AMTEC IIT: Phase 2 Multiarm Study in TNBC

Inclusion Criteria:

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

• Participants are >= 18 years old at time of informed consent.

• Metastatic TNBC, as defined by:

• Estrogen receptor (ER) and progesterone receptor (PR) negative as defined as ER < 10% and PR < 10% by immunohistochemistry according to American Society ofClinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines forhormone receptor testing

• HER2 non-amplified per ASCO/CAP guidelines, defined as:

• IHC score 0/1+

• IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2to CEP17 < 2.0, and if reported, average HER2 gene copy number < 4signals/cells; or

• ISH non-amplified with a ratio of HER2 to CEP17 <2.0, and if reported,average HER2 gene copy number < 4 signals/cells

• Participants with or without germline BRCA mutated TNBC are eligible for studyparticipation

• Participants must have at least one measurable site of disease as defined byResponse Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 that isamenable to biopsy

• Prior therapies for metastatic breast cancer

• Frontline patients who have not received prior systemic therapy for metastaticbreast cancer are eligible

• Patients who have received =< 2 prior chemotherapy regimens for metastaticbreast cancer are eligible

• Participants must have fully recovered from the acute toxic effects of all priortreatment to grade 1 or less, except alopecia which is allowed

• Participants must have a life expectancy >= 16 weeks

• Participant must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Participant must consent to undergo a pre-treatment screening biopsy for enrollmentand subsequent biomarker analyses

• Participants must consent to undergo one mandatory on-study tumor biopsy following a 2-week induction treatment of olaparib. A second on-study biopsy at time of diseaseprogression is optional, but not mandatory

• Participants must not have received previous treatment with PARP inhibitors,including olaparib

• Hemoglobin >= 10.0 g/dL (measured within 28 days prior to administration of studytreatment)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior toadministration of study treatment)

• Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration ofstudy treatment)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to administration of study treatment)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present inwhich case they must be =< 5 x ULN (measured within 28 days prior to administrationof study treatment)

• Participants must have creatinine clearance estimated of >= 51 mL/min using theCockcroft-Gault equation or based on a 24 hour urine test (measured within 28 daysprior to administration of study treatment)

• Participants of childbearing potential must have a negative urine or serum pregnancytest within 28 days of study treatment and confirmed on Day 1 prior to receiving thefirst dose of study medication. If the urine test is positive or cannot be confirmedas negative, a serum pregnancy test will be required

• Participants of childbearing potential agree to use adequate methods ofcontraception, upon signing of informed consent through:

• 6 months after the last dose with olaparib,

• 3 months after the last dose with durvalumab,

• 1 week after the last dose with selumetinib,

• 1 month after the last dose with capivasertib,

• 1 month after the last dose with ceralasertib.

• Participants of childbearing potential are those who are not proven postmenopausal.Postmenopausal is defined as:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in thepost-menopausal range for women under 50

• Radiation-induced oophorectomy with last menses >1 year ago

• Chemotherapy-induced menopause with >1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy)

• Sperm-producing participants must use a condom during treatment and for 3 monthsafter the last dose of olaparib when having sexual intercourse with a pregnantpartner or with an individual of childbearing potential. Partners of sperm-producingparticipants should also use a highly effective form of contraception if they are ofchildbearing potential

• Sperm-producing participants assigned to receive capivasertib must use a condomduring treatment and for 4 months after the last dose of capivasertib whenhaving sexual intercourse with a pregnant partner or with an individual ofchildbearing potential

Exclusion Criteria:

• Any concurrent anticancer treatment

• Individuals in the follow-up phase of a prior investigational study mayparticipate as long as it has been 4 weeks since last dose of the previousinvestigational agent or device

• Concurrent use of hormonal therapy for non-cancer related conditions (e.g.,hormone replacement therapy) is allowed

• Participant's with tumors showing androgen receptor (AR) >= 80% byimmunohistochemistry are excluded

• Other malignancy unless curatively treated with no evidence of disease for >= 5years except: adequately treated non-melanoma skin cancer, curatively treated insitu cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1endometrial carcinoma. Participants with a personal history of treated early stagebreast cancer whose natural history or treatment does not have the potential tointerfere with the safety or efficacy endpoints of the trial, per investigatorassessment, are eligible

• Participants with myelodysplastic syndrome/acute myeloid leukemia or with featuressuggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

• Participant received prior anticancer therapy such as targeted therapies, orsystemic chemotherapy or radiation (except for palliative reasons) within the past 3weeks, or 5 half-lives, whichever is shorter, prior to first day of treatment

• Participants with known active central nervous system (CNS) metastases and/orcarcinomatous meningitis

• Patients with brain metastases may participate provided they do not havesymptomatic uncontrolled disease. The patient can receive a stable dose ofcorticosteroids before and during the study as long as these were started atleast 4 weeks prior to treatment. (note: a scan to confirm the absence of brainmetastases is not required)

• Patients with spinal cord compression are not eligible unless considered tohave received definitive treatment for this and evidence of clinically stabledisease for 28 days

• Patients with carcinomatous meningitis are not eligible

• Concomitant use of known strong CYP3A inhibitors (e.g., ketoconazole, posaconazole),or strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin,rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderateCYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout periodprior to starting study intervention treatment is 5 weeks for enzalutamide orphenobarbital and 3 weeks for other agents

• Major surgery within 4 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)

• Patients that are immunocompromised, including those with human immunodeficiencyvirus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness are noteligible for participation

• Note: HIV-infected participants on effective anti-retroviral therapy withundetectable viral load for >= 6 months are eligible for this trial providedthat there is minimal interactions or overlapping toxicity of theantiretroviral therapy with their study intervention. Refer to drug-specificexclusion criteria for additional considerations

• Patients with known active hepatitis (i.e. hepatitis B or C). Refer to drug-specificexclusion criteria for additional considerations

• Active hepatitis B virus (HBV) is defined by a known positive HBV surfaceantigen (HBsAg) result

• Patients with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody and absence of HBsAg) are eligible

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA. Those with a positiveHCV PCR will be excluded

• Participants unable to swallow orally administered medication and participants withgastrointestinal disorders likely to interfere with absorption of the studymedication

• Participants with visceral crisis defined as severe organ dysfunction as assessed bysigns and symptoms, laboratory studies, and rapid progression of disease

• Active infection requiring systemic antibiotic therapy. Participants requiringsystemic antibiotics for infection must have completed therapy before treatment isinitiated

• Participants considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection. Examplesinclude, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstablespinal cord compression, superior vena cava syndrome, extensive interstitialbilateral lung disease on high resolution computed tomography (HRCT) scan or anypsychiatric illness/social situation that prohibits obtaining informed consent

• Resting electrocardiography (ECG) indicating uncontrolled, potentially reversiblecardiac conditions, as judged by the investigator (e.g., unstable ischemia,uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT intervalby Fridericia's correction formula (QTcF) prolongation > 500 ms, electrolytedisturbances, etc.), or participants with congenital long QT syndrome

• Participants with a history of hypersensitivity reactions to study agent, olaparib,or its excipients

• Participant is pregnant or breastfeeding, or expecting to conceive or fatherchildren within the projected duration of the trial, starting with the screeningvisit through 120 days after the last dose of trial treatment

• Sperm-producing participants are prohibited from donating sperm upon signing ofinformed consent through:

• 3 months following last dose with olaparib

• 4 months following last dose with capivasertib

• 6 months following last dose with ceralasertib

• Involvement in the planning and/or conduct of the study

• Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements

• DRUG-SPECIFIC EXCLUSION CRITERIA: The following criteria require consideration forparticipant eligibility to one or more of the available treatment arms. Participanteligibility may be assessed at the time of initial screening or as part of theon-study assignment to a specific treatment arm

• DURVALUMAB EXCLUSION CRITERIA: Participant has received prior immunotherapy withanti-PD-L1, including durvalumab anti-PD-1, anti-CTLA4 or similar drugs in themetastatic setting

• DURVALUMAB EXCLUSION CRITERIA: Participants may have received prior immunotherapy inthe adjuvant setting, provided

• No documented disease progression on immunotherapy

• Treatment with immunotherapy was >1 year from enrollment on study

• DURVALUMAB EXCLUSION CRITERIA: Participant has evidence of interstitial lung diseaseor active non-infectious pneumonitis

• DURVALUMAB EXCLUSION CRITERIA: Major surgery within 2 weeks of starting studytreatment and participants must have recovered from any effects of any major surgery

• Note: Local surgery of isolated lesions for palliative intent is acceptable perinvestigator discretion

• DURVALUMAB EXCLUSION CRITERIA: Active infection including tuberculosis (clinicalevaluation that includes clinical history, physical examination and radiographicfindings, and tuberculosis (TB) testing in line with local practice), hepatitis B (positive HBV surface antigen (HBsAg) result), hepatitis C, or humanimmunodeficiency virus

• Participants with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.

• Participants positive for hepatitis C (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV ribonucleic acid (RNA)

• Those with controlled human immunodeficiency virus (HIV) are eligible, providedthat:

• Baseline CD4+ T-cell count is >= 200 cells/mm^3, and

• HIV plasma viral load is < 60 copies/ml

• DURVALUMAB EXCLUSION CRITERIA: History of active primary immunodeficiency

• DURVALUMAB EXCLUSION CRITERIA: Current or prior use of immunosuppressive medicationwithin 14 days before the first dose of durvalumab, with the exceptions ofintranasal and inhaled corticosteroids or systemic corticosteroids at physiologicaldoses, which are not to exceed 10 mg/day of prednisone, or an equivalentcorticosteroid. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., computedtomography (CT) scan premedication)

• DURVALUMAB EXCLUSION CRITERIA: Active or prior documented autoimmune or inflammatorydisorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease],diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following areexceptions to this criterion:

• Participants with vitiligo or alopecia

• Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Participants without active disease in the last 5 years may be included butonly after consultation with the study physician

• Participants with celiac disease controlled by diet alone

• DURVALUMAB EXCLUSION CRITERIA: History of allogenic bone marrow transplant or doubleumbilical cord blood transplantation

• DURVALUMAB EXCLUSION CRITERIA: Participants must not have received live vaccineswithin 30 days prior to the first dose of