Table 3.

Clinical trials targeting cell cycle checkpoints as monotherapy and in combination with chemotherapy and other targeted agents.

Trial	Phase	Eligible Patients	Drugs	Dose/Schedule	Findings of Primary/Secondary Endpoints	Notable Common Grade AEs (≥10%)
ATR Inhibitors
DUETTE NCT04239014	Randomized, double-blinded, placebo-controlled phase II	Platinum-sensitive, PARPi-resistant HGSOC	Ceralasertib + olaparib	Arm 1: Ceralasertib 160 mg PO QD on days 1–7; olaparib 300 mg PO BID q28-day cycle Arm 2: Olaparib 300 mg PO BID Arm 3: Placebo PO BID	N/A Note: Withdrawn by the company sponsor in January 2021 based on the interim analysis of the VIOLETTE study NCT03330847 investigating the combination of ceralasertib and olaparib, where study closure was recommended due to insufficient activity.
NCT04655183	Phase I/II	PARPi-resistant, germline BRCA1/2-mutated, HER2-advanced breast cancer	M4344 + niraparib	Niraparib PO QD; M4344 at the dose determined in part 1 of study	N/A Note: Withdrawn by the company sponsor.
NCT04149145	Phase I	PARPi-resistant recurrent ovarian cancer Estimated enrollment: n = 40	M4344 + niraparib	1st phase: 3+3 design of fixed dose niraparib PO QD (with 4-week lead-in); M4344 will be escalated from 100–200 mg PO QD q28-day cycle	Not yet recruiting as of October 2021 Estimated study start date: December 2021
NCT03704467	Phase Ib	Platinum-sensitive, PARPi-resistant, recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer n = 3	Carboplatin + berzosertib (M6620) + avelumab	M6620 90 mg/m2 IV on day 2; avelumab 1600 mg IV on day 1; carboplatin AUC 5 on day 1 q3-week cycle for a maximum of 6 cycles	Note: Originally designed as phase Ib/II trial, but sponsor did not conduct phase II after completing phase Ib and confirming safe combination dose.
NCT04267939	Phase I/Ib	Escalation cohort: All solid tumors (excluding prostate cancer) and positive for DDR deficiency Expansion cohort: Ovarian cancer, PARPi naïve, and with a platinum resistant/refractor y disease and DDR deficiency Expansion cohort: Ovarian cancer, PARPi-resistant, unselected for BRCA mutation status, platinum-status unspecified	BAY189534 4 + niraparib	BAY189534 4 BID QD; niraparib PO QD q28-day cycle	Recruiting Estimated study completion date: December 5, 2025
NCT04826341	Phase I/II	Phase I: Advanced or recurrent solid tumors Phase II: Multi-cohort single arm study HRD cohort: Known HRD cancer and documented evidence of germline or somatic BRCA mutation or other HRD germline mutation, or tumor is HRD positive; PD while taking a PARPi or within 6 months of completing PARPi SCLC cohort: Recurrent SCLC after ≥ 1 prior platinum-based therapy Estimated enrollment: n = 70	Berzosertib (M6620) + sacituzumab govitecan	M6620 IV 20 mg/mL on days 2 and 9; sacituzumab govitecan IV on days 1 and 8 q21-day cycles	Recruiting Estimated study completion date: March 1, 2026
CAPRI NCT03462342	Single-arm, multi-cohort phase II	Cohort A: HGSOC with unknown or negative BRCA germline mutation status with no limit on prior number of regimens Cohort B: HGSOC with unknown or negative BRCA germline mutation status with no more than 3 prior cytotoxic therapies since the development of platinum-resistance Cohort C: Platinum-sensitive HGSOC with germline or somatic BRCA1/2 mutation, other HRD mutation, or positive HRD score on Myriad My Choice immediately following prior PARPi treatment (n = 13)	Ceralasertib + olaparib	Ceralasertib 160 mg PO QD on days 1–7; olaparib 300 mg PO BID q28-day cycle	Cohort C: ORR: 46% (6 PR) Median duration of treatment: 8 mths (range 3–23)	Cohort C: Grade 3 thrombocytopenia: 23% (n = 3); anemia: 16% (n = 2); neutropenia: 16% (n = 2) No grade 4 toxicities
OLAPCO NCT02576444	Single-arm phase II	BRCA-mutated, PARPi pretreated/resistant HGSOC n = 7	Ceralasertib + olaparib	Ceralasertib 160 mg PO QD on days 1–7; olaparib 300 mg PO BID q28-day cycle	1 PR, 3 SD, 3 PD	Anemia, thrombocytopenia (rates not reported)
CHK1 Inhibitors
NCT03057145	Phase I	Advanced solid tumors n = 29; 25 evaluable BRCA-mutant, PARPi-resistant expansion (n = 18)	Prexasertib + olaparib	Olaparib PO on an intermittent schedule during each 28-day cycle; prexasertib IV on days 1 and 15 q28-day cycle	ORR: 22% (4/18 PR) 10/18 pts, (56%) remained on study for 4+ cycles	Neutropenia: (86%); leukopenia (83%); anemia (72%); thrombocytopenia (66%)
NCT02203513	Single-arm, multi-cohort phase II	Cohort 1: Germline or somatic BRCA-mutated HGSOC n = 22 (21 with prior PARPi); 18 evaluable	Prexasertib	Prexasertib 105 mg/m2 IV q14 days q28-day cycle	ORR: 11% (1 CR, 1 PR)	Grade 3/4 AEs: neutropenia (82%); leukopenia (64%); thrombocytopenia (14%)
WEE1 Inhibitors
STAR NCT04197713	Single-arm phase I	Advanced solid tumors in a post-PARPi population Estimated enrollment: n = 54	Adavosertib + olaparib	Olaparib PO BID on days 1–5 and 15–19; adavosertib PO QD on days 8–12 and 22–26 q28 day cycle for 2 years	Recruiting Estimated study completion date: June 30, 2022
NCT02482311	Phase Ib	BRCA1/2-mutant, PARPi-resistant advanced HGSOC cohort n = 30	Adavosertib	Adavosertib PO BID on days 1–3 and 8–10 q21-day cycle	ORR: 3% (n = 1 PR) DCR: 77% (n = 23) Median PFS: 3.9 mths	Diarrhea (61%); nausea (50%); fatigue (43%) across safety population (n = 80)
EFFORT NCT03579316	Randomized phase II	Recurrent ovarian cancer in which progression has been documented following PARPi therapy n = 80 enrolled and randomized; 35 patients evaluable in each arm	Adavosertib ± olaparib	Arm 1: Adavosertib PO QD on days 1–5 and 8–12 q21-day cycle (n = 39) Arm 2: Olaparib PO BID on days 1–21; adavosertib PO QD on days 1–3 and 8–10 q21-day cycle (n = 41)	ORR (90% CI): Arm 1: 23% (12–38) Arm 2: 29% (16–44) CBR (90% CI): Arm 1: 63% (48–76) Arm 2: 89% (76–96) Median PFS (90% CI) Arm 1: 5.5 mths (3.9–6.9) Arm 2: 6.8 mths (4.3–8.3)	Arm 1: 51% with grade 3/4 toxicities: neutropenia (13%); thrombocytopenia (10%); diarrhea (8%) Arm 2: 76% with grade 3/4 toxicities: thrombocytopenia (20%); neutropenia (15%); diarrhea (12%); fatigue (12%); anemia (10%)

Abbreviations; AE, adverse event; AUC, area under curve; BID, twice daily; CBR, clinical benefit rate; CI, confidence interval; DCR, disease control rate; HRD, homologous recombination deficient; IV, intravenous; mths, months; NE, not evaluable, ORR, objective response rate; PARPi, poly (ADP-ribose) polymerase inhibitor; PD, progression of disease; PFS, progression-free survival; PO, by mouth; PR, partial response; pts, patients; QD, once daily; SCLC, small cell lung cancer.