Inclusion Criteria:

• HER2-positive status will be based on pretreatment biopsy material and defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) according to current American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines. Central testing is not required * Known hormone receptor (HR) status as defined by ASCO/CAP guidelines (based on pretreatment biopsy material). Hormone receptor positive status can be determined by either known positive estrogen receptor (ER) or known positive progesterone receptor (PR) status; hormone receptor negative status must be determined by both known negative ER and known negative PR
• Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0 tumors are not eligible at initial breast cancer diagnosis are not eligible)
• Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or lymph nodes per the surgical pathology report are eligible; however, patients with HR+ HER2+ cancers must have node-positive residual disease per the surgical pathology report in order to qualify for the study. The presence of residual invasive disease in the breast is not mandatory for these patients
• Patients with weakly ER-positive (1-10%) breast cancer (based on the pretreatment core biopsy) are eligible even if they have node-negative disease per the surgical pathology report
• The residual disease tissue (breast and/or lymph nodes) is not required to be HER2-positive, as eligibility for NCI-2020-03770 (A011801) is based on a positive HER2 status at the time of the initial breast cancer diagnosis * Note: The presence of micrometastases in lymph nodes after preoperative therapy counts as residual disease, whereas the presence of isolated tumor cells does not
• Patients with synchronous bilateral invasive disease are eligible provided both lesions were confirmed to be HER2-positive, and at least one of the lesions meets the criteria outlined above. Multifocal disease is allowed, as long as the largest biopsied breast tumor was HER2-positive
• Patients must have received neoadjuvant chemotherapy with one of the following regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin (TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P)); docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P)); fluorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FAC-TH(P)), or fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)). Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is acceptable
• Prior receipt of T-DM1 in the neoadjuvant setting is not allowed.
• Prior treatment must have consisted of >= 6 cycles of chemotherapy and HER2-directed therapy, with a total duration of >= 12 weeks, including at least 9 weeks of preoperative taxane and trastuzumab with or without pertuzumab (or Food and Drug Administration [FDA]-approved biosimilars). Patients who have received at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also eligible if they received >= 6 cycles of systemic therapy prior to enrollment. Note: Patients who complete at least nine of a planned twelve doses of weekly paclitaxel, or three of a planned four doses of docetaxel, but discontinue prematurely due to toxicity are eligible. Patients receiving dose-dense chemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane) instead of paclitaxel or docetaxel is permitted. Prior use of subcutaneous trastuzumab (Hylecta) and subcutaneous trastuzumab and pertuzumab (Phesgo) is also allowed.
• Patients who received neoadjuvant systemic therapy which included experimental HER2-targeted therapy/therapies are potentially eligible, as long as the investigational agent was not a HER2-targeted antibody-drug conjugate (e.g. T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib).
• Patients may have received =< 1 cycles of T-DM1 in the adjuvant setting. Note: These patients will be randomized to receive a further 14 cycles of T-DM1 and tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been administered =< 5 weeks prior to registration * Note: Both of the following two criteria need to be met for the patient to be eligible for this study
• An interval of no more than 12 weeks between the completion date of the last definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither given, breast surgical date) and the date of registration. Concurrent radiation therapy is permitted while receiving study treatment
• Patients must be registered on study within =< 180 days of the date of the most recent definitive breast cancer surgery (not including reconstructive surgery)
• All systemic chemotherapy should have been completed preoperatively unless participating in EA1181 (CompassHER2 pathologic complete response [pCR]) or the BIG DECRESCENDO Trial (which is very similar to CompassHER2 pCR in terms of study design, drugs, and eligibility). However, patients who received 4 cycles of neoadjuvant THP off study can receive a further 2-4 cycles of chemotherapy postoperatively to meet eligibility for A011801. Patients who participated in EA1181 or MA41 and proceeded to surgery immediately after the de-escalated trial regimen must receive postoperative chemotherapy to complete a total of >= 6 cycles of systemic treatment prior to enrollment on A011801, as outlined above (e.g. 4 cycles pre-operatively, and 2 cycles post-operatively). The postoperative chemotherapy regimen prescribed is at the discretion of the treating oncologist (i.e. 2-4 cycles AC or THP, other). Continuation of trastuzumab + pertuzumab (HP) pre- or post-operatively as maintenance therapy (while awaiting a surgical date or an official pathology report) is allowed for all study participants
• Toxicities related to prior systemic treatment should have resolved or be at baseline, apart from alopecia and peripheral neuropathy =< grade 1
• Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as follows:
• Breast surgery: total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision
• For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection
• Lymph node surgery ** The axilla needs to be evaluated with either sentinel node biopsy or axillary lymph node dissection. If patients have a sentinel lymph node biopsy and sentinel nodes are negative, no further axillary treatment is necessary. If patients have isolated tumor cells (ITCs) in the setting of residual breast disease, at least one of the following is required: axillary lymph node dissection (ALND) or planned nodal irradiation. If patients have micro- or macro-metastatic nodal disease, ALND and planned nodal irradiation are required. Of note, co-enrollment on Alliance A011202 is not allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted to achieve eligibility)
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.0 x upper limit of normal (ULN) or direct bilirubin within the institutional normal range for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute percentage points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55% after completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated once up to 3 weeks following the initial screening assessment to assess eligibility

Exclusion Criteria:

• No adjuvant treatment with any anti-cancer investigational drug within 28 days prior to registration
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum pregnancy test done =< 7 days prior to registration is required
• Patients with known active and/or untreated hepatitis B or hepatitis C or chronic liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has been treated and cleared and normal liver function are eligible to participate in the study if the other eligibility parameters are met
• Stage IV (metastatic) breast cancer
• History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of registration
• Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the surgical pathology report
• Evidence of recurrent disease following preoperative therapy and surgery
• Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation)
• History of exposure to the following cumulative doses of anthracyclines: doxorubicin > 240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2. For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2
• Cardiopulmonary dysfunction as defined by any of the following:
• History of National Cancer Institute (NCI) CTCAE version (v) 5.0 grade >= 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria class >= II
• Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease
• High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular block (AV)-block (second degree AV-block type 2 [Mobitz 2] or third degree AV-block)
• Significant symptoms (grade >= 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy
• History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with prior trastuzumab treatment (e.g., during preoperative therapy)
• Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg)
• Current severe, uncontrolled systemic disease
• Major surgical procedure unrelated to breast cancer or significant traumatic injury within 28 days prior to registration or anticipation of the need for major surgery during the course of study treatment
• History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product
• Peripheral neuropathy of any etiology that exceeds grade 1
• Assessment by the investigator as being unable or unwilling to comply with the requirements of the protocol
• Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to registration is prohibited.
• Please note that use of sensitive CYP3A substrates should be avoided two weeks before registration and during study treatment. Additionally, CYP3A4 or CYP2C8 inducers are prohibited as concomitant medications within 5 days following discontinuation of tucatinib treatment. Patients who require medications that are known to be sensitive substrates of CYP3A4 with a narrow therapeutic window should be excluded.

Inclusion Criteria:

• Patients must have histologically confirmed glioblastoma (IDH wild-type, MGMT promoter methylated) that has undergone resection or biopsy upon first recurrence. Recurrence at site of prior involvement is defined by histopathological evidence of viable neoplastic cells associated with any of the following: mitotic activity, increased proliferation rate, micro-endothelial proliferation, or pseudo-palisading necrosis
• Prior to resection or biopsy, patients must have measurable disease, defined as at least one bi-dimensional contrast-enhancing lesion with clearly defined margins, with 2 perpendicular diameters of at least 10 mm, visible on >= 2 axial slices
• Patients must have received first-line treatment of temozolomide plus radiotherapy
• Patients must not have received any prior therapy aside from resection or biopsy for their recurrent disease
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of selinexor (KPT-330) in combination with temozolomide in patients < 18 years of age, children are excluded from this study
• Karnofsky performance status >= 60% (Eastern Cooperative Oncology Group [ECOG] =< 2)
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 10 g/dL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/ alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) =< 3 x institutional ULN
• Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retro-viral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• The effects of selinexor (KPT-330) and temozolomide on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as deoxyribonucleic acid (DNA) alkylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 180 days after the last dose of temozolomide. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of study treatment administration
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

• Patients who have had chemotherapy must have full recovery of organ and marrow function following the nadir of the last chemotherapy cycle
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents
• Patients who have previously received bevacizumab
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor (KPT-330) or temozolomide
• History of hypersensitivity to dacarbazine (DTIC), since both dacarbazine and temozolomide are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC)
• Patients with uncontrolled intercurrent illness
• Pregnant women are excluded from this study because selinexor (KPT-330) is a selective inhibitor of nuclear export with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with selinexor (KPT-330), breastfeeding is not allowed for mothers during treatment with selinexor (KPT-330) and for 7 days after the last dose. These potential risks may also apply to other agents used in this study
• Hospitalized patients with severe coronavirus disease of 2019 (COVID-19) who are >= 75 years old, or with a high-risk COVID-GRAM score, or with lactate dehydrogenase (LDH) > 370 (U/L) AND D-Dimer > 600 mcg/L FEU should not receive low-dose selinexor (KPT-330) pending additional results

Inclusion Criteria:

• Patients must have pathologically confirmed pancreatic adenocarcinoma
• Received 4-6 months of induction chemotherapy with fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX), fluorouracil, liposomal irinotecan, luecovorin, oxaliplatin (NALIRIFOX), or gemcitabine/Abraxane, as per standard of care
• Patients must have locally advanced pancreatic cancer according to National Comprehensive Cancer Network (NCCN) Guidelines (version 1.2020) on pancreas protocol CT scan performed within 21 days of registration. Locally advanced disease is defined as any of the following:
• For head or uncinate process tumors:
• Solid tumor contact with superior mesenteric artery > 180 degrees
• Solid tumor contact with the celiac axis > 180 degrees
• Solid tumor contact with the common or proper hepatic arteries > 180 degrees or
• For pancreatic body or tail tumors:
• Solid tumor contact of > 180 degrees with the superior mesenteric artery or celiac axis
• Solid tumor contact with the celiac axis and aortic involvement or
• Unreconstructible superior mesenteric vein or portal vein due to tumor involvement or occlusion (can be due to tumor or bland thrombus)
• The determination of locally advanced pancreatic cancer and plan for non-operative treatment on this clinical trial must be confirmed through local multi-disciplinary review
• Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of M3814 (peposertib) in combination with hypofractionated radiation in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 4,000/mcL
• Absolute neutrophil count >= 1.5 x 10^9/L.
• Hemoglobin >= 9 g/dL
• Platelets >= 100 x 10^9/L
• Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN
• Creatinine =< 1.5 x institutional ULN
• Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female patients of childbearing potential and male patients must be willing to use an adequate method of contraception for the course of the study through 12 weeks after the last dose of study medication.
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function. To be eligible for this trial, patients should be American Heart Association Stage B (people without current or previous symptoms of heart failure but with either structural heart disease, increased filling pressures in the heart or other risk factors) or better and New York Heart Association Functional Classification II (slight limitation of physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation, shortness of breath or chest pain), or better
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

• Patients who have completed induction chemotherapy less than 2 weeks or more than 8 weeks prior to study enrollment
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy grade =< 2
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M3814 (peposertib)
• Evidence of distant metastatic disease
• More than 1 line of chemotherapy for the treatment of localized pancreatic cancer, unless the change in treatment was made only for toxicity
• Prior abdominal radiation
• Active inflammatory bowel disease or connective tissue disease
• Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents
• History of anaphylactic reaction to iodinated intravenous (IV) contrast required for radiation simulation. Patients with mild reactions may be enrolled, but must receive premedications for contrast allergy prior to imaging
• Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2CP, and CYP2C19. Concomitant use of CYP1A2, CYP2B6, and CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:
• Strong inducers of CYP3A4/5, CYP2C9 and CYP2C19: >= 3 weeks prior to study treatment
• Strong inhibitors of CYP3A4/5, CYP2C9 and CYP2C19: >= 1 week prior to study treatment
• Substrates of CYP1A2, CYP2B6, and CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to study treatment
• Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patients may confer with the study doctor to determine if such medications can be discontinued. These must be discontinued >= 5 days prior to study treatment. Patients do not need to discontinue calcium carbonate. H2 blockers and antacids are allowed.
• Patients who have received a live attenuated vaccine within 30 days of dosing with M3814 (peposertib)
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because M3814 (peposertib) is a DNA-protein kinase (PK) inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M3814 (peposertib), breastfeeding should be discontinued if the mother is treated with M3814 (peposertib)
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this investigational regimen

Inclusion Criteria:

• Have histologically or cytologically confirmed recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that is considered incurable by local therapies. Acceptable prior lines of therapy will be determined according to specific cohort 1, 2, 3A and 3B: (a) The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, or larynx; (b) Any known p16 status of tumor must be negative (Note: All participants with an oropharyngeal tumor must have results of p16 status, per local testing); (c) Participants must provide local testing results of programmed cell death ligand 1 (PD-L1) status, if available; Cohort 4: (a) Patients must have primary tumor location in oropharynx. Unknown primary tumors are not included (b) Primary tumor must be HPV-positive, confirmed by positive p16 test or high-risk human papillomavirus (HPV) in-situ hybridization (ISH) in tissue (current or archival) (c) Participants must provide local testing results of PD-L1 status, if available; Cohort 5 (a) The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, or larynx; (b) HPV status must be known (either positive or negative) for patients with primary tumor location in oropharynx with p16 test or high-risk HPV ISH in tissue; (c) Participants must provide local testing results of PD-L1 status
• Participants in Cohorts 1, 2, 3B, 4 and 5 must have measurable disease according to RECIST version 1.1. Participants in Cohort 3A must have evaluable disease (defined as having at least 1 non-target lesion according to RECIST version 1.1
• Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less prior to the first dose of study treatment (except for alopecia or post-radiation skin changes [any grade], Grade less than or equal to [<=]2 peripheral neuropathy and Grade <=2 hypothyroidism stable on hormone replacement)
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion, platelet transfusion, or use of granulocyte colony-stimulating factor within 7 days prior to the date of the laboratory test.Participants should have: a) Hemoglobin >=9 grams per deciliter (g/dL); b) Neutrophils>=1.5 x 10^3/mcg; c) Platelets >=100 x 10^3/mcg

Exclusion Criteria:

• Uncontrolled illness including any medical history or current (non-infectious) interstitial lung disease (ILD)/ pneumonitis/ pulmonary fibrosis, or where suspected ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening
• Participant with untreated brain metastases leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation
• Participant with a history of clinically significant cardiovascular disease
• Received prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives, whichever is longer, before the first administration of study treatment. The maximum required washout is 28 days
• Received radiotherapy for palliative purposes within 7 days of the first administration of study treatment

Inclusion Criteria:

1. Patient has signed the informed consent before all study specific activities are conducted. 2. Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature. Female patients may be of any menopausal status.
• Postmenopausal status is defined by: 1. Age ≥60 years 2. Age <60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) or a follicle-stimulating hormone (FSH) value >40 mIU/mL and an estradiol value<40 pg/mL (140 pmol/L) or in postmenopausal ranges per local reference ranges 3. Documentation of prior surgical sterilization (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, at least 1 month before first dose of trial therapy).
• Premenopausal and perimenopausal women (who do not fit postmenopausal criteria) and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist initiated at least 4 weeks before the start of trial therapy and are planning to continue LHRH agonist treatment during the study treatment.
• For perimenopausal women to be considered of non-childbearing potential, FSH levels must be >40 mIU/ml. 3. Histopathological or cytological confirmed ER+, HER2-, breast cancer, per local laboratory, as per the American Society of Clinical Oncology (ASCO)/College of American Pathologists(CAP) guidelines (Allison et al, 2020, Wolff et al, 2018). Note: In the context of this trial, ER status will be considered positive if ≥10% of tumor cells demonstrate positive nuclear staining by immunohistochemistry, with or without PGR positivity. . 4. At least 1 not previously irradiated measurable lesion as per RECIST version 1.1 and/or at least 1 lytic or mixed (lytic +sclerotic) bone lesion with identifiable soft tissue components meeting the definition of measurability by RECIST version 1.1 that can be evaluated by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. 5. ECOG performance status of 0 or 1. 6. Patient has adequate bone marrow and organ function, as defined by the following laboratory values: 1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L 2. Platelets ≥100 × 10^9/L 3. Hemoglobin ≥9.0 g/dL 4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE grade ≤1 5. Creatinine is ≤ 1.5 x ULN or if creatinine is > 1.5 x ULN, then creatinine clearance must be ≥50 mL/min based on the Cockcroft-Gault formula. Note: C-G formula:
• Creatinine clearance (male) = ([140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72)
• Creatinine clearance (female) = (0.85 × [140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72) 6. Serum albumin ≥3.0 g/dL (≥30 g/L) 7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN. If the patient has liver metastases, ALT and AST ≤ 5 × ULN 8. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.

Exclusion Criteria:

1. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. Note: Patients with stable brain or subdural metastases are allowed if the patient has completed local therapy and was on a stable or decreasing dose of corticosteroids at baseline for management of brain metastasis for at least 4 weeks before starting treatment in this study. The dose must be ≤2.0 mg/day of dexamethasone or equivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 2. Patients with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term, including massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liver involvement >50%. 3. Prior chemotherapy or elacestrant in the advanced/metastatic setting. 4. Patients with known germline BRCA mutation without prior treatment with a PARP inhibitor before study entry. 5. Prior therapy with elacestrant or other investigational selective estrogen receptor degraders (SERDs), or investigational alike agents such as selective estrogen receptor modulators (SERM), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), and proteolysis-targeting chimeras (PROTACs), in the metastatic setting. Prior treatment with fulvestrant is not exclusionary as it is an approved medication. 6. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, except basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy. Other malignancies with low risk of recurrence may be considered eligible with Sponsor approval. 7. Uncontrolled significant active infections. • Patients with HBV and/or HCV infection must have undetectable viral load during screening. • Patients known to be HIV+ are allowed if they have undetectable viral load at baseline. 8. Documented pneumonitis/ILD prior to Cycle 1 Day 1. 9. Major surgery within 28 days before starting trial therapy. 10. Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impact the absorption of the study drug. 11. Known intolerance to elacestrant or any of its excipients. 12. Pregnant and breast-feeding women are excluded from the study. In addition, women of childbearing potential are excluded who: • Within 28 days before starting trial therapy, did not use a highly effective method of contraception. • Do not agree to use a highly effective method of contraception (Appendix F) or abstain from heterosexual intercourse throughout the entire study period and for 120 days after trial therapy discontinuation. 13. Men or women who do not agree to abstain from donating sperm or ova, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days after the last dose of study treatment. 14. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy: • Anti-cancer therapy within 14 days (28 days for anticancer antibody based treatment) or 5 half-lives, whichever is shorter. Please note: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, except alopecia and peripheral sensory neuropathy (Grade ≤2). • Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives, whichever is shorter, (refer to http://medicine.iupui.edu/clinpharm/ddis/ or https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-inter actions-table-substrates-inhibitors-and-inducers). • Herbal preparations/medications within 7 days. These include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. • Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization. 15. Evidence of ongoing alcohol or drug abuse as assessed by the investigator. 16. Any severe medical or psychiatric condition that, in the Investigator's opinion, would preclude the patient's participation in a clinical study.Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A)

Inclusion:

In general, the SmPC of the respective combination drug should be consulted forinstructions/restrictions with respect to interactions with concomitant medications. 1. PIK3CA mutation by local laboratory assessment. 2. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.Exclusion: 1. Prior therapy with alpelisib or any other PI3K inhibitor. 2. Type 1 diabetes or uncontrolled type 2 diabetes (fasting plasma glucose level of >140 mg/dL [7.7 mmol/L], or glycosylated hemoglobin [HbA1c] level of >6.4%). 3. Known intolerance to alpelisib or any of its excipients. 4. Patient is currently receiving or received drugs known to be a BCRP inhibitor within 14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy 5. Patient has ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates or denosumabAdditional Eligibility for the Everolimus Combination (Phase 1b and Arm B)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.Exclusion: 1. Prior therapy with everolimus. 2. Known intolerance to everolimus or any of its excipients.Additional Eligibility for the Abemaciclib Combination (Arm C)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.Exclusion: 1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvant therapy with abemaciclib is exclusionary if the patient relapsed within the past 12 months. 2. Known intolerance to abemaciclib or any of its excipients.Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.Exclusion: 1. Prior therapy with ribociclib in the metastatic setting. Prior adjuvant therapy with ribociclib is also exclusionary if the patient relapsed within the past 12 months. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
• Long QT syndrome
• Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
• Electrolyte abnormalities 5. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.Additional Eligibility for the Palbociclib Combination (Phase 1b)

  Inclusion:

  1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor.Exclusion: 1. Prior therapy with palbociclib in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipientsAdditional Eligibility for the Palbociclib Combination (Arm D)

  Inclusion:

  1. One or up to two prior hormonal therapies in the advanced or metastatic setting.Exclusion: 1. Prior therapy with a CDK4/6i in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipients.Additional Eligibility for the Abemaciclib Combination (Arm D)

  Inclusion:

  1. One or up to two prior hormonal therapies in the advanced or metastatic setting.Exclusion: 1. Prior therapy with any CDK4/6i in the metastatic setting. 2. Known intolerance to abemaciclib or any of its excipients.Additional Eligibility for Ribociclib Combination (Arm D)

  Inclusion:

  1. One or up to two prior hormonal therapies in the advanced or metastatic setting.Exclusion: 1. Prior therapy with a CDK4/6i in the advanced or metastatic setting. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
  • Long QT syndrome
  • Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
  • Electrolyte abnormalities 5. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.

Inclusion Criteria:

1. Aged ≥18 years at Screening 2. Diagnosis of histologically confirmed breast cancer that is unresectable. The following subsets of breast cancer are included: 1. Patients with triple-negative breast cancer, advanced or metastatic 2. Patients with hormone receptor (HR) positive, ER positive, HER2 negative advanced or metastatic breast cancer 3. Has measurable disease in accordance with RECIST 1.1 obtained by imaging within 28 days prior to C1D1 4. Other therapies are not indicated (eg, resistant or intolerant to taxanes and/or an anthracycline-containing regimen) for treatment of advanced or metastatic breast cancer 5. Has a life expectance of at least 24 weeks 6. Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 at screening 7. Has adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days before C1D1 (Note: labs will also be repeated pre-dose on C1D1 to confirm eligibility): a. Hemoglobin ≥9 g/dL (≥90 g/L) b. Adequate renal function by estimated glomerular filtration rate (eGFR) defined as a creatinine clearance >50 mL/min (>0.84 mL/s) (Cockcroft-Gault equation) and normalized to body surface area c. Peripheral absolute neutrophil count (ANC) of ≥1.5×109/L d. Platelet count of ≥100×109/L without growth factor/transfusion e. Total bilirubin <1.5× upper limit of normal (ULN); or ≤3×ULN if the patient has Gilbert's disease f. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5×ULN, with liver metastasis <5×ULN g. International normalized ratio (INR) <1.5 and prothrombin time (PT) ≤1.5×ULN, unless both of the following conditions are met: i. Patient is receiving anticoagulant therapy, and ii. PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulant h. Activated partial thromboplastin time (aPTT) ≤1.5×ULN, unless both of the following conditions are met: i. Patient is receiving anticoagulant therapy, and ii. PT or PTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

1. Received any line of treatment for advanced or metastatic breast cancer within 21 days or 5 half-lives (whichever is longer) prior to randomization 2. Currently receiving any hormone replacement therapy, unless discontinued within 21 days prior to randomization 3. Received IV 5-FU or oral 5-FU analog in the 4 weeks prior to C1D1 4. Received DPD inhibitor within 4 weeks prior to C1D1 5. Has homozygous or compound heterozygous DPYD variants that result in complete or near-complete absence of DPD activity 6. Cardiac: 1. Has history or presence of clinically significant abnormal 12-lead electrocardiogram (ECG) results, in the Medical Monitor or Investigator's opinion 2. Has prolonged QTc (with Fridericia's correction) of >480 msec performed at Screening 3. Has a history of prolonged QTc interval, ventricular tachycardia/fibrillation or significant ventricular arrhythmia, or Torsades de Pointes, or a history of ventricular ablation for arrhythmia 4. Has congenital long QT syndrome or a family history of long QT syndrome 5. Has other clinically significant cardiac disease including, but not limited to, myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or surgery ≤12 months prior to randomization, congestive heart failure
• Class II per the New York Heart Association, or history of myocarditis 7. Is pregnant or breastfeeding

Inclusion Criteria:

• Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-small cell lung cancer (NSCLC) that is not amenable to curative therapy including surgical resection or chemoradiation. Additional Cohort specific disease requirements include: Cohorts 1, 3, 3b, 5, 6 and 7: epidermal growth factor receptor (EGFR) exon 19 deletion (Exon19del) or Exon 21 L858R mutation; Cohort 2: EGFR Exon 20ins mutation. Cohorts 1,5,and6: Participant should not have received any prior systemic therapy for locally advanced or metastatic NSCLC. Cohort 2: Participant should not have received any prior systemic therapy for locally advanced or metastatic NSCLC. Cohorts 3and3b: Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first-line treatment for locally advanced or metastatic disease or in the second-line setting after prior treatment with first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as a monotherapy. Cohort 4: Participants need to currently be on an amivantamab IV Q2W regimen (1,050 mg or 1,400 mg depending on weight) for at least 8 weeks, as part of standard of care, an expanded access program, or as a rollover from a long-term extension, without any amivantamab dose reduction. Cohort 7: Participants must have progressed on or after the combination of amivantamab and lazertinib as the most recent line of treatment. The combination of amivantamab and lazertinib must have been administered as the first-line treatment for locally advanced or metastatic disease. Cohort 2, 3, 3b, and 7 only: Squamous NSCLC are excluded. EGFR mutation must have been identified as determined by Food and Drug Administration (FDA) approved or other validated test of either circulating tumor deoxyribonucleic acid (ctDNA) or tumor tissue in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states [US]) or an accredited local laboratory (sites outside of the US). A copy of the initial test report documenting the EGFR mutation must be included in the participant records and a deidentified copy must also be submitted to the sponsor
• All cohorts except Cohort 4: Participants must have at least 1 measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. If the only target lesion has been previously irradiated, it must show signs of disease progression since radiation was completed If only 1 non-irradiated measurable lesion exists, which undergoes a biopsy and is acceptable as a target lesion, the baseline tumor assessment scans should be performed at least 14 days after the biopsy
• May have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s)
• Have adequate organ (renal, hepatic, hematological, coagulation and cardiac) functions
• Participant must have eastern cooperative oncology group (ECOG) status of 0 or 1
• Cohort 6: Must be eligible for, and agree to comply with, the use of prophylactic anticoagulation with a direct oral anticoagulant or a low molecular weight heparin during the first 4 months of study treatment
• A participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment. Female participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility

Exclusion Criteria:

• Participant has a medical history of interstitial lung disease (ILD), including drug induced ILD or radiation pneumonitis
• Participant has a history of hypersensitivity to any excipients of the investigational products to be used in their enrollment cohort
• Participant has received a live or live attenuated vaccine within 3 months before Cycle 1 Day 1. The seasonal influenza vaccine and non-live vaccines against Coronavirus disease 19 (COVID-19) are not exclusionary
• For all cohorts (with regimens potentially including lazertinib): Participant is currently receiving medications or herbal supplements known to be potent Cytochrome (CYP3A4/5) inducers and is unable to stop use for an appropriate washout period prior to Cycle 1 Day 1
• Other clinically active liver disease of infectious origin
• Participant has a history of clinically significant cardiovascular disease including, but not limited to: a) All cohorts: diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of study treatment(s), or any of the following within 6 months prior to the first dose of study treatment(s): myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary; b) All cohorts (with regimens potentially including lazertinib): Participant has a significant genetic predisposition to venous thromboembolic events (VTE; such as Factor V Leiden); c) All cohorts (with regimens potentially including lazertinib): Participant has a prior history of VTE and is not on appropriate therapeutic anticoagulation as per NCCN or local guidelines; d) prolonged corrected QT interval by Fridericia (QTcF) interval greater than (>) 480 milliseconds (msec) or clinically significant cardiac arrhythmia or electrophysiologic disease (example, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate); e) uncontrolled (persistent) hypertension: systolic blood pressure >160 millimeter(s) of mercury (mmHg); diastolic blood pressure >100 mmHg; f) Congestive heart failure defined as NYHA class III-IV or hospitalization for congestive heart failure (CHF) (any New York Heart Association [NYHA] class) within 6 months of treatment initiation at Cycle 1/day 1 (C1D1); g) pericarditis/clinically significant pericardial effusion; h) myocarditis; i) baseline left ventricular ejection fraction (LVEF) below the institution's lower limit of normal at screening, as assessed by echocardiogram or multigated acquisition (MUGA) scan
• Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before Screening are eligible, provided they have been either off corticosteroid treatment or are receiving low-dose corticosteroid treatment (less than or equal to [<=] 10 milligrams per day [mg/day] prednisone or equivalent) for at least 2 weeks prior to treatment allocation

Inclusion Criteria:

• Have histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is not amenable to curative intent therapy
• Epidermal growth factor resistance-mutation (EGFRm) must be an Ex19del or Ex21 L858R substitution, as detected by food and drug administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA)-certified laboratory in accordance with site standard of care
• Have at least 1 measurable lesion, according to RECIST version (v)1.1, that has not been previously irradiated
• Any toxicities from prior systemic anticancer therapy must have resolved to national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0 grade 1 or baseline level (except for alopecia [any grade], grade <=2 peripheral neuropathy, or grade <=2 hypothyroidism stable on hormone replacement)
• Have an eastern cooperative oncology group (ECOG) performance status of 0 to 1

Exclusion Criteria:

• Medical history of active interstitial lung disease (ILD), including drug-induced ILD or radiation pneumonitis
• Had major surgery excluding placement of vascular access or tumor biopsy or had significant traumatic injury within 4 weeks before the first dose of anticancer treatments or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study
• Participant has uncontrolled tumor-related pain (symptomatic lesions amenable to palliative radiotherapy should be treated prior to first dosing)
• Received an investigational treatment that has not been cleared (based on at least 5 half lives of any pharmaceutical treatment) or within 12 months before the planned first dose of study treatment or is currently enrolled in an investigational study
• Has a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment could likely interfere with any study endpoints of safety or the efficacy of the study treatment(s)

Inclusion Criteria:

• Histologically confirmed (per local evaluation) diagnosis of de novo, previously untreated large B-cell lymphoma (LBCL) according to 2022 world health organization (WHO) classification including:i) Diffuse large B-cell lymphoma (DLBCL), not otherwise specified [including germinalcenter B-cell (GCB) and activated B-cell (ABC) types]ii) High-grade B-cell lymphoma, with MYC and BCL2 rearrangements (HGBL-MYC/BCL2double-hit lymphomas)iii) High-grade B-cell lymphoma, not otherwise specifiediv) T-cell/histiocyte/rich large B-cell lymphoma (THRLBCL)v) Epstein-Barr virus + DLBCL
• International Prognostic Index (IPI) score 1 or 2 with lactate dehydrogenase (LDH) > 1.3 x upper limit of normal (ULN) and/or bulky disease defined as single lesion of ≥ 7 cm OR IPI ≥ 3.
• Measurable disease defined by at least 1 fluorodeoxyglucose (FDG)-avid lesion for FDG-avid subtype and 1 bi-dimensionally measurable (> 1.5 cm in longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI), as defined by the Lugano classification.
• Must have Ann Arbor Stage II-IV disease.

Exclusion Criteria:

• Any significant medical condition, active infection, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.
• Any other subtype of lymphoma. Cases of primary mediastinal (thymic) large B-cell lymphoma (PMBCL), primary cutaneous DLBCL-leg type, Grade 3b FL, indolent lymphoma transformed to large B-cell lymphoma (LBCL), Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma, primary effusion lymphoma, and Burkitt lymphoma.
• Documented or suspected central nervous system (CNS) involvement by lymphoma.
• Other protocol-defined Inclusion/Exclusion criteria apply.

Inclusion Criteria:

• Documented radiographic and histopathologic confirmed primary localized invasive breast cancer.
• Histologically documented TNBC (estrogen receptor negative [ER-]/progesterone receptor negative [PR-]/human epidermal growth factor 2 negative [HER2-]) defined as ER-negative and PR-negative (≤5% positive cells stain by IHC for both ER and PR), and negative HER2eu- status, confirmed on tumor sample.
• HER2eu negative will be defined as one of the following criteria:
• IHC 0 or 1+
• Single-probe average HER2 gene copy number of <6 signalsucleus
• Dual-probe fluorescent in-situ hybridization (FISH) HER2eu chromosome 17 (CEP17) non-amplified ratio of <2
• Globo H IHC H-score ≥15 from the residual primary site/or lymph node (if primary site is not available) tumor obtained at time of definitive surgery or initial diagnosis (only if surgical tumor sample is not available). Globo H expression will be determined during pre-screening by Central lab. Instructions for submission of slides/tumor tissue blocks are provided in the protocol and study Lab Manual.
• No evidence of metastatic disease in chest, abdomen and pelvis by CT or other adequate imagining during the Screening Phase. Imaging within 3 months prior to randomization is acceptable as baseline scan. Bone scans and imaging of the brain at screening is optional, and should be symptom directed.
• High risk patients with no evidence of disease after completing standard treatment and meeting ONE of the following criteria:
• Neoadjuvant chemotherapy followed by definitive surgery: Residual invasive disease following neoadjuvant chemotherapy defined as: A contiguous focus of residual invasive cancer in the surgical breast specimen measuring ≥1 cm in diameter and/or with residual invasive cancer in at least one axillary node (micrometastases or macrometastases), as determined by local pathology review.
• Definitive surgery followed by adjuvant chemotherapy: Pathological Prognostic Stage IIB, Stage IIIA , Stage IIIB, or Stage IIIC disease according to the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual.
• Must have completed at least 4 cycles of a standard taxane and anthracycline-based multi-agent chemotherapy regimen (or a taxane-only regimen if the patient is ineligible for anthracycline treatment) either in the neoadjuvant or adjuvant setting (e.g., National Comprehensive Cancer Network recommended regimens):.
• Randomization must occur (a) within 16 weeks after definitive surgery and radiation therapy (if radiation therapy administered) in patients who received neoadjuvant multiagent chemotherapy or, (b) for patients receiving adjuvant multiagent chemotherapy (not including capecitabine, immune checkpoint inhibitor), within 16 weeks after the completion of the adjuvant multiagent chemotherapy and radiation therapy (if radiation therapy administered). Note: patients may be randomized and initiate study treatment concurrent with adjuvant SOC therapy (observation, capecitabine, immune checkpoint inhibitor ± capecitabine).
• Randomization must occur (a) within 16 weeks after definitive surgery and radiation therapy (if radiation therapy administered) in patients who received neoadjuvant multiagent chemotherapy or, (b) for patients receiving adjuvant multiagent chemotherapy (not including capecitabine, immune checkpoint inhibitor), within 16 weeks after the completion of the adjuvant multiagent chemotherapy and radiation therapy (if radiation therapy administered). Note: patients may be randomized and initiate study treatment concurrent with adjuvant SOC therapy (observation, capecitabine, immune checkpoint inhibitor ± capecitabine).
• All treatment-related toxicities resolved to Grade <1 on National cancer institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0) criteria (except hair loss and ≤Grade 2 neuropathy, which are acceptable).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Females must be either of non-childbearing potential, i.e., surgically sterilized (have documented sterilization, bilateral oophorectomy/salpingectomy at least 3 months before the start of the trial and/or hysterectomy), or one year postmenopausal; or if of childbearing potential must have a negative pregnancy test (urine or serum) at screening.
• Males and females of childbearing potential and their partners must be willing to use effective contraception during the entire Treatment Phase and for at least 4 weeks (28 days) after the last dose of study treatment.
• Adequate hematological, hepatic and renal function as defined below:
• Absolute neutrophil count (ANC) ≥1,500/µL
• Platelets ≥75,000/µL
• Hemoglobin ≥8.5g/dL
• Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≥55 mL/min for subjects with creatinine levels >1.5 × institutional ULN (glomerular filtration rate can also be used in place of creatinine or creatinine clearance may be calculated per institutional standard)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN
• Alkaline Phosphatase (ALP) ≤2.5 × ULN
• Serum total bilirubin ≤1.5 × ULN (unless Gilbert's disease is documented)
• Consent to participate with a signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved patient informed consent for the study prior to beginning any specific study procedures.
• Ability to understand and willingness to complete all protocol required procedures.

Exclusion Criteria:

• Local recurrence of or previous history of ipsilateral or contralateral invasive breast cancer within 10 years prior to randomization [for synchronous tumors see Exclusion criteria #3]
• Definitive clinical or radiologic evidence of metastatic disease
• Synchronous bilateral breast cancer, unless both tumors are confirmed as TNBC.
• Have received any anti-cancer vaccines
• Concomitant treatment with anticancer therapy other than adjuvant SOC therapy (capecitabine; immune checkpoint inhibitor), or other investigational therapy, if expected during the study
• A history of other malignancies (except appropriately treated melanoma in situ, non melanoma skin carcinoma, carcinoma in situ of the uterine cervix, follicular or papillary thyroid cancer or other non-breast malignancies with a similar outcome to those mentioned above) within 5 years prior to randomization.
• Have any active autoimmune disease or disorder that requires systemic immunosuppressive/immunomodulatory therapy. NOTE: Autoimmune diseases that are confined to the skin (e.g., psoriasis) that can be treated with topical steroids alone are allowed during the study.
• Oral/parenteral corticosteroid treatment (>5 mg/day of prednisone/equivalent), within 2 weeks prior to randomization or anytime during the study. NOTE: inhaled steroids for treatment of asthma; and topical steroids are allowed during the study.
• Any known uncontrolled concurrent illness that would limit compliance with study requirements, including but not limited to ongoing or active infections, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric disorders, or substance abuse.
• Any known hypersensitivity to active/inactive ingredients in the study drug formulation or known severe allergy or anaphylaxis to fusion proteins.
• Prior receipt of a glycoconjugate vaccine for cancer immunotherapy.
• Known history or positive for human immunodeficiency virus (HIV positive), unless on effective anti-retroviral therapy with undetectable viral load within 6 months of therapy (note: HIV testing not required for study entry).
• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection prior to randomization. Patients who have completed curative therapy and have undetectable viral load for HCV are eligible. For patients with evidence of chronic HBV infection, the HBV viral load must be undetectable on suppressive therapy. (note: HBV/HCV testing is not required for study entry).
• Any condition, including significant diseases and/or laboratory abnormalities that would place the patient at unacceptable risk for study participation.
• Currently pregnant or breastfeeding women.
• Currently participating in or has participated in a breast cancer therapeutic clinical trial within 4 weeks (28 days) prior to randomization.

• Refrain from donating fresh unwashed semen.
• Use contraception as follows as specified in the protocol 2. Female participants:
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
• Is a women of nonchildbearing potential OR
• Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency during the study intervention period and for at least 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of study intervention.
• Additional requirements for pregnancy testing during and after study intervention are provided in the protocol.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 14. Is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.Participants are excluded from the study if any of the following criteria apply:Medical Conditions 1. Has known or suspected leptomeningeal disease. 2. Has uncontrolled or significant cardiovascular disease. 3. Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1, with exceptions as stated in the protocol. 4. Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. 5. Has known HIV infection. 6. Has active hepatitis B or C infection. 7. Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per local institutions' requirements and screening guidance are eligible. 8. Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab. 9. Is unable to receive trastuzumab treatment due to medical contraindications. 10. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site. 11. Has any condition that would prevent treatment with the physician's choice of chemotherapy. 12. Has any issue or condition that in the opinion of the investigator would contraindicate the participant's participation in the study or confound the results of the study. Prior/Concomitant Therapy 13. Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation. 14. Was treated with any local or systemic antineoplastic therapy (including hormonal therapies for breast cancer) or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to randomization. 15. Has a history of trauma or major surgery within 4 weeks prior to randomization. Other Exclusions 16. Has a known hypersensitivity to any components of the study drugs, including chemotherapy. 17. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.

• Written informed consent (stage I) and HIPAA authorization for release of personal health information obtained prior to performing any study-specific procedures. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Male or female age ≥ 18 years at the time of consent.
• Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory.
• Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. If there is insufficient tissue from the most recently collected sample, earlier tissue may be used on a case-by-case basis if permission is granted by the sponsor investigator.
• Patient has locoregional recurrence of breast cancer: locoregional recurrence is defined as invasive recurrence in the ipsilateral breast, axilla, regional nodes, or chest wall.

  Inclusion Criteria for Treatment Phase:

  Subject must meet all of the following applicable inclusion criteria to participate inthis study:
  • Written informed consent (stage II/ main consent) and HIPAA authorization for release of personal health information obtained prior to performing any study-specific screening procedures. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • Male or female age ≥ 18 years at the time of consent. NOTE: Both pre- and post-menopausal women are eligible. Post-menopausal status is defined as:
  • Prior bilateral oophorectomy
  • Age ≥60
  • Age <60 and amenorrhea for the last 12 or more months(in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range.
  • ECOG Performance Status of 0-1 within 28 days prior to registration.
  • If patient is receiving tamoxifen or toremifene, a washout period of 5 half-lives (i.e. 35 days) prior to registration is required (during that period the participant can take AI).
  • Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory.
  • Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. If there is insufficient tissue from the most recently collected sample, earlier tissue may be used on a case-by-case basis if permission is granted by the sponsor investigator.
  • Patients have had adequate local treatment for locoregional recurrence (LRR) of breast cancer.
  • Locoregional recurrence is defined as recurrence in the ipsilateral breast, axilla, regional lymph nodes, or chest wall.
  • Local treatment is defined as either surgery, radiation therapy, or a combination of both if indicated.
  • Adequate local therapy is surgery with negative microscopic margins. Radiation therapy is mandated for patients with microscopically involved margins and recommended for all patients who had not received radiotherapy as part of their primary treatment.
  • Patients who have distant metastatic disease will not be eligible.
  • Prior treatment with neoadjuvant and adjuvant chemotherapy and ET is allowed.
  • Patients must enroll within 6 months of the last local treatment, either local surgery or radiation; or systemic chemotherapy (if patient is receiving chemotherapy), whichever occurred last. Chemotherapy after local therapy is allowed. ET for recurrent disease is allowed for up to 12 months prior to enrollment.
  • Patient has no contraindication to the adjuvant ET in the trial and is planned to be treated or continue treatment with ET.
  • Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.
  • Hematological
  • Absolute Neutrophil Count (ANC): ≥ 1.5 x 109/L
  • Platelets: ≥ 100 x 109/L
  • Hemoglobin (Hgb): ≥ 9.0 g/dL
  • Renal
  • --Estimated glomerular filtration rate (eGFR): ≥ 30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula
  • Hepatic
  • Bilirubin: ≤ upper limit of normal (ULN) except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN
  • Aspartate aminotransferase (AST): ≤ 2.5 × ULN except for patients with liver metastasis, who are only included if the AST is < 5 × ULN
  • Alanine aminotransferase (ALT): ≤ 2.5 × ULN except for patients with liver metastasis, who are only included if the ALT is < 5 × ULN
  • Coagulation
  • --International Normalized Ratio (INR) : ≤ 1.5 × ULN (unless is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug)
  • Electrolytes ---Potassium, Magnesium, and Total Calcium (corrected for serum albumin): Within normal limits or corrected to within normal limits with supplements.
  • Standard 12-lead ECG values defined as
  • QTcF interval at screening < 450 msec (QT interval using Fridericia's correction)
  • Resting heart rate 50-90 bpm (determined from the ECG)
  • Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 14 days prior to registration and must be willing to use a highly effective method of contraception that does not contain estrogen and/or progesterone. See the protocol for definition of childbearing potential.
  • As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
  • Ability to swallow and retain oral medication.

  Exclusion Criteria for Treatment Phase:

  Subjects meeting any of the criteria below may not participate in the study:
  • Patient with a known hypersensitivity to any of the excipients of ribociclib.
  • Patient who has received prior CDK4/6 inhibitor for recurrent disease. Patients who received a CDK4/6 inhibitor in the adjuvant setting may participate if they have been off therapy for at least 1 year prior to diagnosis of recurrent disease.
  • Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
  • Pregnant or breastfeeding or planning to become pregnant during the trial (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
  • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial.
  • Patients with distant metastases of breast cancer beyond regional lymph nodes as defined by AJCC (8th edition).
  • Treatment with any investigational drug within 30 days prior to registration or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. Enrollment or planned enrollment in another study that does not involve an investigational drug will be allowed at the discretion of the treating investigator.
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol: (e.g., chronic pancreatitis, chronic active hepatitis, HIV, active untreated or uncontrolled fungal, bacterial or viral infections, etc.). Testing to be done at investigator's discretion.
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
  • History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
  • Documented cardiomyopathy
  • History of Left Ventricular Ejection Fraction (LVEF) < 50%
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
  • Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
  • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug)
  • Inability to determine the QTcF interval
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block)
  • Systolic Blood Pressure (SBP) >160 or <90 mmHg
  • Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
  • Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pummelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
  • Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
  • Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
  • Patient with an uncontrolled psychiatric condition that, in the investigator's judgment, may cause unacceptable safety risks, impede research integrity and compliance, or interfere with the objectives of the study.