ZAP-IT: ZN-c3 + Carboplatin + Pembrolizumab in mTNBC

NCT06351332 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 24-005
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

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)

Conditions

Breast Cancer; HER2-negative Breast Cancer; Breast Cancer Female; Triple Negative Breast Cancer; Hormone Receptor Negative Malignant Tumor Breast Triple

Keywords

Breast Cancer; Breast Cancer Female; Triple Negative Breast Cancer; Hormone Receptor Negative Malignant Tumor Breast Triple; HER2-negative Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Number of Participants Experiencing Dose Limiting Toxicity (DLT)

  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.

  Up to 3 weeks

• Maximum Tolerated Dose (MTD)

  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.

  Up to 3 weeks

• Objective Response Rate (ORR)

  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.

  Up to 6 months

Secondary Outcomes (5)

• Clinical Beneficial Rate (CBR)

  Up to 48 months

• Median Progression Free Survival (PFS)

  Up to 48 months

• Median Overall Survival (OS)

  Up to 5 years

• Duration of Response (DOR)

  Up to 48 months

• Grade 3-5 Treatment-Related Toxicity Rate

  Up to 48 months

Study Arms (2)

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.

Drug: Azenosertib; Drug: Carboplatin; Drug: Pembrolizumab

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

Drug: Azenosertib; Drug: Carboplatin; Drug: Pembrolizumab

Interventions

Azenosertib DRUG

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

Also known as: ZN-c3, KP-2638

Phase 1: Dose Escalation Arm; Phase 2: AZENOSERTIB + PEMBROLIZUMAB + CARBOPLATIN

Carboplatin DRUG

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

Also known as: C6H12N2O4Pt, platinum, diammine[1,1-cyclobutanedicarboxylato(2-)- O,O']-, (SP-4-2)

Phase 1: Dose Escalation Arm; Phase 2: AZENOSERTIB + PEMBROLIZUMAB + CARBOPLATIN

Pembrolizumab DRUG

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

Also known as: Keytruda, MK-3475, Humanized X PD-1-mAB (H409A11) IgG4, C6504H10004N1716O2036S46

Phase 1: Dose Escalation Arm; Phase 2: AZENOSERTIB + PEMBROLIZUMAB + CARBOPLATIN

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed invasive breast cancer, with either locally advanced or metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
• Either the primary invasive tumor and/or the metastasis must be triple-negative, defined as:
• Hormone-receptor poor, ER- and PR-negative, or staining present in ≤10% by immunohistochemistry (IHC)
• HER2-negative: 0 or 1+ by IHC, or FISH\<2.0
• Participants must have at least one lesion that is not within a previously radiated field that is measurable per RECIST version 1.1. Bone lesions are not considered measurable by definition. See Section 11 for the evaluation of measurable disease. Biopsy of the lesion that will be used for disease evaluation (measurable disease) is not allowed in the phase 2 portion of this study.
• Prior chemotherapy: Patients have received 1-3 prior chemotherapeutic regimen for metastatic breast cancer, one of which must have contained an antibody drug conjugate. Prior cytotoxic chemotherapy must be discontinued at least 14 days before initiation of protocol therapy in the study. The patient must also not have progressed on a prior platinum in the metastatic setting. Receipt of platinum in neo\\adjuvant setting is allowed, with a disease recurrence later than 6 months post platinum treatment end.
• Prior biologic therapy: Patients must have discontinued all biologic therapy at least 14 days before treatment start date participation.
• Prior immune checkpoint inhibitor is allowed. Patients with prior history of prior immune-related adverse events with immune checkpoint inhibitors will be excluded.
• Prior radiation therapy: Patients may have received prior radiation therapy in either the metastatic or early-stage setting. Radiation therapy must be completed at least 14 days prior to study treatment initiation, unless given for palliation when 7 days is acceptable, and patients should have recovered from adverse effects of radiation to grade ≤1.
• Age ≥ 18
• ECOG performance status ≤ 2
• Participants must have normal organ and marrow function as defined below:
• ANC ≥1.5 × 109 /L (excluding measurements obtained within 7 days after administration of short-acting hematopoietic growth factors, or within 3 weeks after longacting hematopoietic growth factors).
• Platelet count ≥100 × 109 /L (excluding measurements obtained within 3 days after transfusion of platelets or within 3 weeks after administration of platelet growth factor).
• Hemoglobin ≥9.5 g/dL (excluding measurements obtained within 2 weeks after blood transfusion.

You may not qualify if:

• Major surgical procedures \<28 days from treatment start date.
• Participants who have received a prior inhibitor of WEE1 kinase activity.
• Participants who have progressed on prior platinum chemotherapy. Patients who received prior pembrolizumab and carboplatin are eligible as long as they didn't progress while on this regimen. Patients who received pembrolizumab and other non-platinum chemotherapy are eligible, even if they progressed on this regimen.
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 1 month before day 1 of study treatment will be excluded.
• Patients with current residual grade ≥2 neuropathy or grade ≥2 toxicity (except alopecia or anorexia) from prior therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to azenosertib, carboplatin or pembrolizumab.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Participant may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN).
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA \<10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
• Participants receiving any medications, substances, or foods (ie, grapefruit juice) listed below are ineligible (Please refer to Section 5.6 for list of restricted co-medications):
• Concurrent treatment with drugs or foods that are strong or moderate cytochrome P450 (CYP)3A4/ CYP3A5 inhibitors or P-gp inhibitors or strong or moderate CYP3A4/CYP3A5 inducers, strong CYP3A4/CYP3A5 inhibitors should be discontinued before five half-lives, and CYP3A4/CYP3A5 inducers should be discontinued 14 days prior to the first dose of the study drugs.
• Participants who have an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV (Appendix B), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutrition. In addition, patients are ineligible if they have a psychiatric illness or a social situation that could limit their ability to comply with the study requirements.

Sponsors & Collaborators

• Filipa Lynce, MD: lead
• Merck Sharp & Dohme LLC: collaborator
• Zentalis Pharmaceuticals: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

Carboplatin; Platinum; pembrolizumab; Immunoglobulin G

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Filipa Lynce, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: April 2, 2024
• First Posted: April 8, 2024
• Study Start: May 1, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): September 1, 2029
• Last Updated: January 12, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (1)