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

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed invasive breastcancer, with either locally advanced or metastatic disease. Patients withoutpathologic or cytologic confirmation of metastatic disease should have unequivocalevidence 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% byimmunohistochemistry (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 radiatedfield that is measurable per RECIST version 1.1. Bone lesions are not consideredmeasurable 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 formetastatic breast cancer, one of which must have contained an antibody drugconjugate. Prior cytotoxic chemotherapy must be discontinued at least 14 days beforeinitiation of protocol therapy in the study. The patient must also not haveprogressed on a prior platinum in the metastatic setting. Receipt of platinum inneo\adjuvant setting is allowed, with a disease recurrence later than 6 months postplatinum treatment end.

• Prior biologic therapy: Patients must have discontinued all biologic therapy atleast 14 days before treatment start date participation.

• Prior immune checkpoint inhibitor is allowed. Patients with prior history of priorimmune-related adverse events with immune checkpoint inhibitors will be excluded.

• Prior radiation therapy: Patients may have received prior radiation therapy ineither the metastatic or early-stage setting. Radiation therapy must be completed atleast 14 days prior to study treatment initiation, unless given for palliation when 7 days is acceptable, and patients should have recovered from adverse effects ofradiation 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 afteradministration of short-acting hematopoietic growth factors, or within 3 weeksafter longacting hematopoietic growth factors).

• Platelet count ≥100 × 109 /L (excluding measurements obtained within 3 daysafter transfusion of platelets or within 3 weeks after administration ofplatelet growth factor).

• Hemoglobin ≥9.5 g/dL (excluding measurements obtained within 2 weeks afterblood transfusion.

• Serum creatinine ≤1.5 × upper limit of normal (ULN) or creatinine clearance (CrCl) ≥60 mL/min using the Cockcroft-Gault equation or by 24-hour urinecollection test.

• Total bilirubin (sum of conjugated + unconjugated) ≤1.5 × ULN or ≤3 × ULN inthe case of Gilbert's disease.

• ALT and AST ≤2.5 × ULN. If liver function abnormalities are due to underlyingliver metastases: AST and ALT ≤3 × ULN.

• Participants who are HBsAg positive are eligible if they have received HBVanti-viral therapy for at least 4 weeks and have undetectable HBV viral load priorto enrollment.

• Note: Participants should remain on anti-viral therapy throughout study interventionand follow local guidelines for HBV anti-viral therapy post completion of studyintervention.

--Hepatitis B screening tests are not required unless:

• Known history of HBV infection

• As mandated by local health authority

• Participants with a history of HCV infection are eligible if HCV viral load isundetectable at screening.

• Note: Participants must have completed curative anti-viral therapy at least 4weeks prior to enrollment.

• Hepatitis C screening tests are not required unless:

• Known history of HCV infection

• As mandated by local health authority

• HIV-infected participants must have well-controlled HIV on ART, defined as:

• Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time ofscreening

• Participants on ART must have achieved and maintained virologic suppressiondefined as confirmed HIV RNA level below 50 or the LLOQ (below the limit ofdetection) using the locally available assay at the time of screening and forat least 12 weeks before screening

• It is advised that participants must not have had any AIDS-definingopportunistic infections within the past 12 months.

• Participants on ART must have been on a stable regimen, without changes indrugs or dose modification, for at least 4 weeks before study entry (Day 1) andagree to continue ART throughout the study ---The combination ART regimen mustnot contain any antiretroviral medications that interact with CYP3A4inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-anddrug-interactions-table-substrates-inhibitors-and-inducers)

• Biopsies will be performed in phase 2 only. Must be willing to undergo tumorbiopsies within 21 days of C1D1 and +/-48h of C2D1 for research purposes. End oftreatment biopsy will be optional. If a biopsy is not felt to be possible or safelyaccessible, permission to waive the biopsy(ies) can be obtained from thesponsor-investigator.

• Patients who undergo an attempted on-treatment research biopsy and in whominadequate tissue is obtained are still eligible to continue protocol therapy.

• Clinical biopsy performed within the required time frame before enrollment canreplace study biopsy if there is residual material (at least 10 FFPE tumorcontaining slides).

• Female subjects of childbearing potential must have a negative serum pregnancy testat screening. This must be performed or repeated within 72h of treatment start.

• The effects of azenosertib on the developing human fetus are unknown. Women ofchildbearing potential and men must agree to use adequate methods of contraception.All women are considered to be of childbearing potential unless they fulfill one ofthe following criteria at screening:

• Post-menopausal defined as age ≥50 and amenorrheic for at least 12 months

• Women age <50 if they have been amenorrheic for at least 12 months and have aserum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) level inthe postmenopausal range (per institutional standards).

• Documentation of irreversible surgical sterilization by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy, or bilateral tubal ligation

• Appropriate contraception should be used throughout the duration of studyparticipation, and for six months after the last dose of azenosertib or 120 days (5half-lives) after the last dose of pembrolizumab, whichever comes last. Acceptablemethods of contraception include abstinence, tubal ligation, intra-uterine devices,and vasectomized partner. Additionally, male patients should refrain from donatingsperm from the start of dosing until 6 months after discontinuing azenosertib. Ifmale patients wish to father children they should be advised to arrange for freezingof sperm samples prior to the start of study treatment.

• Participant must be able to swallow pills.

• Ability to understand and the willingness to sign a written informed consentdocument.

• Patients with a history of treated central nervous system (CNS) metastases areeligible. Treated brain metastases are defined as those having no evidence ofprogression for ≥ 1 month after treatment, or hemorrhage for >/= 2 weeks aftertreatment and no ongoing requirement for corticosteroids, as ascertained by clinicalexamination and brain imaging (magnetic resonance imaging or CT scan) during thescreening period. Any corticosteroid use for brain metastases must have beendiscontinued without the subsequent appearance of symptoms for ≥2 weeks before thefirst study drug. Treatment for brain metastases may include whole brainradiotherapy, radiosurgery, or a combination as deemed appropriate by the treatingphysician.

• Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial.

Exclusion Criteria:

• 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 whoreceived prior pembrolizumab and carboplatin are eligible as long as they didn'tprogress while on this regimen. Patients who received pembrolizumab and othernon-platinum chemotherapy are eligible, even if they progressed on this regimen.

• Known brain metastases that are untreated, symptomatic, or require therapy tocontrol symptoms. Patients with CNS metastases treated by neurosurgical resection orbrain biopsy performed within 1 month before day 1 of study treatment will beexcluded.

• Patients with current residual grade ≥2 neuropathy or grade ≥2 toxicity (exceptalopecia or anorexia) from prior therapy.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to azenosertib, carboplatin or pembrolizumab.

• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Participant may not have a percutaneous endoscopic gastrostomy (PEG) tube or bereceiving total parenteral nutrition (TPN).

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration.

• Has received a live vaccine or live-attenuated vaccine within 30 days before thefirst dose of study intervention. Administration of killed vaccines is allowed.

• Known additional malignancy that is progressing or has required active treatmentwithin 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 insitu of the bladder, that have undergone potentially curative therapy are notexcluded. Participants with low risk early-stage prostate cancer (T1-T2a, Gleasonscore ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated inactive 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 restrictedco-medications):

--Concurrent treatment with drugs or foods that are strong or moderate cytochromeP450 (CYP)3A4/ CYP3A5 inhibitors or P-gp inhibitors or strong or moderateCYP3A4/CYP3A5 inducers, strong CYP3A4/CYP3A5 inhibitors should be discontinuedbefore five half-lives, and CYP3A4/CYP3A5 inducers should be discontinued 14 daysprior to the first dose of the study drugs.

• Participants who have an uncontrolled intercurrent illness, including, but notlimited to, ongoing or active infection, uncontrolled hypertension, unstable anginapectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York HeartAssociation Class III or IV (Appendix B), active ischemic heart disease, myocardialinfarction within the previous six months, uncontrolled diabetes mellitus, gastricor duodenal ulceration diagnosed within the previous 6 months, chronic liver orrenal disease, or severe malnutrition. In addition, patients are ineligible if theyhave a psychiatric illness or a social situation that could limit their ability tocomply with the study requirements.

• Participants who have refractory nausea and vomiting, chronic gastrointestinaldiseases, or previous significant bowel resection that would preclude adequateabsorption of azenosertib.

• Participant with mean resting corrected QT interval (specifically QTc calculatedusing the Fridericia formula [QTcF]) 470 msec, on baseline ECG, or congenital longQT syndrome.

• History or current evidence of congenital or family history of long QT syndrome orTorsade de Pointes (TdP).

• Taking medications with a known risk of TdP.

• Concomitant medication that leads to significant QT prolongation

• Has an active infection or active TB requiring systemic therapy.

• Has active autoimmune disease that has required systemic treatment in the past 2years except replacement therapy (eg., thyroxine, insulin, or physiologiccorticosteroid)

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e.,dosing exceeding 10 mg daily of prednisone or equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study treatment.

• Has not adequately recovered from major surgery or has ongoing surgicalcomplications.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality or other circumstance that might confound the results of the study,interfere with the participant's participation for the full duration of the study,such that it is not in the best interest of the participant to participate, in theopinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

• Has had an allogenic tissue/solid organ transplant.