Table 1.

Selected completed clinical trials in adult patients.

	Agent	Target or Mechanism	Trial phase/Tumor type	Regimen (single agent unless specified)	Outcome	NCT Number	Reference
Targeting mitochondrial metabolism	CPI-613	Inhibits KGDH and PDH	1/relapse/refractory AML	CPI-613 + cytarabine + mitoxantrone	ORR 48% (n=26), pts >60 years of age CR/CRi 46% (12/26), poor-risk cytogenetics CR/CRi 48% (11/23)	[]	[129]
			1/newly diagnosed metastatic pancreatic adenocarcinoma	CPI-613 + mFOLFIRINOX	16.6% CR, 50% PR, 11% SD, 22% PD	[]	[105]
			1/locally advanced or metastatic pancreatic cancer		Unreported	[]
			1/recurrent small cell lung cancer		Unreported	[]
			1/2/advanced or metastatic cholangiocarcinoma		Unreported	[]
			2/relapsed/refractory SCLC		No treatment responses, median OS 4.3 months	[]	[104]
	Dichloroacetate (DCA)	Inhibits PDK and activates PDH	1/refractory or metastatic solid tumors		Well tolerated, 35% SD	[]	[130]
			1/recurrent head and neck cancers		Unreported	[]
			2/WHO grade III-IV gliomas		Well tolerated	[]	[131]
	AG-22 (enasidenib)	IDH inhibitor	1/2 relapsed/refractory IDH2 mutated AML		ORR 38.5%, with 20.2% CR	[]	[132]
	AG-120		1/glioma		73% SD in patients in dose escalation cohort and 88% in expansion cohort	[]	[133]
			1/cholangiocarcinoma		6% of patients with PR, and 56% SD; 6-month PFS 40%	[]	[134]
			1/IDH1 mutated AML		ORR 41.6%	[]	[135]
	AG-881		1/IDH mutant solid malignancies		22% of patients remained on therapy after about 2.5 years	[]	[45]
Targeting apoptotic pathways	ABT-199 (venetoclax)	BCL-2 inhibitor	II/mantle cell lymphoma	Venetoclax + ibrutinib	42% response rate	[]	[136]
			III/relapsed/refractory CLL	Venetoclax + rituximab	PFS 84.9% at 2 years	[]	[137]
	Birinapant	Mimics SMAC	1/relapsed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer	Birinapant + conatumumab	18 pts enrolled; well-tolerated; 1 pt with PR and 4 pts with SD; median time on study 1.9 months	[]	[138]
			2/relapsed/refractory epithelial ovarian cancer		SD in 2/11 pts; closed after 11 patients enrolled as clinical benefit unlikely	[]	[139]
	Debio 1143		1/advanced or metastatic solid tumors and lymphoma		5/31 patients with SD for a median duration of 93 days	[]	[140]
			1/poor-risk AML	Debio 1143 + cytarabine + daunorubicin	38% CR	[]	[141]
	LCL 161		2/relapsed/refractory multiple myeloma	LCL-161 +/− cyclophosphamide	No responses with single-agent; with combination, median PFS 10 months in 5 of 25 patients (1 pt with CR, 3 pts with PR)	[]	[142]
	ME-344	Decreases mitochondrial ATP production and ROS	1/refractory solid tumors		1 of 30 pts with PR for >1 year, 4 pts with SD	[]	[143]
			1/previously treated, locally advanced or metastatic small cell lung, ovarian, and cervical cancers	ME-344 + topotecan	ORR 2.4%, clinical benefit rate 53.7%, 21 of 41 pts with SD; Terminated due to lack of efficacy	[]	[144]
	Minnelide	Regulation of Sirt3, increase ROS, active caspase-3	1/refractory GI malignancies		Well tolerated, disease control observed with progression after dose reduction or treatment breaks	[]	[145]
	ONC201	Induces transcription of TNF-related apoptosis by inducing TRAIL ligand	1/advanced solid tumors		8/10 pts with stable disease; Suspended due to lack of funding	[]	[146]
			1/advanced solid tumors		Recruiting; preliminary data with 1 pt with prostate ca with stable disease at 6 months and 2 pts with prostate cancer after 4 cycles	[]	[147]

Abbreviations: ATP adenosine triphosphate, CR complete response, CRi Complete response with incomplete hematologic recovery, KDGH alpha-ketoglutarate dehydrogenase, PDH pyruvate dehydrogenase, PDK pyruvate dehydrogenase kinase, PFS progression-free survival, PR partial response, Pt(s) patient(s), ROS reactive oxygen species, SD stable disease, TNF tumor necrosis factor, TRAIL TNF-related apoptosis inducing ligand, ORR overall response rate