Immune checkpoint therapy for pancreatic cancer

Table 1 Clinical trials on cytotoxic T lymphocyte antigen 4

Target molecule	Drug name	Study phase	Study design	Status	Condition	Intervention	Cohort	Estimated enrollment	Dose	End point	Study Arm	Adverse event	Response	Survival	Ref.
CTLA-4	Ipilimumab (BMS-734016/MDX-010)	1	NA	Active	PC	Palliative	Locally advanced	28	DE	Safety (MTD, DLT)	Ipilimumab, Gemcitabine	NA	NA	NA	NCT01473940
				Not recruiting			Metastatic			Efficacy (RR, PFS, OS)
		2	Randomized	Recruiting	PC	Palliative	Metastatic	92	3 mg/kg	Safety (AE)	Ipilimumab, GVAX (Arm A)	NA	NA	NA	NCT01896869
										Efficacy (OS, PFS, ORR, DoR)	FOLFIRINOX (Arm B)
	Tremelimumab (CP-675/CP-675,206)	2	NA	Recruiting	PC, BlC, BC	Palliative	Metastatic	77	NA	Safety	Tremelimumab (Arm A)	NA	NA	NA	NCT02527434
										Efficacy (ORR, DoR, DCR, PFS, OS, BoR)	Durvalumab (Arm B)
											Tremelimumab, Durvalumab (Arm C)
		2	Randomized	Recruiting	PC	Palliative	Metastatic	130	NA	Safety	Durvalumab (Arm A)	NA	NA	NA	NCT02558894
										Efficacy (ORR, DoR, DCR, PFS)	Durvalimab, Tremelimumab (Arm B)
										PK
										Antidrug Antibody Presence
		1	Randomized	Recruiting	PC, NSCLC, HNSCC	Palliative	Locally advanced	108	NA	Safety (AE, DLT)	Durvalumab, Mogamulizumab (Arm A)	NA	NA	NA	NCT02301130
							Metastatic				Tremelimumab, Mogamulizumab (Arm B)
		1	Non-randomized	Recruiting	PC, NSCLC, BC, MM	Palliative	Metastatic	30	1 mg/kg	Safety (AE)	Durvalumab, Tremelimumab, Radiotherapy	NA	NA	NA	NCT02639026
										Efficacy

ORR: Overall response rate; DLT: Dose limiting toxicity; AE: Adverse event; MTD: Maximum tolerance dose; NA: Not available.

Table 2 Clinical trials on programmed cell death 1

Target molecule	Drug name	Study phase	Study design	Status	Condition	Intervention	Cohort	Estimated enrollment	Dose	End point	Study Arm	Adverse event	Response	Survival	Ref.
PD-1	Nivolumab (BMS-936558/MDX-1106/ONO-4538)	1|2	Randomized	Recruiting	PC	Neoadjuvant	Resectable	50	3 mg/kg	Safety	Cy/GVAX ( Arm A)	NA	NA	NA	NCT02451982
						Adjuvant				Efficacy (IRAEs, OS, DFS)	Cy/GVAX, Nivolumab (Arm B)
										Median-[IL17A] in Vaccine-induced Lymphoid Aggregates
		1|2	Non-randomized	Recruiting	PC, NSCLC, RCC, CrC, EC, UC	Palliative	Metastatic	49	NA	Safety	Nivolumab, Temsirolimus (Arm A)	NA	NA	NA	NCT02423954
										Efficacy	Nivolumab, Irinotecan (Arm B)
										RD	Nivolumab, Irinotecan, capecitabine (Arm C)
		1	Non-randomized	Recruiting	PC, NSCLC, CrC, MM, HNSCC, GBM	Palliative	Locally advanced	270	3 mg/kg	Safety (AE)	Phase 1a:	NA	NA	NA	NCT02526017
										Efficacy (OS; mOS, oyOS, DOR, PFS, ORR; CR, PR)	FPA008 (Arm A)
										Tolerability	FPA008, Nivolumab (Arm B)
										RD	Phase 1b:
										PK	MTD/RD FPA008, Nivolumab
										Immunogenicity
										PDA biomarkers
		1	Non-randomized	Recruiting	PC, OC, BC, CrC, RCC, MM, PrC, NSCLC	Palliative	Locally advanced	300	3 mg/kg	Safety	DE AM0010 (Arm A)	NA	NA	NA	NCT02009449
							Metastatic			Tolerability	DE AM0010, Paclitaxel/Docetaxel, Carboplatin/Cisplatin (Arm B)
										PK	DE AM0010, FOLFOX, (Arm C)
											DE AM0010, gemcitabine/nab-paclitaxel (Arm D)
											DE AM0010, Capecitabine (Arm E)
											DE AM0010, Paclitaxel (Arm F)
											DE AM0010, Pazopanib (Arm G)
											DE AM0010, Pembrolizumab (Arm H)
											DE AM0010, Nivolumab (Arm I)
											DE AM0010, Gemcitabine/carboplatin (Arm J)
	Pembrolizumab (MK-3475/SCH 900475)	2	NA	Not recruiting	PC	Palliative	Locally advanced	54	200 mg	Safety (IRAEs)	Cy/GVAX, Pembrolizumab, SBRT	NA	NA	NA	NCT02648282
										Efficacy (DMFS, OS, LPFS)
		2	Randomized	Active	PC	Palliative	Locally advanced	76	NA	Safety (TEAE)	ACP-196 (Arm A)	NA	NA	NA	NCT02362048
				Not recruiting			Metastatic			Efficacy	ACP-196, Pembrolizumab (Arm B)
		1|2	Randomized	Recruiting	PC	Neoadjuvant	Resectable	56	200 mg	Safety (DLT)	Pembrolizumab, Capecitabine, Radiotherapy	NA	NA	NA	NCT02305186
							Borderline resectable			Efficacy (DFS, OS, RR)
										[TILs]
		1|2	Non-randomized	Recruiting	PC, SCLC, OC, BC, Sarcoma	Palliative	Metastatic	90	2 mg/kg	Safety (AE)	Pembrolizumab, Gemcitabine (Arm A)	NA	NA	NA	NCT02331251
										Efficacy (ORR, OS, PFS)	Pembrolizumab, Gemcitabine, Docetaxel (Arm B)
										RD	Pembrolizumab, Gemcitabine, Nab-paclitaxel (Arm C)
											Pembrolizumab, Gemcitabine, Vinorelbine (Arm D)
											Pembrolizumab, Irinotecan (Arm E)
											Pembrolizumab, Liposomal, Doxorubicin (Arm F)
		1	Non-randomized	Recruiting	PC	Palliative	Locally advanced	50	200 mg	Safety	Pembrolizumab, Defactinib, Gemcitabine	NA	NA	NA	NCT02546531
							Metastatic			Efficacy
		1	NA	Active	PC, RC, NSCLC, BlC, ASN, RCC, CC, HCC, BC, MM, HNSCC, Sarcoma	Palliative	Metastatic	12	NA	Safety	Pembrolizumab, p53MVA	NA	NA	NA	NCT02432963
				Not recruiting						Efficacy (Clinical Response)
										Tolerability
		2	Non-randomized	Suspended	PC, ChC, GeC, CrC, HCC	Palliative	Metastatic	290	2 mg/kg	Safety	Pebrolizumab, Young TIL, Aldesleukin, Cyclophosphamide, Fludarabine	NA	NA	NA	NCT01174121
										Efficacy
		1	NA	Recruiting	PC	Palliative	Locally advanced	9	2 mg/kg	Safety (DLT)	Pembrolizumab, Reolysin, Gemcitabine/Irinotecan/Leucovorin with 5-FU	NA	NA	NA	NCT02620423
							Metastatic			Efficacy (ORR, PFS, OS)
		1|2	NA	Recruiting	PC, ChC, GeC, CrC	Palliative	Locally advanced	128	DE	Safety	Pembrolizumab, mFOLFOX6, Celecoxib	NA	NA	NA	NCT02268825
							Metastatic			Efficacy (RR, PFS, OS)
		1	Non-randomized	Recruiting	PC, OC, BC, CrC, RCC, MM, PrC, NSCLC	Palliative	Locally advanced	300	3 mg/kg	Safety	DE AM0010 (Arm A)	NA	NA	NA	NCT02009449
							Metastatic			Tolerability	DE AM0010, Paclitaxel/Docetaxel, Carboplatin/Cisplatin (Arm B)
										PK	DE AM0010, FOLFOX, (Arm C)
											DE AM0010, gemcitabine/nab-paclitaxel (Arm D)
											DE AM0010, Capecitabine (Arm E)
											DE AM0010, Paclitaxel (Arm F)
											DE AM0010, Pazopanib (Arm G)
											DE AM0010, Pembrolizumab (Arm H)
											DE AM0010, Nivolumab (Arm I)
											DE AM0010, Gemcitabine/carboplatin (Arm J)
	Pidilizumab (CT-011)	2	NA	Suspended	PC	Adjuvant	Resectable	29	3 mg/kg	Safety	Pidilizumab, Gemcitabine	NA	NA	NA	NCT01313416
										Efficacy (Median DFS)
		1	Non-randomized	Withdrawn	PC, OC, BC, CC, Sarcoma	Palliative	NA	0	DE	Safety	Pidilizumab, p53 Vaccine	NA	NA	NA	NCT01386502
										Efficacy

AE: Adverse event; NA: Not available.

Table 3 Clinical trials on programmed cell death ligand 1

Target molecule	Drug name	Study phase	Study design	Status	Condition	Intervention	Cohort	Estimated enrollment	Dose	End point	Study Arm	Adverse event	Response	Survival	Ref.
PD-L1	Durvalumab (MEDI4736)	2	Non-randomized	Not recruiting	PC, GeC, OC, NSCLC, BC, RCC, CrC	Palliative	Metastatic	136	750 mg > 30 kg,	Safety Efficacy (ORR, PFS, OS)	Durvalumab	NA	NA	NA	NCT02669914
									10 mg/kg < 30 kg
		2	NA	Recruiting	PC, BlC, BC	Palliative	Metastatic	77	NA	Safety	Tremelimumab (Arm A)	NA	NA	NA	NCT02527434
										Efficacy (ORR, DoR, DCR, PFS, OS, BoR)	Durvalumab (Arm B)
											Tremelimumab, Durvalumab (Arm C)
		1	Non-randomized	Recruiting	PC, HNSCC, MM, CrC, BC, CEC	Palliative	Locally advanced	40	NA	Safety (AE)	Durvalumab, Selumetinib	NA	NA	NA	NCT02586987
							Metastatic			Efficacy (ORR, BoR, DoR)
										Tolerability
										PK
		2	Randomized	Recruiting	PC	Palliative	Metastatic	130	NA	Safety	Durvalumab (Arm A)	NA	NA	NA	NCT02558894
										Efficacy (ORR, DoR, DCR, PFS)	Durvalimab, Tremelimumab (Arm B)
										PK
										Antidrug Antibody Presence
		1|2	Non-randomized	Recruiting	PC	Palliative	Metastatic	26	NA	Safety (DLT)	Durvalumab , nab-Paclitaxel, Gemcitabine (Arm A)	NA	NA	NA	NCT02583477
										Efficacy (ORR, DoR, DCR, PFS)	Durvalumab, AZD5069 (Arm B)
										PK
		1	Randomized	Recruiting	PC, NSCLC, HNSCC	Palliative	Locally advanced	108	NA	Safety (AE, DLT)	Durvalumab, Mogamulizumab (Arm A)	NA	NA	NA	NCT02301130
							Metastatic				Tremelimumab, Mogamulizumab (Arm B)
		1	Non-randomized	Recruiting	PC, NSCLC, BC, MM	Palliative	Metastatic	30	1 mg/kg	Safety (AE)	Durvalumab, Tremelimumab, Radiotherapy	NA	NA	NA	NCT02639026
										Efficacy

NA: Not available.

Table 4 Immune checkpoint inhibitors based on American Society of Clinical Oncology's meeting abstracts

Target molecule	Drug name	Study phase	Study design	Status	Condition	Intervention	Cohort	Estimated enrollment	Dose	End point	Study Arm	Adverse event	Response	Survival	Ref.
CTLA-4	Tremelimumab	1	Non-randomized	Recruiting	PC	Palliative	Metastatic	60	NA	Safety	Durvalumab, SBRT (Arm A)	NA	NA	NA	Duffy et al[28]
	(CP-675/CP-675,206)									Efficacy (ORR, PFS)	Tremelimumab, SBRT (Arm B)
										Tolerability	Durvalumab, Tremelimumab, SBRT (Arm C)
										PK
PD-1	Nivolumab	2	Randomized	Recruiting	PC	Palliative	Metastatic	94	3 mg/kg	Safety (TRT)	Cy/GVAX/Nivolumab, CRS-207/Nivolumab (Arm A)	NA	NA	NA	Le et al[25]
	(BMS-936558/MDX-1106/ONO-4538)									Efficacy (OS, PFS, RR)	Cy/GVAX, CRS-207 (Arm B)
		1	Randomized	Recruiting	PC, NSCLC, BC	Palliative	Locally advanced	138	3 mg/kg	Safety (DLT, TEAEs)	Nivolumab, nab-Paclitaxel (Arm A)	NA	NA	NA	Firdaus et al[45]
							Metastatic			Efficacy (PFS, OS, DCR, ORR, DR)	Nivolumab, nab-Paclitaxel, Gemcitabine (Arm B)
	Pembrolizumab	1|2	Non-randomized	Recruiting	PC, GeC, OC, NSCLC, BC, BlC, MM, HNSCC,	Palliative	Locally advanced	400	200 mg	Safety	Part A: Pembrolizumab, DE Pexidartinib (PLX3397)	NA	NA	NA	Wainberg et al[50]
	(MK-3475/SCH 900475)						Metastatic			Efficacy (ORR; CR, PR)	Part B: RD Pexidartinib (PLX3397), Pembrolizumab
PD-L1	Durvalumab (MEDI4736)	1	Non-randomized	Recruiting	PC	Palliative	Metastatic	60	NA	Safety	Durvalumab, SBRT (Arm A)	NA	NA	NA	Duffy et al[31]
										Efficacy (ORR, PFS)	Tremelimumab, SBRT (Arm B)
										Tolerability	Durvalumab, Tremelimumab, SBRT (Arm C)
										PK
		1|2	NA	Recruiting	PC, NSCLS, mBC	Palliative	Metastatic	160	NA	Safety (AE, DLT)	Part 1: Durvalumab, DLT Ibrutinib	NA	NA	NA	Borazanci et al[74]
										Efficacy	Part 2: Durvalumab, RD Ibrutinib
										Tolerability
										RD
										PK

ORR: Overall response rate; DLT: Dose limiting toxicity; NA: Not available.

Table 5 Immune checkpoint inhibitors based on articles

Target molecule	Drug	Study phase	Study design	Condition	Intervention	Cohort	Enrollment	Dose	End point	Study Arm	Adverse event	Response	Survival	Ref.
CTLA-4	Ipilimumab	2	Non-randomized	PC	Palliative	Locally advanced	27	3 mg/kg	Efficacy (ORR; CR, PR)	Ipilimumab	11% Grade 3-4 irAEs (Colitis: 1, Encephalitis: 1, Hypophysitis: 1)	No RECIST-response	NA	Royal et al[23]
	(BMS-734016/MDX-010)					Metastatic						SD: delayed progression, RECIST-progressive disease (n:1)
		1	Randomized	PC	Palliative	Locally advanced	30	10 mg/kg	Safety (AE)	Ipilimumab (Arm A)	73%, 80% irAEs (Arm A, B)	SD: growth < 20% growth cut-off, 7w (n:1) , 22w (n:1) (Arm A) regression 17w (n:1), stabilization 59w (n:1), 71w (n:1) (Arm B)	mOS (95%CI:) IPI vs IPI, GVAX: 3.6 (2.5-9.2), 5.7 (4.3-14.7);	Le et al[24]
						Metastatic			Efficacy (OS, ORR)	Ipilimumab, GVAX (Arm B)	20% Grade 3-4 irAEs (Colitis: 1, GBS: 1, Nephritis: 1) (Arm A), (Rash: 1, Colitis: 1, Pneumonitis: 1) (Arm B)		HR = 0.51, 95%CI: 0.23-1.08, P = 0.072.
											irAEs (p: 0.037)		yOS (95%CI:) IPI vs IPI, GVAX: 7% (1%-45%), 27% (11%-62%)
	Tremelimumab (CP-675/CP-675,206)	1	Non-randomized	PC	Palliative	Metastatic	34	15 mg/kg	Safety (AE, DLT, MTD)	Tremelimumab DE (C6, C10, C15), Gemcitabine	Grade 3-4 irAEs (Asthenia: 1, Nausea: 1, Diarrhea: 1, Anemi: 1, Pruritus: 1, Hypertransaminasemia: 1) (C 10), (Asthenia: 3, Nausea: 2, Diarrhea:1, Anemi: 1, Neutropenia: 2, Hypertransaminasemia: 1, Thrombocytopenia:2) (C 15) SAE:11 (Dehydration-diarrhea: 1, ACS: 1, PE: 1, Hyperbilirubinemia: 1, Hematemesis: 1) (C10) (AKI: 1, GIB: 1, Hyperbilirubinemia: 2) (C15)	PR: 8w (n:2) (10.5%: 2/19)	mOS (95%CI:) C6 (6 mg/kg Tremelimumab), C10 (10 mg/kg Tremelimumab), C15 (15 mg/kg Tremelimumab): 5.3 (1.2-14.6), 8.0 (2.3-16.9), 7.5 (6.0-9.5)	Aglietta et al[27]
									Efficacy (OS, OR, PFS)			SD: > 10w [n:7 (n:2 completed study)]
PD-L1	BMS-936559	1	Non-randomized	PC, NSCLC, MM, CrC, OC, GeC, RRC, BC	Palliative	Locally advanced	207 (14 PDA)	DE	Safety (AE, MTD, DLT)	BMS-936559	NA	No objective PDA-response	NA	Brahmer et al[79]
						Metastatic			Efficacy (ORR)
									PK

PDA: Pancreatic ductal adenocarcinoma; MTD: Maximum tolerance dose; ORR: Overall response rate; DLT: Dose limiting toxicity; NA: Not available; CTLA-4: Cytotoxic T lymphocyte antigen 4; PD-L1: Programmed cell death ligand 1.