Table 2. Anti-tumor activity of metformin in locally advanced and hematologic cancers.
| Cancer type | Phase | Primary outcome/Conclusion | Dosing regimen | Combination | Enrollment No. | Status | Results | Clinical trial identifier/Reference |
|---|---|---|---|---|---|---|---|---|
| AML | Phase I | MTD of metformin plus cytarabine | Metformin PO BID on days 1-15 and cytarabine IV over 3 hours BID on days 4-10. | metformin, cytarabine | 28 | Recruiting | NA | NCT01849276 |
| Breast | Phase II RCT | pCR rate (evaluated in 5 months) | Docetaxel 75mg/m2 IV, epirubicin 75mg/m2 IV and cyclophosphamide 500mg/m2 IV day 1 of each 21 day cycle; 6 cycles; metformin 500mg TID PO (500mg daily in 1st cycle) | metformin, docetaxel, epirubicin, cyclophosphamide | 200 | Recruiting | NA | NCT01929811 |
| Breast | Phase II RCT | Clinical response rate | Letrozole 2.5mg PO daily, metformin 500mg BID PO daily x 1week; metformin 1000mg (am) & 500 mg (pm) PO daily x 1week; metformin 1000mg BID PO daily x 22 weeks | metformin, letrozole | 208 | Recruiting | NA | NCT01589367 |
| Breast | Phase II RCT | To evaluate if using new chemotherapy drugs with standard neoadjuvant chemotherapy agents increases pCR. | AMG 479 (Ganitumab) 12 mg/kg IV every 2 weeks during 12 week cycle + metformin 850 mg PO every week during 12 weekly cycles post-randomization | metformin, ganitumab | 800 | Recruiting | NA | NCT01042379 |
| Breast | Phase III RCT | Invasive disease-free survival | Metformin HCl PO BID (QD for first 4 weeks), for up to 5 years. | metformin monotherapy | 3649 | Active but not recruiting | NA | NCT01101438 |
| Breast | Phase III RCT | Evaluating atypia after 12 and 24 months of metformin | Metformin HCl 850 mg PO BID for 24 months on arm 1, including 4 weeks escalation dosing of 850 mg PO QD. Patients initially randomized to the placebo arm (Arm 2) may crossover to the metformin arm (Arm 1) for months 13-24. | metformin monotherapy | 400 | Not yet recruiting | NA | NCT01905046 |
| Chronic Lymphocytic Leukemia | Phase II | Time to treatment failure (assessed every 3 months) | Initial dose of metformin will be 500 mg PO QD for 1 week, escalated to 500 mg BID after 1 week, and finally to 1000 mg BID in week 3 if tolerated. | metformin monotherapy | 53 | Recruiting | NA | NCT01750567 |
| Colorectal | Phase II | Disease Control Rate (assessed up to 1 year) | FOLFOX6+Metformin or FOFIRI + Metformin | metformin, FOLFOX6, FOFIRI | 48 | Recruiting | NA | NCT01926769 |
| Endometrial | Phase II | CBR | Metformin 500 mg PO QD for days 1-4 of cycle 0 and then BID after that. Metformin to be taken for 7 - 10 days in cycle 0 before cycle 1 begins; letrozole 2.5 mg PO QD in a 28 day cycle; everolimus 10 mg PO QD in a 28 day cycle. | metformin, letrozole, everolimus | 64 | Recruiting | NA | NCT01797523 |
| Endometrial | Phase II RCT | Pathological response rate (evaluated at 12 weeks) | Metformin 500 mg PO third daily and megestrol acetate 150 mg PO QD for 3 months | metformin, megestrol acetate | 150 | Recruiting | NA | NCT01968317 |
| Endometrial | Phase II, III RCT | PFS (Phase II) (assessed up to 5 years) | Day 1- paclitaxel IV over 3 hours and carboplatin IV; metformin PO BID on days 1-21 (QD in cycle 1). Treatment repeats every 21 days for 6 cycles. Patients then receive maintenance therapy- metformin PO BID on days 1-21. Course repeated every 21 days. | metformin, paclitaxel, carboplatin | 540 | Recruiting | NA | NCT02065687 |
| Glioblastoma Multiforme | Phase I | MTD and PFS assessed at 6 months | Temozolomide 150 mg/m2 PO on alternate weeks days 1-7, 15-21 of a 28 day cycle; metformin 1000 mg PO BID for 28 day cycle. | metformin, temozolomide | 144 | Recruiting | NA | NCT01430351 |
| Lung | Phase II | PFS (assessed for up to 52 weeks) | Metformin 1000 mg PO BID added to standard of care platinum based chemotherapy | metformin, platinum based chemotherapy | 60 | Recruiting | NA | NCT02019979 |
| Lung | Phase II RCT | PFS assessed at 1 year | Gefitinib + metformin; metformin starting at 500 mg TID PO. After 1 week, increase dose to 1000 mg as the 1st dose of the day and 500 mg as the 2nd dose. After another week, increase to 1000 mg TID. Metformin treatment will be initiated 1 week before TKI therapy if possible. | metformin, gefitinib | 168 | Recruiting | NA | NCT01864681 |
| Ovary | Phase I | Assess safety and tolerability of the treatment | Escalating doses of metformin will be added to carboplatin IV / paclitaxel IV chemotherapy for up to 6 cycles. | metformin, carboplatin, paclitaxel | 20 | Not yet recruiting | NA | NCT02312661 |
| Ovarian, Fallopian Tube or Primary Peritoneal | Phase I | Success rates of the combination chemotherapy | Day 1- paclitaxel IV over 3 hours, carboplatin IV, metformin HCl BID on days 1-21; treatment repeated every 21 days for 6 cycles | metformin, paclitaxel, carboplatin | 18 | Not yet recruiting | NA | NCT02050009 |
| Pancreas | Phase II | PFS at 12 months | Everolimus + octreotide LAR + metformin | metformin, everolimus, octreotide LAR | 43 | Recruiting | NA | NCT02294006 |
| Pancreas | Phase II RCT | RFS after surgery (assessed every 2 months during treatment and every 3 months after completion, till 24 months) | Metformin 500 mg BID initially, if tolerated, dose to be increased to 1000 mg BID in the 2nd week; gemcitabine 1000 mg/m2 (IV, 30 minutes) on days 1, 8, and 15 for 3 weeks, followed by 1 week without treatment, and also receive placebo (Arm I)/ metformin (Arm II) on days 1-28. Course repeated every 4 weeks for up to 6 cycles. | metformin, gemcitabine | 300 | Recruiting | NA | NCT02005419 |
| Prostate | Phase I | DLT assessed at 28 days | Enzalutamide PO QD and metformin HCl PO BID. Courses repeat every 28 days | metformin, enzalutamide | 24 | Not yet recruiting | NA | NCT02339168 |
| Solid tumors | Phase I | To evaluate DLT when metformin is added to a chemotherapy regimen that is well tolerated. | Stage 1- patients randomized to 2 arms- concurrent arm (metformin + chemo) and delayed arm (chemo alone). Stage 2- patients in delayed arm crossed over to concurrent arm; metformin dose- 500mg BID + chemotherapy | metformin, chemotherapy | 100 | Completed | Metformin plus chemotherapy had a lower rate of DLTs (6.1%) as compared to those who received only chemotherapy (7.8%); Patients showing DLT with metformin included the ones already known to have adverse effects with chemotherapy; Post-treatment with metformin, AMPK phosphorylation increased by 4-6 folds, 46% showed stable disease and 28% of the patients who had quantifiable tumor markers showed favorable changes. | NCT01442870 [49] |
| Uterus | Phase II RCT | pCR (assessed at 6 months) | Metformin 500mg BID PO + levonorgestrel 52mg IUD for 6 months | metformin, levonorgestrel | 165 | Recruiting | NA | NCT01686126 |
Abbreviations: RFS, recurrence free survival; PFS, Progression free survival; DLT, dose limiting toxicity; MTD, Maximum tolerable dose; pCR, Pathological complete response; RCT, Randomized control trial; CBR, Clinical benefit rate; IHC, immunohistochemistry; HOMA, Homeostasis model assessment; CI, Confidence interval; PO, taken by mouth; QD, once a day; BID, two times a day; TID, three times a day; IUD, Intra-uterine device