Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Azenosertib · 8 trials · 17 indications
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 |
|---|---|---|
| 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 | EXPERIMENTAL | Azenosertib 400mg administered once daily on a 5 days on, 2 days off intermittent schedule |
| Part 2c | 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 |
|---|---|---|
| Azenosertib | DRUG | Wee1 inhibitor, 25mg and 100mg tablets, taken orally per protocol. |
| 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: * Participants must have histologically or cytologically confirmed recurrent or persistent uterine serous carcinoma. For the purposes of this study, uterine carcinomas (with the exception of carcinosarcomas) that have any component that is considered serous will be considered a ...
Azenosertib is an investigational small molecule being studied for the treatment of solid tumors, including uterine serous carcinoma, breast cancer, high-grade serous ovarian, fallopian tube or primary peritoneal cancer, ovarian cancer, and osteosarcoma. It is being developed by Zentalis Pharmaceuticals and is currently in Phase 1 clinical development.
Azenosertib is a small molecule that targets WEE1, a kinase involved in cell cycle regulation. By inhibiting WEE1, it aims to disrupt DNA damage repair in cancer cells. This mechanism is being evaluated in clinical trials for various solid tumors, including ovarian cancer and uterine serous carcinoma.
Azenosertib is being developed by Zentalis Pharmaceuticals, Inc., a biopharmaceutical company. Zentalis is publicly traded under the ticker symbol ZNTL. The drug is currently in Phase 1 clinical trials for multiple oncology indications.
Azenosertib is in Phase 1 clinical development. It has received FDA designations including Fast Track and Accelerated Approval. However, it is still investigational and has not been approved for any indication. Clinical trials are ongoing to evaluate its safety and efficacy.
Azenosertib has been studied in several clinical trials, including NCT04814108 for uterine serous carcinoma, NCT04833582 for osteosarcoma in combination with gemcitabine, and NCT05198804 for platinum-resistant ovarian cancer with niraparib. An active trial, NCT06351332, is evaluating it with carboplatin and pembrolizumab in metastatic triple-negative breast cancer.
Yes, Azenosertib is also known as ZN-c3. Clinical trial titles and protocols refer to the drug as Azenosertib (ZN-c3), confirming that both names refer to the same investigational compound being developed by Zentalis Pharmaceuticals.