Table 1.

Clinical trials on biguanides in combination with molecularly targeted therapy in cancer.

Trial name (ID)	Study design	Treatment setting	Standard arm	Experimental arm	Patients	Primary endpoints	Status
(NCT01650506)I	Phase 1, open label	BC	Erlotinib +M		8	MTD	Completed
CGMT(NCT01864681)II	Phase 2, randomized, double masking	NSCLC	Gefitinib + placebo	Gefitinib +M	224	PFS	Completed
GEM(NCT01210911)III	Phase 2, randomized, quadruple masking	Pancreatic cancer	Gefitinib + Erlotinib +Placebo	Gefitinib + Erlotinib +M	120	Survival	Completed
(NCT01087983)IV	Phase 1, non-randomized, open label	AC	Lapatinib+ Sirolimus		111	MTD	Completed
			Lapatinib +M
(NCT01477060)V	Phase 2, randomized, open label	MBC	Arm A: Lapatinib		32	PFS	Terminated
			Arm B: M
			Arm C: Lapatinib +M
(NCT04428086)VI	Phase 1, randomized, open label	ST, Adults	Arm 1: Apatinib + Rosuvastatin		36	Cmax, AUC	Not yet recruiting
			Arm 2: Apatinib +M
(NCT03071705)VII	Phase 2, randomized, double masking	NSCLC	TKI	TKI+M	120	OS	Completed
(NCT02495103)VIII	Phase 1 & 2, non-randomized, open label	HLRCC, SDH-RCC, RCC	phase 1: Vandetanib+M		7	MTD	Completed
			phase 2: Vandetanib+M			ORR
(NCT02672488)IX	Phase 2, randomized, open label	HCC	Sorafenib	Sorafenib +M	82	OS	Unknown
(NCT01578551)X	Phase 2, randomized, open label	adenocarcin oma	Paclitaxel + Carboplatin + Bevacizumab	Paclitaxel+ Carboplatin+ Bevacizumab+ M	25	PFS	Terminated
(NCT02143050)XI	Phase 1, open label	Melanoma	Dabrafenib + Trametinib +M		53	Toxicity	Unknown
	Phase 2, open label					CRR
(NCT01638676)XII	Phase 1& 2, open label	Melanoma	Vemurafenib+M		55	AE	Unknown
METALLICA(NCT04300790)XIII	Phase 2, randomized, multicenter, two cohort, open label	BC	CohortA: Normal fasting glycemia (M+ Fulvestrant + Alpelisib) CohortB: Fasting glycemia (M + Fulvestrant + Alpelisib)		68	% of patients with G3–4 HG	Not yet recruiting
(NCT03006172)XIV	Phase 1, non-randomized, open label	BC, ST	Stage I, Arm A: GDC-0077		256	Toxicity	Recruiting
			Stage I, Arm B: GDC-0077 + Palbociclib + Letrozole
			Stage I, Arm C: GDC-0077 + Letrozole
			Stage II, Arm B: GDC-0077 + Palbociclib + Letrozole			Phase 2 Dose of GDC-0077, AE
			Stage II, Arm C: GDC-0077 + Letrozole
			Stage II, Arm D: GDC-0077 + Fulvestrant
			Stage II, Arm E: GDC-0077 + Palbociclib + Fulvestrant
			Stage II, Arm F: GDC-0077 + Palbociclib + Fulvestrant + M
			Stage II, Arm G: GDC-0077 + Trastuzumab + Pertuzumab
(NCT03829020)XV	Phase 1, open label	Recurrent/Refractory PCM	M+ Nelfinavir + Bortezomib		36	MTD	Recruiting
INSIDE(NCT03151772)XVI	Early phase 1, non-randomized, open label	GBM	M		3	Bioavailabilty	Recruiting
			Disulfiram			Bioavailabilty
IMPACT(NCT03378297)XVII	Early Phase 1, randomized, open label	OC	Arm: no intervention		143	Changes in the expression of biomarkers	recruiting
			Arm: M
			Arm: Acetylsalicylic acid
			Arm: Olaparib
			Arm: Letrozol
(NCT02948283)XVIII	Phase 1, open label	Relapsed/Refractory MM or CLL	M+ Ritonavir		3	safety, tolerability, feasibility	Active, not recruiting
(NCT01430351)XIX	Phase 1, non-randomized, open label	GBM	Arm 1 (TMZ)		144	Incidence of toxicities	Active, not recruiting
			Arm 2 (TMZ, memantine hydrochloride)
			Arm 3 (TMZ, mefloquine)
			Arm 4 (TMZ, M)
			Arm 5 (TMZ, memantine hydrochloride, mefloquine)
			Arm 6 (TMZ, memantine hydrochloride, M)
			Arm 7 (TMZ, mefloquine, M)
			Arm 8 (TMZ, memantine hydrochloride, M, mefloquine)
MACIST(NCT02496741)XX	Phase 1b, open label	Glioma; CCA; CHS	M+ chloroquine		15	MTD	Completed
ENDOLA(NCT02755844)XXI	Phase 1 &2, open label	Recurrent EC	Olaparib, M+ metronomic cyclophosphamide		35	RP2D of combined therapy	Active, not recruiting
HERMET(NCT03238495)XXII	Phase 2, randomized, open label	HER2+ BC	Chemotherapy	Chemotherapy+ M	100	pCR	Recruiting
met-HEReMYTA (NCT02488564)XXIII	Phase 2, open label	HER2+ BC	Liposomal doxorubicin +Docetaxel+Trastuzumab+M		49	pCR	Completed
DLBCL(NCT02531308)XXIV	Phase 2, open label	DLBCL	R-CHOP + M		5	PFS	Terminated
(NCT01797523)XXV	Phase 2, open label	EC	Letrozole + M + RAD001		62	CBR	Active, not recruiting
(NCT01627067)XXVI	Phase 2, open label	BC	Everolimus + Exemestane + M		23	PFS	Terminated
(NCT02917629)XXVII	Phase 2, randomized, double masking	Stage I-IV Oral Cavity or OPC Undergoing Definitive Treatment	Placebo	ACTOplus met XR	13	Ki-67 expression in tumor tissue	Terminated
(NCT01529593)XXVIII	Phase 1, open label	Advanced Cancers	Temsirolimus + M		87	MTD	Active, not recruiting
(NCT03017833)XXIX	Phase 1, open label	Advanced/Metastatic Relapsed/Refractory Cancers	M + Sapanisertib		50	AE, Clinical and laboratory values, Vital sign measurements, GI symptoms, incidence of neurotoxicity	Recruiting
(NCT02048384)XXX	Phase 1, randomized, open label	Metastatic PAC	M	M+ Rapamycin	22	Safety, feasibility	Completed
(NCT02874430)XXXI	Phase 2, open label	Localized BC or UC	M+Doxycycline		46	% of stromal cells expressing CAV1	Recruiting
(NCT03026517)XXXII	Phase 1, open label	Melanoma	Dabrafenib +Trametinib + Phenformin		40	DFS	Active, not recruiting

As of Sep 1, 2020

AC: advanced cancer, AE: adverse event, AUC: Area Under the Plasma Concentration-Time Curve, CAV1: Caveolin-1, CBR: Clinical Benefit Rate, CCA: Cholangiocarcinoma, CHS: Chondrosarcoma, CLL: Chronic Lymphocytic Leukemia, Cmax: maximum observed concentration, CRR: clinical response rate, DFS: Disease-free survival, DLBCL: Diffuse Large B-Cell Lymphoma, EC: Endometrial Cancer, GBM: glioblastoma, HCC: Hepatocellular Carcinoma, HG: hyperglycemia, HNSCC: Head and Neck Squamous Cell Carcinoma, M: metformin, MBC: metastatic breast cancer, MM: Multiple Myeloma, MTD: Maximum Tolerated Dose, NSCLC: non-small cell lung cancer, OC: ovarian cancer, ORR: overall response rate, OS: overall survival, OPC: Oropharynx Cancer, PAC: Pancreatic Adenocarcinoma, PCM: Plasma Cell Myeloma, pCR: Pathologic complete response, PFS: progression free survival, RP2D: Recommended phase 2 trial dose, ST: solid tumor, TKI: erlotinib, afatinib, gefitinib, TMZ: temozolomide, TNBC, triple negative breast cancer, UC: Uterine Cancer