The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

Shi, Congqi; Qin, Kaiyu; Lin, Anqi; Jiang, Aimin; Cheng, Quan; Liu, Zaoqu; Zhang, Jian; Luo, Peng

doi:10.1186/s13046-022-02469-0

Journal of Experimental & Clinical Cancer Research

Table 3 Ongoing and completed clinical trials exploring the efficacy of combination DNA targeting and immunotherapy agents

From: The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

Clinical trial ID	Cancer type	DDR-targeted inhibitor	ICI	Targets	Phase	Clinical endpoint	Status	Refs
NCT04334941	SCLC	Talazoparib	Atezolizumab	PARP+PD-L1	Phase 2	PFS, OS	Recruiting	[81]
NCT04068831	Renal Cell Carcinoma	Talazoparib	Avelumab	PARP+PD-L1	Phase 2	ORR, PFS	Recruiting	[16]
NCT03964532	Advanced Breast Cancer	Talazoparib	Avelumab	PARP+PD-L1	Phase 1 Phase 2	AEs, ORR, PFS, OS	Recruiting	[16]
NCT04678362	Urothelial Carcinoma	Talazoparib	Avelumab	PARP+PD-L1	Phase 2	PFS, OS, DOR	Recruiting	[82]
NCT04173507	Lung Non-Squamous Non-Small Cell Carcinoma	Talazoparib	Avelumab	PARP+PD-L1	Phase 2	ORR, DCR, Toxicity, PFS, OS, DOR,	Active, not recruiting	[16]
NCT03565991	BRCA or ATM Mutant Solid Tumors	Talazoparib	Avelumab	PARP+PD-L1	Phase 2	OR, TTR, PFS, OS, DOR	Active, not recruiting	[83]
NCT02912572	Metastatic Endometrial Cancer	Talazoparib	Avelumab	PARP+PD-L1	Phase 2	PFS, ORR, DOR, irPFS	Recruiting	[16]
NCT04052204	Advanced or Metastatic Solid Tumors	Talazoparib	Avelumab	PARP+PD-L1	Phase 1 Phase 2	DLT, DOR, TTR, PFS, OS	Terminated	[38]
NCT03330405	Solid Tumors	Talazoparib	Avelumab	PARP+PD-L1	Phase 2	DLT, OR, TTR, PFS, OS, DOR	Active, not recruiting	[83]
NCT03637491	Solid tumors	Talazoparib	Avelumab	PARP+PD-L1	Phase1 Phase 2	DLTs, OR, AEs	Terminated Has Results	[83]
NCT04187833	Melanoma	Talazoparib	Nivolumab	PARP+PD-1	Phase 2	BOR, PFS, irOR, irPFS, OS, AEs	Recruiting	[75]
NCT04158336	Solid Tumors	Talazoparib	Pembrolizumab	PARP+PD-1	Phase 1 Phase 2	Safety and Tolerability, MTD, RP2D	Recruiting	[75]
NCT03101280	Advanced Gynecologic Cancers and TNBC	Rucaparib	Atezolizumab	PARP+PD-L1	Phase 1	DLTs, OS, DOR, PFS	Completed	[83]
NCT04276376	Solid Tumors	Rucaparib	Atezolizumab	PARP+PD-L1	Phase 2	ORR	Recruiting	[75]
NCT03824704	Solid Tumors	Rucaparib	Nivolumab	PARP+PD-1	Phase 2	ORR, PFS, DOR	Terminated Has Results	[84]
NCT04624178	Leiomyosarcoma	Rucaparib	Nivolumab	PARP+PD-1	Phase 2	ORR, PFS	Recruiting	[85]
NCT03338790	mCRPC	Rucaparib	Nivolumab	PARP+PD-1	Phase 2	ORR, RR-PSA, PFS	Active, not recruiting Has Results	[83]
NCT03639935	Biliary Tract Cancer	Rucaparib	Nivolumab	PARP+PD-1	Phase 2	PFS, OS	Recruiting	[84]
NCT03572478	Prostate Cancer or Endometrial Cancer	Rucaparib	Nivolumab	PARP+PD-1	Phase 1 Phase 2	DLTs	Terminated Has Results	[83]
NCT02873962	Relapsed Ovarian, Fallopian Tube or Peritoneal Cancer	Rucaparib	Nivolumab	PARP+PD-1	Phase 2	ORR, Safety and Tolerability, PFS, DOR	Recruiting	[84]
NCT03958045	SCLC	Rucaparib	Nivolumab	PARP+PD-1	Phase 2	PFS, DCR, OS, ORR	Recruiting	[16]
NCT03522246	Ovarian Cancer	Rucaparib	Nivolumab	PARP+PD-1	Phase 3	PFS, OS, ORR, DOR, Safety and Tolerability	Active, not recruiting	[83]
NCT02935634	Advanced Gastric Cancer	Rucaparib	Nivolumab Ipilimumab	PARP+PD-1 + CTLA-4	Phase 2	ORR, DOR, AEs	Active, not recruiting	[16]
NCT03869190	Urothelial Cancer	Niraparib	Atezolizumab	PARP+PD-L1	Phase 1 Phase 2	ORR, pCR, PFS, OS	Recruiting	[16]
NCT04313504	Head and Neck Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	ORR, AEs, PFS, OS	Recruiting	[86]
NCT03955471	Ovarian Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	ORR, DOR, PFS, OS, DCR	Terminated	[87]
NCT04068753	Cervix Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	Toxicity, DOR, PFS, OS	Recruiting	[38]
NCT04544995	Neuroblastoma and Osteosarcoma	Niraparib	Dostarlimab	PARP+PD-1	Phase 1	DLTs, PFS, ORR	Recruiting	[88]
NCT04673448	Pancreatic, Ovarian or Fallopian Tube Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 1	bOR, PFS, DOR, OS, DC, AEs	Recruiting	[89]
NCT04701307	Lung Small Cell Carcinoma and Neuroendocrine Tumor	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	PFS, ORR, DCR, OS	Recruiting	[90]
NCT04493060	Pancreatic Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	DCR, ORR, TTNT, OS	Recruiting	[89]
NCT05126342	Ovarian, Peritoneal or Fallopian Tube Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	ORR, PFS, DCR, OS, TFST	Not yet recruiting	[91]
NCT03016338	Endometrial Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	CBR, ORR, DOR, PFS	Active, not recruiting	[92]
NCT03307785	Advanced or Metastatic Solid Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 1	DLTs, ORR, DOR, DCR	Active, not recruiting Has Results	[83]
NCT04584255	Breast Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	TILs, pCR	Recruiting	[93]
NCT04940637	Lung Cancer or Mesothelioma	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	PFS, ORR, DCR, DOR, OS	Recruiting	[94]
NCT03651206	Ovarian Cancer and Endometrial Cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 2 Phase 3	RR, OS, PFS, TTST	Recruiting	[84]
NCT04779151	Solid Tumors	Niraparib	Dostarlimab	PARP+PD-1	Phase 2	ORR	Not yet recruiting	[96]
NCT03602859	Ovarian cancer	Niraparib	Dostarlimab	PARP+PD-1	Phase 3	PFS, OS	Active, not recruiting	[83]
NCT03308942	NSCLC	Niraparib	Dostarlimab Pembrolizumab	PARP+PD-1	Phase 2	ORR, PFS, OS	Completed Has Results	[83]
NCT04508803	Breast Cancer	Niraparib	HX008(Pucotenlimab)	PARP+PD-1	Phase 2	ORR, PFS, OS, CBR, DOR	Recruiting	[86]
NCT03404960	Pancreatic Cancer	Niraparib	Nivolumab Ipilimumab	PARP+PD-1 + CTLA-4	Phase 1 Phase 2	PFS, Safety and Tolerability, DOR, ORR	Active, not recruiting	[51]
NCT04178460	Gastric Cancer, TNBC, Biliary Tract Carcinoma and Endometrial Carcinoma	Niraparib	MGD013(Tebotelimab)	PARP+ PD-1 + LAG-3	Phase 1	Safety and Validity profiles	Terminated	[97]
NCT02657889	TNBC or Ovarian Cancer	Niraparib	Pembrolizumab	PARP+PD-1	Phase 1 Phase 2	DLTs, ORR, Safety and Tolerability, DOR	Completed Has Results	[83]
NCT04475939	NSCLC	Niraparib	Pembrolizumab	PARP+PD-1	Phase 3	PFS, OS, TTP	Recruiting	[98]
NCT04885413	Endometrial Cancer	Niraparib	Sintilimab	PARP+PD-1	Phase 2	ORR, DOR, PFS, DCR	Recruiting	[99]
NCT05162872	Nasopharyngeal Carcinoma	Niraparib	Sintilimab	PARP+PD-1	Phase 2	ORR, DOR, PFS, DCR, OS	Recruiting	[91]
NCT02734004	Advanced Ovarian, Breast, Lung, and Gastric Cancers	Olaparib	Durvalumab	PARP+PD-L1	Phase1 Phase 2	DCR, ORR, Safety and Tolerability	Active, not recruiting	[83]
NCT03334617	NSCLC	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, DOR, PFS, DCR, OS	Recruiting	[83]
NCT02484404	Recurrent Ovarian, TNBC, Lung, Prostate, and Colon Cancers	Olaparib	Durvalumab	PARP+PD-L1	Phase 1 Phase 2	ORR, RP2D, AEs	Recruiting	[30, 49, 80, 84]
NCT04644289	Epithelial Ovarian Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	Safety, Feasibility	Recruiting	[100]
NCT03923270	Small-cell Lung Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 1	AEs, PFS, OS	Recruiting	[51]
NCT03851614	MMR proficient Colorectal Cancer, Pancreatic Cancer, and Leiomyosarcoma	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, CBR, PFS	Active, not recruiting	[84]
NCT03534492	Bladder Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	pCRR, Toxicity	Completed	[101]
NCT03167619	TNBC	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	PFS, OS, ORR	Active, not recruiting	[83]
NCT05222971	Biliary Tract Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	PFS, OS, Toxicity	Recruiting	[91]
NCT03594396	Advanced or mTNBC	Olaparib	Durvalumab	PARP+PD-L1	Phase 1 Phase 2	pCR, RR	Active, not recruiting	[75]
NCT03544125	TNBC	Olaparib	Durvalumab	PARP+PD-L1	Phase 1	AEs, ORR, DOR, PFS, OS	Completed	[16]
NCT03801369	mTNBC	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, OS	Recruiting	[16]
NCT03737643	Ovarian cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 3	PFS, pCR, ORR	Recruiting	[16]
NCT03459846	Bladder Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	PFS, OS, DOR, ORR	Active, not recruiting	[83]
NCT03991832	Solid Tumors	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, PFS, OS	Recruiting	[102]
NCT02882308	Head and Neck Squamous Cell Carcinoma	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, pCR	Completed	[84]
NCT03772561	Advanced Solid Tumors	Olaparib	Durvalumab	PARP+PD-L1	Phase 1	ORR	Recruiting	[84]
NCT03775486	Lung Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	PFS, OS, DOR, ORR	Active, not recruiting	[16]
NCT05209529	TNBC	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	OS, pCR	Not yet recruiting	[91]
NCT04538378	Lung Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, PFS, Safety and Tolerability, OS	Recruiting	[103]
NCT04336943	Prostate Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	Undetectable PSA, AEs	Recruiting	[104]
NCT03951415	Endometrial Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	PFS, ORR, OS	Active, not recruiting	[44]
NCT04169841	Solid Tumors	Olaparib	Durvalumab, Tremelimumab	PARP+PD-L1 + CTLA-4	Phase 2	PFS	Recruiting	[16]
NCT02953457	Recurrent or Refractory Ovarian, Fallopian Tube or Primary Peritoneal Cancer with BRCA Mutation	Olaparib	Durvalumab Tremelimumab	PARP+PD-L1 + CTLA-4	Phase 2	DLTs, PFS, OS	Active, not recruiting	[84]
NCT03699449	Recurrent Ovarian Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	ORR, OS, PFS	Recruiting	[16]
NCT04306367	Bile Duct Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	RR, DOR, PFS, OS, Safety and Tolerability	Recruiting	[105]
NCT03810105	Prostate Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	PSA detection	Recruiting	[16]
NCT02546661	Bladder Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 1	Safety and Tolerability, ORR, DCR, PFS, DOR, OS	Active, not recruiting	[83]
NCT04269200	Endometrial Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 3	PFS, OS, ORR, DOR, TFST	Recruiting	[16]
NCT03741426	Renal Cancer	Olaparib	Durvalumab	PARP+PD-L1	Phase 2	Proof-of-Mechanism, AEs	Recruiting	[16]
NCT04641728	Cervical Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, DOR, DRR, PFS	Active, not recruiting	[106]
NCT04380636	NSCLC	Olaparib	Pembrolizumab	PARP+PD-1	Phase 3	PFS, OS, ORR, DOR, AEs	Recruiting	[44]
NCT04483544	Cervical Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	irORR, PFS, TEAEs, DOR	Recruiting	[44]
NCT02861573	mCRPC	Olaparib	Pembrolizumab	PARP+PD-1	Phase 1 Phase2	AEs, ORR, DCR, OS, DOR, PFS	Recruiting	[83]
NCT04191135	Advanced TNBC	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	PFS, OS	Active, not recruiting	[93]
NCT04123366	Solid Tumors	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, DOR, PFS, OS, AEs	Recruiting	[16]
NCT04548752	Pancreatic Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	PFS, OS, ORR, AEs	Recruiting	[89]
NCT03834519	Prostate Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 3	OS, rPFS	Active, not recruiting	[107]
NCT04666740	Metastatic Pancreatic Ductal Adenocarcinoma	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	PFS, OS	Recruiting	[108]
NCT05033756	Breast Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, DOR, PFS, OS, Safety and Toxicity	Not yet recruiting	[91]
NCT03976362	Squamous NSCLC	Olaparib	Pembrolizumab	PARP+PD-1	Phase 3	PFS, OS, AEs	Active, not recruiting	[51]
NCT04633902	Metastatic Melanoma	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, PFS, OS, Safety and Toxicity	Recruiting	[90]
NCT05201612	Metastatic Colorectal Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, PFS, OS, DCR, DOR	Not yet recruiting	[91]
NCT05093231	Pancreatic Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, Safety and Toxicity, PFS, DOR, OS	Not yet recruiting	[109]
NCT03740165	Ovarian Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 3	PFS, OS	Active, not recruiting	[16]
NCT05203445	Breast Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	MRGB	Recruiting	[91]
NCT05156268	Endometrial Carcinosarcoma	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR	Recruiting	[91]
NCT03025035	Breast Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, PFS, OS, CBR, DOR	Recruiting	[93]
NCT04417192	Ovarian Cancer	Olaparib	Pembrolizumab	PARP+PD-1	Phase 2	ORR, CRS, OS, PFS	Recruiting	[100]
NCT02485990	Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer	Olaparib	Tremelimumab	PARP+CTLA-4	Phase 1	AEs, MTD, PFS, OS, ORR, DCR, DOR	Terminated	[16]
NCT04034927	Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer	Olaparib	Tremelimumab	PARP+CTLA-4	Phase 2	PFS, DLT, OS, AEs	Active, not recruiting	[16]
NCT02571725	BRCA mutant Ovarian Cancer	Olaparib	Tremelimumab	PARP+CTLA-4	Phase 1 Phase 2	RP2D, ORR, PFS	Active, not recruiting	[75]
NCT02660034	Solid Tumors	Pamiparib	Tislelizumab	PARP+PD-1	Phase 1	AEs, DLT, ORR, DOR, PFS, OS, DCR, CBR	Completed Has Results	[83]
NCT03061188	Solid tumors	Veliparib	Nivolumab	PARP+PD-1	Phase 1	MTD, AEs, ORR, CBR, PFS	Active, not recruiting Has Results	[75]
NCT04216316	Advanced Squamous Cell NSCLC	Berzosertib	Pembrolizumab	ATR + PD-1	Phase 1 Phase 2	RP2D, PFS, OS	Recruiting	[110]
NCT04266912	Solid Tumors	Berzosertib	Avelumab	ATR + PD-L1	Phase 1 Phase 2	AEs, DLTs, MTD, CBR, RR, PFS, OS	Recruiting	[75]
NCT05061134	Melanoma	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 2	ORR, DOR, TTR, PFS	Recruiting	[111]
NCT03334617	NSCLC	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 2	ORR, DCR, DOR, PFS, OS	Recruiting	[75]
NCT04298008	Biliary Tract Cancer	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 2	DCR, ORR, PFS, OS, DOR	Recruiting	[112]
NCT03780608	Gastric Adenocarcinoma and Malignant Melanoma	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 2	ORR	Active, not recruiting	[16]
NCT03833440	NSCLC	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 2	DCR, ORR, PFS, OS, DOR	Recruiting	[16]
NCT02664935	NSCLC	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 2	OR, PFS, DCB	Active, not recruiting	[44]
NCT02264678	Solid Tumors	Ceralasertib	Durvalumab	ATR + PD-L1	Phase 1 Phase 2	Safety and Tolerability, Cmax, Tmax	Recruiting	[75]
NCT04095273	Solid Tumors	Elimusertib	Pembrolizumab	ATR + PD-1	Phase 1	TEAEs, DLTs, RP2D	Recruiting	[110]
NCT03495323	Advanced Solid Tumors	Prexasertib	LY3300054	CHK1 + PD-L1	Phase 1	Toxicity	Completed	[113]
NCT02546661	Bladder Cancer	Adavosertib	Durvalumab	WEE1 + PD-L1	Phase 1	AEs, ORR, DCR, PFS, OS, DOR	Active, not recruiting	[114]
NCT02617277	Solid Tumors	Adavosertib	Durvalumab	WEE1 + PD-L1	Phase 1	DLTs, TEAEs, ORR, PFS	Active, not recruiting	[51]

AE Adverse event, bOR Best objective response, BOR Best overall response, CBR Clinical benefit rate (CBR = CR + PR + SD), Cmax Maximum observed plasma concentration, CRS Chemotherapy response score, DC Disease control, DCB Durable clinical benefit, DCR Disease control rate, DLT Dose limiting toxicity, DOR Duration of response, DRR Durable response rate, irOR Immune-related overall response, irORR Immune-related overall response rate, irPFS Immune-related progression free survival, mCRPC Metastatic castration-resistant prostate cancer, MMR Mismatch repair, MRGB MRI-guided biopsy, MTD Maximum tolerated dose, mTNBC Metastatic triple-negative breast cancer, NSCLC Non-small cell lung cancer, OR Objective response, ORR Overall response rate, OS Overall survival, pCR Pathologic complete response, pCRR Pathological complete response rate, PFS Progression-free survival, PSA Prostate-specific antigen, rPFS Radiographic progression-free survival, RP2D Recommended phase II dose, RR Response rate, RR-PSA Prostate-specific antigen response rate, SCLC Small cell lung cancer, TEAEs Treatment emergent adverse events, TFST Time to initiation of the first subsequent anticancer therapy, TILs Tumor-infiltrating lymphocytes, Tmax Time to observed Cmax, TNBC Triple-negative breast cancer, TTNT Time to next treatment, TTP Time to progression, TTR Time to tumor response, TTST Time to subsequent treatment

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