Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Analgesics

Central Nervous System Depressants

Pembrolizumab

Carboplatin

Antibodies

Antibodies, Monoclonal

Hormones

Nitrous Oxide

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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

WEE1 inhibitor, 25 or 100 mg tablet, taken orally per protocol.

Azenosertib

Platinum coordination compound, 5-, 15-, 45-, and 60-mL vials, via intravenous (into the vein) infusion per institutional standards.

Humanized immunoglobulin G4 monoclonal antibody, 4-mL vials, via intravenous (into the vein) infusion per protocol.

Filipa Lynce, MD

This research is being done to evaluate the safety and effectiveness of a drug currently known as Azenosertib (ZN-C3) in combination with the drugs carboplatin and pembrolizumab in metastatic triple-negative breast cancer.

The names of the study drugs involved in this study are:

* Azenosertib (a type of WEE1 inhibitor)
* Carboplatin (a type of platinum compound)
* Pembrolizumab (a type of monoclonal antibody)

This is a non-randomized, open-label, phase I/II study designed to evaluate the safety and efficacy of azenosertib in combination with carboplatin and pembrolizumab in participants with metastatic triple negative breast cancer (TNBC) Azenosertib is a medication that targets WEE1, an important protein in tumor growth.

The U.S. Food and Drug Administration (FDA) has not approved azenosertib as a treatment for metastatic triple-negative breast cancer.

The FDA has approved carboplatin as a treatment option for metastatic triple-negative breast cancer and it is considered standard of care for breast cancer.

The FDA has approved pembrolizumab for metastatic triple-negative breast cancer, but it is currently approved only for PD-L1 positive cancer.

The research study procedures include screening for eligibility, study treatment visits, blood tests, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, electrocardiograms (EKGs), and tumor biopsies in Phase 2.

It is expected that about 12-18 people will take part in the phase 1 portion and 60 people for the phase 2 portion of this research study.

Zentalis Pharmaceuticals is funding this research study and providing Azenosertib. Merck is supporting this research study by providing pembrolizumab.

A Phase I/II Single-arm Trial of Azenosertib (ZN-c3) Combined With Carboplatin and Pembrolizumab in Patients With Metastatic Triple-negative Breast Cancer (ZAP-IT)

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

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.

CBR is defined as the number of participants who achieved complete response (CR), partial response (PR), and stable disease (SD) lasting more than 24 weeks based on RECIST 1.1 criteria.

PFS based on Kaplan-Meier methodology is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.

OS is Overall survival based on the Kaplan-Meier method is defined as the time from registration to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant.

DOR based on Kaplan-Meier methodology is defined as the time from date of first documented confirmed objective response to date of first documented progressive disease (PD). Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.

The percentage of participants who experienced a maximum grade 3-5 treatment-related adverse event based on the Common Toxicity Criteria for Adverse events Version 5.0 (CTCAEv5) as reported on case report forms.

Spots Global Cancer Trial Database for hormone receptor negative malignant tumor breast triple