Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Zn-c3, C29H34N8O2, KP-2638
Azenosertib · 9 trials · 17 indications
Time from randomization to the first documented tumor progression (per RECIST v1.1) or death from any cause, whichever occurs first.
Replication fork speed assessed by DNA fiber assays in PDO models. Responder defined as participants achieving complete response (CR) or partial response (PR) based on RECISTv1.1 criteria. Wilcoxon rank sum tests will be used to compare the percentage change in replication fork speed with exposure to WEE1 inhibition in co-clinical models between overall response responder and non-responder.
Replication fork speed assessed by DNA fiber assays in PDO models. PFS6 is a binary endpoint where patients that are alive and progression free (per RECIST 1.1) at 6 months are considered responders. All other patients (those that died or progressed prior to 6 months or those with less than 6 months of follow-up for progression) are considered non-responders. Wilcoxon rank sum tests will be used to compare the percentage change in replication fork speed with exposure to WEE1 inhibition in co-clinical models between overall response responder and non-responder.
Participants who achieve partial response (PR) or complete response (CR) per RECIST v1.1 criteria.
To determine the safety and tolerability of ZN-c3 in subjects with recurrent or persistent USC.
To investigate the antitumor activity of ZN-c3 in subjects with recurrent or persistent USC
Detailed DLT consideration outline in protocol section 5.4. Toxicities are to be assess according to the CTCAE v5. Management and dose modifications associated with the above adverse events outlined in protocol section 6.
The MTD is defined as the highest dose level with ≤1 DLT in a cohort of 6 participants. See previous primary outcome measure for the DLT definition. If 0 out of 3 participants experience DLT, next dose level will be proceeded. If \>=1 out of the group suffer DLT, dose escalation will be stopped and 3 additional participants will be entered at the next lowest dose level. If \<=1 out of 6 DLTs, this dose level is considered as MTD.
ORR was defined as the proportion of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Incidence and severity of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects during Cycle 1
Frequency and severity of AEs and dose modifications
ORR as defined by the revised RECIST Guideline version 1.1 and assessed by ICR.
EFS at 18 weeks is defined as time from study enrollment until date of disease progression, or detection of disease at a previously uninvolved site, or date of death of the subjects at 18 weeks.
Incidence and severity of adverse events (AEs)
Incidence and severity of dose-limiting toxicities (DLTs)
Incidence and severity of adverse events (AEs) Incidence of dose interruptions, reductions, and discontinuations due to treatment-related AEs
To investigate the safety and tolerability of single agent ZN-c3, including identification of the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D), based on the incidence and severity of adverse events (AEs) and dose-limiting toxicities (DLTs) in DLT-evaluable subjects.
To characterize and compare the PK (Cmax.) of ZN-c3 following a single dose of ZN-c3 under fed and fasting conditions.
To investigate the clinical activity of WEE1 inhibition based on the objective response rate (ORR) as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
| Arm | Type | Description |
|---|---|---|
| Arm A Azenosertib 400 mg administered daily on a 5 days on, 2 days off intermittent schedule | EXPERIMENTAL | - |
| Experimental: Arm C Investigator's choice of chemotherapy at the dose defined by the protocol | ACTIVE_COMPARATOR | - |
| Azenosertib | EXPERIMENTAL | 25 participants will be enrolled and will complete study procedures as follows: * Baseline visit with assessments and CT or MRI scan. * CT or MRIs scans every 2 cycles. * Cycle 1 through End of Treatment: --Days 1 through 5, 8 through 12, and 15 through 19: Predetermined dose of Azenosertib 1x daily. * End of Treatment visit. |
| Part 1a/1b (Completed Enrollment) | EXPERIMENTAL | Azenosertib 400mg administered once daily on a 5 days on, 2 days off intermittent schedule. |
| Part 2a: Arm 1 (Completed Enrollment) | EXPERIMENTAL | Azenosertib 400mg administered once daily on a 5 days on, 2 days off intermittent schedule |
| Part 2a: Arm 2 (Completed Enrollment) | EXPERIMENTAL | Azenosertib 300mg administered once daily on a 5 days on, 2 days off intermittent schedule |
| Part 2b (Completed Enrollment) | EXPERIMENTAL | Azenosertib 400mg administered once daily on a 5 days on, 2 days off intermittent schedule |
| Part 2c (Enrolling) | EXPERIMENTAL | Azenosertib 400mg administered once daily on a 5 days on, 2 days off intermittent schedule |
| Azenosertib Single Agent | EXPERIMENTAL | Azenosertib (ZN-c3) taken orally with food |
| Phase 1: Dose Escalation Arm | EXPERIMENTAL | Participants will be enrolled in a standard 3+3 dose-escalation scheme to establish a Maximum Tolerated dose (MTD) of Azenosertib, starting at Dose Level 0, de-escalating to Dose Level -1, and escalating to Dose Levels 1 and 2. * Baseline visit with CT or MRI scan. * CT or MRI scan every 9 weeks until 27 weeks then every 12 weeks. * Cycle 1 through End of Treatment: * Days 1 through 5, 8 through 12, and 15 through 19 of 21 Day Cycle: Predetermined dose of Azenosertib 1 x daily. * Day 1 of 21 Day Cycle: Predetermined dose of Pembrolizumab 1x daily. * Days 1 and 8 of 21 Day Cycle: Predetermined dose of Carboplatin 1x daily. * End of Treatment visit * Follow up: every 6 months * Dose de-escalation and escalation will follow dose-limiting toxicities specifications (DLTs) per the protocol. The MTD is the highest dose level with ≤1 DLT in a cohort of 6 participants and the study will proceed to Phase 2. |
| Phase 2: AZENOSERTIB + PEMBROLIZUMAB + CARBOPLATIN | EXPERIMENTAL | Participants will complete: * Baseline visit with CT or MRI scan and tumor biopsy. * CT or MRI scan every 9 weeks until 27 weeks then every 12 weeks. * Cycle 1 through End of Treatment: * Days 1 through 5, 8 through 12, and 15 through 19 of 21 Day Cycle: Predetermined dose of Azenosertib 1x daily. * Day 1 of 21 Day Cycle: Predetermined dose of Pembrolizumab 1x daily. * Days 1 and 8 of 21 Day Cycle: Predetermined dose of Carboplatin 1x daily. * Tumor biopsy during Cycle 2. * End of Treatment visit * Follow up: every 6 months |
| Azenosertib and Niraparib | EXPERIMENTAL | Azenosertib in combination with Niraparib |
| Azenosertib in combination with Gemcitabine | EXPERIMENTAL | Azenosertib (ZN-c3) in combination with Gemcitabine |
| Part 1: Azenosertib + carboplatin | EXPERIMENTAL | Azenosertib in combination with carboplatin |
| Part 1: Azenosertib + PLD | EXPERIMENTAL | Azenosertib in combination with pegylated liposomal doxorubicin (PLD) |
| Part 1: Azenosertib + paclitaxel | EXPERIMENTAL | Azenosertib in combination with paclitaxel |
| Part 1: Azenosertib + gemcitabine | EXPERIMENTAL | Azenosertib in combination with gemcitabine |
| Part 2: Azenosertib + bevacizumab | EXPERIMENTAL | Azenosertib in combination with bevacizumab |
| Single Agent Dose Escalation | EXPERIMENTAL | Subjects with solid tumors with advanced or metastatic disease who are refractory or ineligible to standard therapy(ies) or for whom no standard therapy is available. |
| Single Agent Food Effect Cohort | EXPERIMENTAL | Subjects with solid tumors with advanced or metastatic disease who are refractory or ineligible to standard therapy(ies) or for whom no standard therapy is available. This cohort will give subjects the option to continue treatment after PK assessments are completed. |
| Single Agent Dose Expansion | EXPERIMENTAL | Subjects with recurrent, platinum-resistant HGSOC; histologically confirmed USC; or either CCNE1-amplified/cyclinE1-positive solid tumors; or subjects who roll over from ZN-c3 pharmacology studies. |
| Name | Type | Description |
|---|---|---|
| Investigator's choice of Chemotherapy | DRUG | The investigator will select the chemotherapy in accordance with the protocol defined requirements. The possible choices as defined by the protocol: * Paclitaxel * Gemcitabine * Pegylated liposomal doxorubicin (PLD) * Topotecan The selected chemotherapy will be administered intravenously |
| Azenosertib | DRUG | Azenosertib 400 mg will be administered orally. |
| Carboplatin | DRUG | Platinum coordination compound, 5-, 15-, 45-, and 60-mL vials, via intravenous (into the vein) infusion per institutional standards. |
| Pembrolizumab | DRUG | Humanized immunoglobulin G4 monoclonal antibody, 4-mL vials, via intravenous (into the vein) infusion per protocol. |
| Niraparib | DRUG | Niraparib |
| Gemcitabine | DRUG | Gemcitabine is an approved drug |
| Pegylated liposomal doxorubicin | DRUG | Pegylated liposomal doxorubicin (PLD) is an approved drug |
| Paclitaxel | DRUG | Paclitaxel is an approved drug |
| Bevacizumab | BIOLOGICAL | Bevacizumab is an approved drug |
Inclusion Criteria: 1. Female age ≥ 18 years 2. High-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer 3. Measurable disease per RECIST Version 1.1 4. Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 5. The subject's tumor tissue must be positive fo...
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Azenosertib is an investigational cancer therapy being studied in several tumor types, including platinum-resistant high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, uterine serous carcinoma, triple-negative breast cancer, and osteosarcoma. It is not yet approved for any indication and remains in clinical development.
Azenosertib targets WEE1, a kinase that regulates cell cycle checkpoints. It is a small-molecule WEE1 inhibitor. By inhibiting WEE1, azenosertib interferes with the DNA damage response and cell cycle progression in tumor cells. Several of its trials enroll patients selected by biomarkers such as cyclin E1 protein expression.
Azenosertib is being developed by Zentalis Pharmaceuticals, Inc., which trades on the Nasdaq under the ticker ZNTL. The company is the sponsor of the clinical program evaluating the drug across multiple cancer indications, including ovarian cancer, uterine serous carcinoma, and triple-negative breast cancer.
Azenosertib is in clinical development across Phase 1, Phase 2, and Phase 3 studies. The most advanced is a Phase 3 trial in platinum-resistant high-grade serous ovarian, primary peritoneal, or fallopian tube cancers positive for cyclin E1 protein expression. Azenosertib is investigational and has not been approved by the FDA.
Azenosertib is being studied in several registered trials. These include NCT07546500, a Phase 3 study versus investigator's choice chemotherapy in platinum-resistant ovarian, primary peritoneal, or fallopian tube cancers; NCT06369155, a Phase 2 biomarker study in uterine serous carcinoma; NCT06351332, a Phase 1 study with carboplatin and pembrolizumab in triple-negative breast cancer; and NCT05198804, a completed Phase 1 study with niraparib in platinum-resistant ovarian cancer.
Yes, azenosertib is also known as ZN-c3. The two names refer to the same WEE1 inhibitor developed by Zentalis Pharmaceuticals. Trial records use both names, so searches for ZN-c3 and azenosertib lead to the same clinical program.