Table 2.
Recent clinical trials investigating oral metformin use in cancers [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]. N/A: not applicable.
| Tumor Location |
Trial Reference |
ID/ Phase |
Tumor/Patient Characteristics | Number of Participants | Treatment | Result | Other Comments |
|---|---|---|---|---|---|---|---|
| Various Solid Tumors |
[38] | Phase Ib | Variety of advanced solid tumors refractory to standard therapies | 9 | Everolimus + metformin (n = 9; metformin 500 mg twice daily) | Combination therapy was poorly tolerated | Open-label, prospective, single-center, dose-escalation study, The Netherlands |
| [39] | -- | Variety of advanced solid tumors (metastatic or unresectable) | 24 | Sirolimus + metformin (n = 11; maintenance on 1000 mg once daily) vs. sirolimus (n = 13) |
Combination therapy did not improve mTOR inhibition | Open-label, randomized | |
| [40] | NCT01442870 Phase I | Variety of solid tumors (nondiabetic, histologically confirmed solid tumors receiving adjuvant or systemic chemotherapy) | 100 | Concurrent chemotherapy + metformin (n = 49; 500 mg twice daily) vs. delayed chemotherapy + metformin (n = 51; 500 mg twice daily) |
Metformin is safe to use in combination with a wide range of chemotherapy regimens | Delayed-start, randomized | |
| [41] | NCT02496741 Phase Ib | IDH1-mutated solid tumors including chondrosarcoma (refractory grade II-III), glioma (WHO grade II-IV), and intrahepatic cholangiocarcinoma | 17 | Chloroquine + metformin (n = 17; maximum of 1500 mg twice daily) | Combination treatment with chloroquine and metformin did not induce clinical response | Prospective, open-label, dose-escalation, The Netherlands | |
| Glioma | N/A |
NCT04945148 Phase II |
Glioblastoma, IDH-wildtype | 640 | Metformin (1500–3000 mg daily) plus radiation and temozolomide | No results available | Open-label, prospective, single-center, France |
| N/A |
NCT02149459 Phase I |
Brain neoplasms | 18 | Metformin (dose not specified), radiation, and low carbohydrate diet | No results available | Open-label, prospective, single-center, Israel | |
| N/A |
NCT02780024 Phase II |
Glioblastoma | 50 | Metformin (dose not specified) and neoadjuvant temozolomide followed by combined radiation and temozolomide | No results available | Open-label, prospective, single-center, Canada | |
| N/A |
NCT03243851 Phase II |
Recurrent or refractory glioblastoma | 81 | Metformin (ramp up to 2000 mg daily) and low dose temozolomide | No results available | Open-label, prospective, single-center, South Korea | |
| N/A |
NCT03151772 Phase I |
Glioblastoma | 3 | Metformin (850 mg daily) and disulfiram for 3 days preoperatively | No results available, study was terminated for low enrollment | Open-label, prospective, single-center, Sweden | |
| N/A |
NCT04691960 Phase II |
Glioblastoma | 36 | Metformin (ramp up to 850 mg three times daily) and ketogenic diet | No results available | Open-label, prospective, single-center, US | |
| N/A |
NCT05183204 Phase II |
Glioblastoma | 33 | Metformin (ramp up to 850 mg three times daily as tolerated), ketogenic diet and Paxalisib| | No results available | Open-label, prospective, single-center, US | |
| N/A |
NCT01430351 Phase I |
Glioblastoma and gliosarcoma | 144 | Metformin (dose not specified), mefloquine, memantine, hydrochloride, hydrochloride, and temozolomide | No results available | Open-label, prospective, single-center, US | |
| Bladder Tumors |
[26] | NCT03379909 Phase II | Non-muscle-invasive bladder cancer (intermediate-risk) | 49 (target) | Metformin (maximum of 3000 mg daily) | Ongoing | Multicenter, open-label |
| Breast Tumors |
[16] | NCT00490139 Phase III | HER2-positive primary breast cancer | 8381 | Substudy analysis of diabetic study participants on/off metformin therapy (dose not specified; all patients previously taking for DM) in patients receiving relevant anti-HER2 therapies, described elsewhere | Diabetic patients with HER2-positive breast cancer demonstrated better outcomes when treated with metformin compared to diabetic breast cancer patients not on metformin, whereas outcomes of patients with HR-negative status were not affected by diabetes treatment status | Randomized, adjuvant trial |
| [11] | NCT01654185 Phase II | Hormone receptor positive locally advanced or metastatic breast cancer | 60 | Aromatase inhibitor (exemestane or letrozole) + metformin (n = 30; maintenance on 500 mg daily) vs. aromatase inhibitor (exemestane or letrozole) + placebo (n = 30) |
No improved efficacy was observed in the addition of metformin to aromatase inhibitor treatment | Randomized, China | |
| [42] | NCT01266486 Phase I | Treatment-naïve primary breast cancer | 40 | Metformin (n = 40; maintenance on 1500 mg daily) | Metformin treatment precipitated two distinct metabolic responses in tumors | Window study design, UK | |
| [14] | NCT01310231 Phase II | Metastatic breast cancer (nondiabetic) | 40 | Chemotherapy + metformin (n = 22; maintenance on 850 mg daily) vs. chemotherapy + placebo (n = 18) |
Combined chemotherapy with metformin had no demonstrated effect on PFS, OS, or RR | Randomized, double-blind, Canada | |
| [12] | NCT01885013 Phase II | Metastatic breast cancer (HER2-negative, nondiabetic) | 122 | Chemotherapy (doxorubicin + cyclophosphamide) + metformin (n = 57; maintenance on 2000 mg daily) vs. chemotherapy (doxorubicin + cyclophosphamide) (n = 65) |
The addition of metformin did not provide a meaningful clinical benefit to PFS or OS but was found to decrease the incidence of severe neutropenia | Open-label, multicenter, randomized | |
| [13] | NCT01650506 Phase I | Metastatic triple negative breast cancer who had received at least one prior therapy | 8 | Erlotinib + metformin (n = 8; maximum dose was 850 mg thrice daily) | Combination therapy was well-tolerated but did not result in objective tumor response | USA | |
| [15] | IRCT20100706004329N7 | Breast fibroadenoma (nondiabetic) | 175 | Metformin (n = 83; maximum dose was 1000 mg daily) vs. placebo (n = 92) |
The effect of metformin is most obvious in smaller masses and appears to have a favorable effect compared to placebo in terms of reducing chances of significant enlargement of tumors | Iran | |
| [17] | NCT01627067 Phase II | Metastatic, hormone receptor-positive, HER2-negative breast cancer (obese or overweight, postmenopausal) | 22 | Everolimus + exemestane + metformin (n = 22; 1000 mg twice daily) | This treatment combination had moderate clinical benefit | USA | |
| Colorectal Tumors | [24] | -- | Stage II-III colon cancer | 120 out of total 3759 enrolled in TOSCA | Goal of original TOSCA study was to compare 3- vs. 6-month treatment with fluoropyrimidine-oxaliplatin adjuvant chemotherapy (post-resection)
|
Neither metformin use, nor DM, nor metformin dosage were associated with OR/RFS | Subanalysis |
| [23] | NCT01312467 Phase IIa | Nondiabetic, obese patients with recent history of colorectal adenoma | 32 | Metformin (n = 32; maintenance on 1000 mg twice daily) | Metformin intervention did not reduce rectal mucosa pS6 (marker of polyp suppression) or Ki-67 (marker of proliferation) levels | USA | |
| [25] | Phase II | Refractory colon cancer | 41 | Irinotecan + metformin (n = 41; maintenance on 2500 mg daily) | Irinotecan/metformin was able to provide disease control, with diarrhea as a significant side effect | Single-center | |
| Lung Tumors | [18] | NCT01864681 Phase II | Non-small cell lung cancer (locally advanced, stage IIIb-IV, EGFR mutated, treatment-naïve, nondiabetic) | 224 | Gefitinib + metformin (n = 100; maintenance on 1000 mg twice daily) vs. gefitinib + placebo (n = 100) |
Combination treatment resulted in non-significantly worse outcomes and was accompanied by more side effects (diarrhea) | Multicenter, double-blind, China |
| [22] | NCT01578551 Phase II | Chemo-naïve or metastatic nonsquamous NSCLC (stage IIIB or IV; nondiabetic) | 25 | Carboplatin + paclitaxel + bevacizumab + metformin (n = 19; 1000 mg twice daily) vs. carboplatin + paclitaxel + bevacizumab (n = 6) |
The metformin combination treatment group experienced increased PF | Single center, open-label, USA | |
| [19] | NCT03071705 Phase II | Lung adenocarcinoma (EGFR-mutated, stage IIIb-IV) | 139 | EGFR-TKI (erlotinib, afatinib, or gefitinib) + metformin (n = 69; 500 mg twice daily) vs. EGFR-TKI (erlotinib, afatinib, or gefitinib) (n = 70) |
The addition of metformin to EGFR-TKI standard therapy significantly improved PFS and OS in advanced lung adenocarcinoma patients | Randomized, open-label, prospective, Mexico | |
| [20] | NCT02186847 Phase II | NSCLC (unresectable, stage III; nondiabetic) | 167 | Chemoradiation + metformin (n = 86; maintained on 2000 mg daily) vs. chemoradiation (n = 81) |
There was no survival benefit associated with metformin addition to traditional chemoradiation therapy | Randomized, open-label, multicenter, international | |
| [21] | NCT02115464 Phase II | Locally advanced NSCLC (nondiabetic) | 54 | Chemoradiation (platinum-based) + metformin (n = 26; maintained on 2000 mg daily) vs. chemoradiation (platinum-based) (n = 28) |
Trial was stopped early due to low accrual; the addition of metformin to chemoradiotherapy was associated with a worse treatment outcome and increased toxicity | Randomized, open-label, multicenter, Canada | |
| Ovarian Tumors | [27] | ChiCTR-IOR-17011859 | Epithelial ovarian cancer (nondiabetic) | 47 | Debulking + paclitaxel/carboplatin + metformin (n = 20; 850 mg daily) Debulking + paclitaxel/carboplatin (n = 24) |
There was no evidence of metformin effect on PFS | China |
| [29] | NCT02312661 Phase I | Advanced epithelial ovarian cancer (FIGO III-IV) | 15 | Paclitaxel/carboplatin + metformin (n = 15; maximum dose of 1000 mg thrice daily) | The recommended phase II dose is 1000 mg thrice daily and there is a potential pharmacokinetic interaction between metformin and carboplatin, though the combination is well-tolerated | Dose escalation study, the Netherlands | |
| [28] | NCT01579812 Phase II | Advanced-stage (IIC/III/IV) epithelial ovarian cancer (nondiabetic) | 38 evaluable | Neoadjuvant metformin + debulking surgery + adjuvant chemotherapy plus metformin (n = 23; maintenance on 1000 mg twice daily) vs. neoadjuvant chemotherapy and metformin + interval debulking surgery + adjuvant chemotherapy plus metformin (n = 15) |
Addition of metformin is associated with better OS and a significant cancer stem cell population reduction | USA | |
| Prostate Tumors | [43] | EudraCT number 2014–005193-11 | Prostate cancer (newly diagnosed, localized, scheduled for radical prostatectomy) | 100 | Metformin (n = 50; maintenance on 1000 mg twice daily) vs. placebo (n = 50) |
Ongoing | Randomized, placebo-controlled, double-blind, window of opportunity, UK |
| [30] | NCT01677897 Phase II | Prostate cancer (metastatic, castration-resistant, with PSA progression while on abiraterone therapy) | 25 | Abiraterone + metformin (n = 25; 1000 mg twice daily) | Combination therapy resulted in no clinical benefit and did not affect progression; higher-than-expected gastrointestinal toxicity was also reported | Pilot study, Switzerland | |
| [31] | NCT01796028 Phase II | Prostate cancer (metastatic, castration-resistant, nondiabetic) | 99 | Docetaxel + metformin (n = 50; 850 mg twice daily) vs. docetaxel + placebo (n = 49) |
No improvement was observed in metformin group vs. placebo | French, prospective, multicenter, randomized, placebo-controlled | |
| [32] | NCT02614859 Phase II | Prostate cancer (nondiabetic, recurrent PC, overweight or obese with BMI > 25) | 29 | Bicalutamide + metformin (n = 20; 1000 mg twice daily) vs. bicalutamide (n = 9) | This study was ended early due to predicted inability to reach its primary endpoint (achievement of undetectable PSA at 32 weeks) | Randomized, open-label, USA | |
| Skin Tumors | [44] | NCT02325401 | HNSCC | 39 | Metformin (n = 39; maintenance on 2000 mg daily) | Metformin is capable of modulating the HNSCC microenvironment | Window of opportunity (post-biopsy, pre-resection) |
| [33] | NCT01840007 Phase I | Metastatic melanoma (patients who progressed after first-line treatment and were not eligible or did not respond to ipilimumab) | 17 | Metformin (n = 17; 1000 mg thrice daily) | Metformin shows no efficacy and poor safety in treating metastatic melanoma | Multicenter, pilot, prospective, open-label, France | |
| [45] | NCT02083692 | HNSCC (nondiabetics) | 50 | Metformin (n = 49; maintenance on 1000 mg twice daily) | Metformin treatment alters the immune tumor microenvironment, regardless of HPV status | Non-randomized | |
| [46] | NCT02325401 Phase I | Locally advanced HNSCC (nondiabetic, stage III-IV) | 20 | Cisplatin + radiotherapy + metformin (n = 20; maximum dose was 3000 mg daily) | Cisplatin did not appear to affect metformin pharmacokinetics | USA | |
| [47] | NCT02581137 Phase IIa | Oral premalignant lesions (nondiabetic) | 26 | Metformin (n = 26; maintenance on 2000 mg daily) | Metformin treatment was associated with good histological response and decreased mTOR activity | Open-label | |
| [48] | NCT02083692 | HNSCC | 50 | Metformin (n = 39 completed; maintenance on 1000 mg twice daily) | Metformin treatment alters the immune tumor microenvironment and results in increased apoptosis in HPV-, tobacco+ HNSCC patients compared to HPV+ HNSCC patients | USA | |
| Uterine Tumors | [34] | Phase III | Endometrioid endometrial cancer or atypical endometrial hyperplasia (pre-surgery) | 88 | Metformin (n = 45; maintenance on 850 mg twice daily) vs. placebo (n = 43) |
Pre-surgical treatment with metformin does not reduce tumor proliferation | Multicenter, randomized, double-blind, pre-surgical window study design, UK |
| [36] | NCTO1877564 | Endometrial cancer (nondiabetic, obese, pre-surgery) | 13 | Metformin (maintenance at 850 mg twice daily) | Pre-surgical treatment with metformin alters steroid receptor signaling of EC cells | Window design | |
| [37] | jRCT2031190065 | Endometrial cancer | 120 (target) | Medroxyprogesterone acetate vs. medroxyprogesterone acetate + metformin (750 mg daily) vs. medroxyprogesterone acetate + metformin (1500 mg daily) |
Ongoing | Prospective, randomized, open, blinded-endpoint, dose–response, multicenter, Japan | |
| [35] | NCT03618472 | Endometrial cancer (nondiabetic) | 49 | Metformin (n = 25; 850 mg daily) vs. placebo (n = 24) |
Pre-surgical metformin treatment significantly decreased proliferative tissue marker Ki-67 | Randomized, double-blind, placebo-controlled, Thailand | |
| Leukemia | N/A |
NCT01324180 Phase I |
Relapsed acute lymphoblastic leukemia | 14 | Metformin (twice daily in dose escalation schema) in combination with vincristine, dexamethasone, PEG-asparaginase, doxorubicin, and intrathecal cytarabine | Completed | Single group assignment, interventional, dose-escalating, open-label |
| N/A |
NCT01849276 Phase I |
Relapsed/refractory acute myeloid leukemia | 2 | Metformin (twice daily in dose escalation schema on days 1–15) + intravenous cytarabine | Terminated (due to slow accrual) | Single group assignment, interventional, open-label | |
| Lymphoma | N/A |
NCT03200015 Phase II |
Diffuse large B-cell lymphoma (DLBCL) | 15 | Metformin (ramp up to 850 mg thrice daily) + rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone | Unknown | Single group assignment, interventional, open-label |
| N/A |
NCT02531308 Phase II |
DLBCL | 5 | Metformin (ramp up to 850 mg twice daily) + rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, pegfilgrastim | Terminated (slow accrual) | Single group assignment, interventional, open-label | |
| Myeloma | N/A |
NCT03829020 Phase I |
Recurrent plasma cell myeloma and refractory plasma cell myeloma | 36 | Metformin (dose escalation schema) + bortezomib, nelfinavir | Recruiting | Single group assignment, interventional |
| N/A |
NCT02948283 Phase I |
Recurrent plasma cell myeloma and refractory plasma cell myeloma | 3 | Metformin (twice daily in dose escalation schema) + ritonavir | Completed | Single group assignment, interventional |