Table 11.

Summary of the clinical evidence of PPAR agonists in malignancies.

Disease	Target	Drug Name	Clinical Phase (Sample Size)	Main Findings/Primary Endpoint	Reference/Clinical Trial Identifier
Cushing′s disease/ Pituitary tumors	PPARγ	Rosiglitazone Rosiglitazone	II-terminated (2)	▪ Primary endpoint: Number of treatment responders	NCT00612066
			II-terminated (1)	▪ Primary endpoint: Efficacy of rosiglitazone maleate on Cushing disease	NCT00616642
			NA-ongoing (24)	▪ Primary endpoint: Levels of growth hormone, insulin-like-factor 1 (IGF-1), and tumor volume	NCT03309319
Medullablastoma	PPARα	Fenofibrate	II-ongoing (40)	▪ Primary endpoint: Response rate	NCT01356290
Oral leukoplakia	PPARγ	Pioglitazone	II (44)	▪ Induced clinical and/or histologic response in 15 of 21 subjects	[282]
			II-terminated (52)	▪ Primary endpoint: Histologic response and clinical response	NCT00951379
		Rosiglitazone	II-completed (25)	▪ Primary endpoint: Proportion of subjects with complete or partial response in either clinical or histological outcomes	NCT00369174
Oral Cavity / Oropharngeal cancer	PPARγ	Pioglitazone	II-terminated (39)	▪ Primary endpoint: Absolute change in proliferation index (Ki-67) expression	NCT02917629
Anaplastic thyroid carcinoma	PPARγ	Efatutazone/ CS-7017	I (15)	▪ Dose-dependently increased median time to disease progression and survival duration ▪ Increased ANGPTL4 levels and plasma adiponectin	[283]
			II-ongoing (19)	▪ Primary endpoint: Response rate	NCT02152137
PAX8-PPARγ anaplastic thyroid carcinoma	PPARγ	Pioglitazone	II (1)	▪ Reduced acetabular soft tissue metastasis, thyroglobulin, and severe pain upon weight bearing	[284]
Differentiated thyroid carcinoma	PPARγ	Rosiglitazone	II (20)	▪ Five partial responders, three stable disease and 12 progressive disease ▪ No complete or partial responders	[285]
Non-small cell lung carcinoma	PPARγ	Efatutazone/ CS-7017	I (16)	▪ Six patients showed partial response, four with stable disease and six with progressive disease ▪ Well-tolerated	[286]
			II-completed (111)	▪ Primary endpoint: Progression-free survival rate	NCT00806286
			I (14)	▪ Five patients with partial response, four with stable disease, six with progressive disease ▪ Dose-dependently increased of adiponectin level	[287]
			II-completed (90)	▪ Primary endpoint: Proportion of subjects with progression free survival	NCT01101334
		Pioglitazone	II (6)	▪ Reduced proliferation, inflammatory and B-cell survival pathway gene expression ▪ Upregulated complement activation and chemokine signaling gene expression	[288]
			II (92)	▪ No difference in treatment effect ▪ Decreased cellular proliferation	[289]
			II-ongoing (86)	▪ Primary endpoint: Progression-free survival	NCT02852083
Colorectal cancer	PPARγ	Efatutazone/ CS-7017	II-completed (86)	▪ Improved progression-free survival	NCT00986440
			II (100)	▪ No effect on progression-free survival rate ▪ Prolonged overall progression-free survival duration	[290]
Prostate carcinoma	PPARγ	Rosiglitazone	III (105)	▪ No difference in prostate specific antigen doubling time and disease progression	[291]
		Troglitazone	II (41)	▪ One responder, three partial responders and eight non-responders in androgen-dependent prostate cancer group ▪ Four partial responder and 25 non-responders in castration-resistant prostate cancer	[292]
Castration-resistant prostate cancer	PPARγ	Pioglitazone	II (61)	▪ Prostate-specific antigen response in 23 subjects, with 14 with stable disease and 24 non-responders ▪ Reduction or complete regression of bone lesion shown in six of 16 subjects	[293]
	PPARα & PPARγ	Fenofibrate, Pioglitazone, Rosiglitazone	II-terminated (49)	▪ Primary endpoint: Prostate specific antigen doubling time	EUCTR 2006-001398-44
Acute myeloid leukemia	PPARα	Bezafibrate	II (20)	▪ Three subjects had no responses, six subjects had progressive disease ▪ Of the 11 subjects that continued treatment for > 4 weeks without concomitant AML therapy, four had improved hematological scores, with no disease progression in remaining 7 subjects	[294]
			II (18)	▪ Higher toxicities rates with one subject having hematological response	[295]
	PPARγ	Pioglitazone	II-ongoing (94)	▪ Primary endpoint: Overall survival	NCT02942758
Chronic myeloid leukemia	PPARγ	Pioglitazone	I/II-ongoing (100)	▪ Primary endpoint: Cumulative incidence of patients achieving a deep molecular response	NCT02767063
			II-ongoing (26)	▪ Primary endpoint: Number of participants with treatment-related adverse events, treatment free survival after pioglitazone and tyrosine kinase inhibitor discontinuation	NCT02889003
			II-ongoing (31)	▪ Primary endpoint: Treatment-free remission after imatinib discontinuation, number of participants with treatment-related adverse events	NCT02852486
			II-terminated (9)	▪ Primary endpoint: Adverse events, proportion of subjects who achieve and maintain major molecular response	NCT02730195
			II-unknown status (20)	▪ Primary endpoint: Rate of complete molecular response	NCT02687425
			II (24)	▪ Enhanced molecular response	[296]
Cutaneous T-cell lymphoma	PPARγ	Rosiglitazone	II (4)	▪ Reduced skin scores of scaling in two subjects, unchanged in one patient ▪ One subject achieved >50% partial response, while the rest had stable disease ▪ Pruritus alleviated for 3 of 4 subjects ▪ Quality of life unchanged	[297]
Endemic Burkitt′s lymphoma	PPARα	Bezafibrate	II (95)	▪ Disease progression was 29%, 0%, and 0% in low-, intermediate-, and high-dose cohorts respectively ▪ Stable disease/no clinical change at 46%, 71%, and 71% in low-, intermediate-, and high-dose cohorts respectively ▪ Complete clinical response at 39%, 44%, and 68% in low-, intermediate-, and high-dose cohorts respectively	[298]
Multiple myeloma	PPARα	Fenofibrate	II-terminated (6)	▪ Primary endpoint: Response rate	NCT01965834
	PPARγ	Efatutazone	I-terminated (9)	▪ Primary endpoint: Maximum tolerated dose	NCT01504490
			I/II-unknwon status (54)	▪ Primary endpoint: Response rate	NCT01010243
Melanoma	PPARγ	Pioglitazone	I (6)	▪ Progression-free survival ranged from 4–13 months ▪ Four patients with stable disease, one with mixed response with no objective response in radiation field, and one partial responder ▪ Steep decline of melanoma inhibitory activity and improvement of oncological scores in one subject with stable disease ▪ Longer progression-free survival in two subjects with extensive metastatic liver	[299]
Melanoma/Soft Tissue Sarcoma	PPARγ	Pioglitazone	II (40)	▪ Objective response at 11% and disease stabilization > 6 months at 11% for melanoma subjects ▪ Objective response at 19% and disease stabilization > 6 months at 14% for soft-tissue sarcoma subjects ▪ Complete remission in one melanoma subject and three sarcoma subjects ▪ Subjects with normal C-reactive protein levels and subjects with C-reactive levels that decreased by >30% had prolonged progression-free survival	[300]
Skin squamous cell carcinoma	PPARγ	Pioglitazone	II-ongoing (40)	▪ Primary endpoint: Number of squamous cell carcinomas	NCT02347813
Liposarcoma	PPARγ	Troglitazone	II (3)	▪ Induced intracellular lipid accumulation and increased expression levels of PPARγ mRNA	[302]
			II-completed (85)	▪ NA	NCT00003058
		Rosiglitazone	II (12)	▪ Did not induce redifferentiation, reduced proliferation, and upregulation of PPARγ, adipsin, and fatty acid binding protein genes	[303]
Refractory breast cancer	PPARγ	Troglitazone	II (22)	▪ Three patients with stable disease	[304]
Breast cancer	PPARγ	Pioglitazone	I/II (38)	▪ No difference in Ki-67 expression and PPARγ expression ▪ Improved adiponectin and insulin sensitivity	[305]
Acromegaly (macroadenoma and microadenoma)	PPARγ	Rosiglitazone	II (5)	▪ Decreased serum IGF-1 at higher dosage of rosiglitazone (20 mg/day) ▪ No change to growth hormone levels	[306]
Progressive pediatric malignancies	PPARα	Fenofibrate	II (101)	▪ Well-tolerance of antiangiogenic multi-drug treatment ▪ Induced partial response and stable disease in ependymoma and low-grade glioma ▪ Favorable response in miscellaneous central nervous system (CNS) and non-CNS tumors, with nine of 18 having stable disease and five of 18 having partial response ▪ Increased serum TSP-1	[307]
Advanced or metastatic solid tumors	PPARγ	Pioglitazone	I-completed (28)	▪ Primary endpoint: Maximum tolerated dose of pioglitazone and carboplatin	NCT02133625
		Efatutazone/ CS-7017	I (32)	▪ Induced sustained partial response in one patient with myxoid liposarcoma ▪ Twelve of 32 patients had stable disease, with seven of 12 having a ≥81 days stable disease ▪ Well-tolerated	[308]