm: MET hydrochloride (850 mg QD * ≥ 7 days before surgery) Arm: placebo | Short-term treatment with MET significantly reduced the proliferative marker Ki-67 index in women with endometrioid endometrial cancer awaiting surgical staging | [167] |
Phase 2, randomized, parallel assignment, open label, for treatment | • Endometrial atypical hyperplasia • Well-differentiated endometrial adenocarcinoma • 150 participants enrolled | Arm: megestrol acetate and MET (500 mg TID * 3 months) Arm: megestrol acetate | As a fertility-sparing treatment, MET plus MA was associated with a higher early CR rate compared with MA alone in patients with atypical endometrial hyperplasia | [168] |
Phase 2, randomized, parallel assignment, open label, for treatment | • Complex endometrial hyperplasia with atypia • Grade 1 endometrial endometrioid adenocarcinoma • 165 participants enrolled | Arm: levonorgestrel IUD + MET (500 mg BID) Arm: levonorgestrel IUD drug + behavior: levonorgestrel IUD + weight loss intervention | Complete response rates at 6 months were encouraging for patients with endometrial adenocarcinoma and endometrial hyperplasia with atypia across the three groups | [169] |
Phase 1, single group assignment, open label, for treatment | • Epithelial ovarian cancer • 15 participants enrolled | Arm: MET + carboplatin + paclitaxel | The recommended phase II dose of MET in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg TID | [170] |
Phase 2, single group assignment, open label, for treatment | • Ovarian, fallopian tube, and primary peritoneal cancer • 90 participants enrolled | Arm: MET (a) Neoadjuvant MET, debulking surgery, and adjuvant chemo plus MET (b) Neoadjuvant chemo and MET, interval debulking surgery, and adjuvant chemo plus MET | MET impacted epithelial ovarian cancer CSCs and was associated with better-than-expected OS | [14] |
Phase 2, randomized, parallel assignment, double blinded, for treatment | • Pre-prostatectomy prostate cancer • 20 participants enrolled | Arm: MET hydrochloride (extended-release MET hydrochloride QD for 4–12 weeks before surgery) Arm: placebo | MET distributes into human prostate tissue, suggesting that MET could exert its effects directly on tissue targets Concomitant MET with radiotherapy and androgen deprivation therapy was associated with inferior biochemical outcome | |
Phase 2, single group assignment, open label, for treatment | • Metastatic castration-resistant prostate cancer • 25 participants enrolled | Arm: MET (1000 mg BID in uninterrupted 4-week cycles) + abiraterone | The addition of MET to abiraterone does not affect further progression and has no meaningful clinical benefit A higher-than-expected gastrointestinal toxicity attributed to MET was observed | [173] |
Phase 2, randomized, parallel assignment, open label, for treatment | • Overweight or obese prostate cancer patients • 29 participants enrolled | Arm: observation and bicalutamide Arm: MET (1000 mg BID) and bicalutamide | Although MET plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. MET monotherapy induced modest PSA declines. MET, given alone and in combination, displayed immune modifying effects, primarily within NK and T cells subsets | [174] |
Phase 2, single group assignment, open label, for treatment | • Chemotherapy-naïve castration-resistant prostate cancer • 44 participants enrolled | Arm: MET (1000 mg BID) | Treatment with MET is safe in non-diabetic patients, and it yields objective PSA responses and may induce disease stabilization | [190] |
Phase 2, randomized, parallel assignment, quadruple blinded, for treatment | • Metastatic hormone-refractory prostate cancer • 100 participants enrolled | Arm: placebo Arm: MET (850 mg BID) | MET addition failed to improve the standard Docetaxel regimen in metastatic castration-resistant prostate cancer | [175] |
Phase 1, randomized, parallel assignment, open label, for treatment | • Solid tumor • 105 participants enrolled | Arm: MET + chemotherapy | Post-MET increase in AMPK phosphorylation may potentially explain lack of disease progression in nearly half of our patients MET can be given safely with chemotherapy | [21] |
Phase 2, randomized, parallel assignment, single blinded, for prevention | • Malignant solid tumor • 121 participants enrolled | Arm: MET (2,000 mg per day * 12 months) Behavioral: self-control weight loss Arm: coach directed behavioral weight loss | MET treatment did not show significant changes in serum urate compared to baseline MET impacted gut microbiota composition, altered circulating short-chain fatty acids, including increasing acetate, which correlated with lower fasting insulin Similar weight loss was observed in the behavioral weight loss arm and the MET arm | |
non-randomized, parallel assignment, open label, for basic science | • Acute lymphoblastic leukemia • 102 participants enrolled | Arm: MET (850 mg TID + prednisone * 7 days and * 28 days) | MET was a protective factor against both therapeutic failure and early relapse The combined use of MET with chemotherapy is effective in patients with elevated levels of ABCB1 gene expression | [150] |