• ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks prior to screening
• Female and male patients must have histologically confirmed invasive breast cancer that meets the following criteria:
• Clinical stage II-III (American Joint Committee on Cancer [AJCC] 7th edition) at diagnosis, based on initial evaluation by clinical examination and/or breast imaging; no metastatic disease allowed
• ER- and PR- should meet one of the following criteria:
• =< 10% cells stain positive, with weak intensity score (equivalent to Allred score =< 3)
• =< 1% cells stain positive, with weak or intermediate intensity score (equivalent to Allred score =< 3)
• HER2 negative (not eligible for anti-HER2 therapy) will be defined as:
• Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR
• IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells OR
• ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC
• NOTE: Patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol; multifocal or multicentric breast cancers are eligible as long as all tumors fulfill eligibility criteria
• NOTE: Patients that have a discrepancy in ER/PR/HER2 status between original diagnosis and surgical specimen (if ER/PR/HER2 status were repeated) are not eligible for study participation (i.e. ER/PR/HER2 has to fulfill above criteria in both scenarios)
• Patients must have completed neoadjuvant taxane +/- anthracycline; patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen
• NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll
• NOTE: Patients that were not able to complete their planned neoadjuvant chemotherapy for any reason (i.e. toxicities, etc.) are eligible to participate as long as no further systemic standard of care therapy is planned by the treating physician
• Must have completed definitive resection of primary tumor
• Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible
• Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable
• Sentinel node biopsy either pre or post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) are allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory
• Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery; residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring >= 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination; this is required due to constraints in deoxyribonucleic acid (DNA) extraction for PAM50 analysis
• NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not qualify as residual invasive disease in the breast
• NOTE: Despite lymph node involvement if residual invasive cancer in the breast is < 1 cm in diameter patients are not eligible for participation
• Radiotherapy may be given before or after protocol treatment per standard of care guidelines; when radiotherapy is planned prior to protocol treatment administration, patients may be registered and screened while receiving radiation
• Post-mastectomy radiotherapy is required for all patients with the following:
• Primary tumor >= 5 cm (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery
• For patients with primary tumors < 5 cm or with < 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post-mastectomy radiotherapy is at the discretion of the treating physician
• Radiation of regional nodal basins is at the discretion of the treating radiation oncologist
• NOTE: Breast radiotherapy (whole breast or partial) is required for patients who underwent breast-conserving therapy, including lumpectomy or partial mastectomy
• Hemoglobin (Hgb) > 9.0 g/dL
• Platelets > 100,000 mm^3
• Absolute neutrophil count (ANC) > 1500 mm^3
• Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
• Bilirubin =< 1.5 x ULN upper limit of normal (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
• Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• No history of TNBC invasive breast cancer within 5 years of enrollment, no concurrent malignancies of any sort
• No clinically significant infections as judged by the treating investigator
• Patients with active >= Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade 2 neuropathy are ineligible
• Adjuvant chemotherapy after surgery other than that specified in this protocol is not allowed; luteinizing hormone-releasing hormone (LHRH) agonists and adjuvant bisphosphonate or denosumab use is allowed
• Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratification
• Tumor tissue specimen from the definitive surgery has been collected and is ready to ship to the ECOG-American College of Radiology Imaging Network (ACRIN) Central Biorepository and Pathology Facility (CBPF) within 21 weeks post-surgery
• The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will perform the PAM50 analysis and notify the ECOG-American College of Radiology Imaging Network (ACRIN) operations office within three (3) weeks of receipt of the tumor tissue specimen via secure electronic messaging to the ECOG-ACRIN database; results will not be reported to the submitting institution
• NOTE: Tissue must be submitted any time during screening period, even if patient is getting radiation
• NOTE: Every effort should be made to submit the tumor tissue specimen to the ECOG-ACRIN CBPF immediately
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): No specific timeframe between registration and randomization needs to be observed, as long as:
• Patients randomized to the chemotherapy arms have their cycle 1/ day 1 (platinum based or capecitabine) start within 3 weeks (15 working days) following randomization date
• Randomization occurs no more than 24 weeks from surgery date
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery completed
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): ECOG performance status 0 or 1 within 2 weeks prior to randomization
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Radiotherapy may be given before or after protocol treatment. when radiotherapy is planned prior to protocol treatment administration, patients must have completed adjuvant radiotherapy >= 2 weeks prior to randomization for protocol therapy, if applicable
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must have completed treatment with any investigational agent >= 30 days prior to randomization for protocol therapy, if applicable
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must be randomized within 24 weeks from surgery
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Hemoglobin (Hgb) > 9.0 g/dL
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Platelets > 100,000 mm^3
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Absolute neutrophil count (ANC) > 1500 mm^3
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): International normalized ratio (INR) =< 3 (to be done/tested only for subjects on warfarin)
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Bilirubin =< 1.5 x ULN (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Aspartate aminotransferase (AST, SGOT) =< 2.5 x ULN
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Alanine aminotransferase (ALT, SGPT) =< 2.5 x ULN

1. Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study treatment may not begin until a subject is registered. 2. Patients must provide informed written consent 3. ECOG performance status 0-1. 4. Clinical stage operable I, II or III invasive mammary carcinoma, which is ER-positive by IHC and HER2-negative by Herceptest (0 or 1+) or not amplified by FISH as per routine clinical testing Patients who have measurable residual tumor at the primary site Patients who will undergo surgical treatment with either segmental resection or total mastectomy 5. Measurable tumor i. Measurable disease: a mass that can be reproducibly measured by physical exam and calipers or ultrasound and is at least 1 cm in size 6. The pathology report from the initial diagnosis has been reviewed by either UTSW or Parkland Hospital, Department of Pathology and meets eligibility criteria. Available core biopsies from the time of diagnosis have been requested. These may include the paraffin block or sections from the paraffin-embedded tumor blocks. 7. Post-menopausal female subjects ≥18 years of age, as defined by any of the following:
• Subjects at least 55 years of age;
• Subjects under 55 years of age and amenorrhoeic for at least 12 months or follicle-stimulating hormone (FSH) values ≥40 IU/L and estradiol levels ≤20 IU/L;
• Prior bilateral oophorectomy or prior radiation castration with amenorrhea for at least 6 months.
• (There is no upper age limit for enrollment to this study) 8. No prior chemotherapy for this primary breast cancer. 9. Patients with a prior history of contralateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer. 10. Women may have been taking tamoxifen or raloxifene as a preventive agent prior to study entry but must have discontinued the drug for at least 21 days prior to study enrollment. 11. Subjects must have ended hormone replacement therapy (HRT) (e.g., conjugated estrogens tablets, USP, [Premarin]), at least 7 days prior to receiving the first dose of randomized therapy. 12. Patients must have adequate hepatic and renal function. All tests must be obtained less than 4 weeks from study entry. This includes: 1. Creatinine <1.5X upper limits of normal 2. Bilirubin, SGOT, SGPT <1.5X upper limits of normal 13. Able to swallow and retain oral medication 1. Patients with locally advanced disease who are candidates for other preoperative chemotherapy at the time of initial evaluation. This may include patients with locally advanced disease such as:
• Inflammatory breast cancer (T4d)
• Fixed axillary lymph node metastases (N2)
• Metastasis to ipsilateral internal mammary node (N3) 2. Locally recurrent breast cancer 3. Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.) 4. Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality. 5. Severe uncontrolled malabsorption condition or disease (i.e. grade II/III diarrhea, severe malnutrition, short gut syndrome) 6. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. 7. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of letrozole.

• Patients with histologically confirmed newly diagnosed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): Federation of Gynecology and Obstetrics (FIGO) clinical stages IB2/IIA with positive para-aortic nodes, or FIGO clinical stages IIB/IIIB/IVA with positive pelvic or para-aortic lymph nodes (PALN). Pelvic or PALN nodal status confirmed by PET/CT scan or fine needle biopsy or extra peritoneal biopsy or laparoscopic biopsy. The PALN must be inferior to the T12/L1 interspace
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 2,500/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL (> 50,000 for patients with hematologic malignancies)
• Hemoglobin >= 8 g/dL (can be transfused with red blood cells pre-study)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
• Creatinine clearance =< 1.5 mg/dL to receive weekly cisplatin
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible for cisplatin if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min. For the purpose of estimating the CCr, the formula of Cockcroft and Gault for females should be used
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
• Patient does not have a known allergy to cisplatin or compounds of similar biologic composition
• Patient is not actively breastfeeding (or has agreed to discontinue breastfeeding before the initiation or protocol therapy)
• Thyroid-stimulating hormone (TSH) within normal limits or normal free T4 in those with abnormal TSH
• Ability to understand and the willingness to sign a written informed consent document
• Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
• A stable regimen of highly active anti-retroviral therapy (HAART)
• No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests
• Patients who have received prior radiation therapy to the pelvis or abdominal cavity, PALN radiation, or previous therapy of any kind for this malignancy or pelvic, PALN, or abdominal radiation for any prior malignancy
• Patients with PALN nodal metastasis above the T12/L1 interspace
• Patients who had a radical hysterectomy with positive PALNs are not eligible
• Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
• Patients previously treated with systemic anticancer therapy (e.g., chemotherapy, targeted therapy, immunotherapy) within 3 years prior to entering the study
• Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1
• Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or steroids as CT scan contrast premedication) may be enrolled
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Patients requiring treatment with a RANKL inhibitor (e.g., denosumab) who cannot discontinue it before treatment with atezolizumab
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
• Patients positive for hepatitis C virus (HCV) antibody
• History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen or type 2 diabetes mellitus are eligible
• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
• Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
• Rash must cover less than 10% of body surface area (BSA)
• Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or steroids)
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Patients with active tuberculosis (TB) are excluded
• Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
• Received intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
• Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab
• Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time during the study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Severe, active co-morbidity defined as follows:
• Current (within 28 days of cycle 1, day 1) signs and/or symptoms of bowel obstruction
• Patients who require parental hydration and/or nutrition
• Patients who require drainage gastrostomy tube
• Evidence of bleeding diathesis or clinically significant coagulopathy
• Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture
• History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
• Significant cardiovascular or cerebrovascular disease including:
• Uncontrolled hypertension (systolic blood pressure [SBP] >= 150; diastolic blood pressure [DBP] >= 90)
• History of myocardial infarction within 6 months
• Unstable angina
• New York Heart Association functional classification II, III or IV
• Baseline ejection fraction =< 50% as assessed by echocardiogram or multigated acquisition scan (MUGA)
• Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 6 months
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or peripheral arterial thrombosis) within 6 months
• History of abdominal/pelvic or tracheoesophageal fistula or gastrointestinal perforation and/or abscess within 6 months prior to initiation of treatment
• If patients are of child-bearing potential and do not agree to use two forms of birth control then they are ineligible
• Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy following radiation as part of their cervical cancer treatment are ineligible
• Patients scheduled to be treated with adjuvant consolidation chemotherapy at the conclusion of their standard chemoradiation
• Pregnant women are excluded from this study because radiation therapy has 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 atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab
• 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, for the duration of study participation, and for the 5 months (150 days) after the last dose of the study agent. 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
• Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g. osteoporosis) is allowed
• Patients with known primary central nervous system (CNS) malignancy or CNS metastases are excluded
• Patients with a prior known history of vesicovaginal, enterovaginal or colovaginal fistula

• Patients must be able to swallow and retain oral medication
• Patients must be ≥ 18 years of age
• Female patients of no childbearing potential must be post-menopausal. Postmenopausal female subjects should be defined prior to protocol enrollment by any of the following:
• Participants at least 60 years of age; OR
• Participants under 60 years of age and naturally (spontaneous, no alternative pathologic or physiological cause) amenorrhea for at least 12 months; OR
• Medical ovarian failure confirmed by follicle-stimulating hormone (FSH) and estradiol levels in the post menopausal range per local institutional normal range; OR
• Prior bilateral oophorectomy; OR
• Prior radiation castration with amenorrhea for at least 6 months; OR
• Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (such as goserelin acetate or leuprolide acetate) is permitted for induction of ovarian suppression as long as it has been initiated at least 28 days prior to study enrollment
• Patients must have ECOG performance status 0
•1
• Patients must have clinical stage IV or inoperable locoregional recurrent invasive mammary carcinoma that is:
• ER+ and/or PgR+ (≥ 1% positive stained cells) by immunohistochemistry (IHC)
• HER2-negative (by IHC or FISH, per ASCO guidelines)
• FGFR1
•4 amplified
• Patients must have evaluable (may have either measurable or non-measurable) disease
• Patients must have available tissue for FGFR determination
• Patients must have had at least one line of therapy in the metastatic setting
• Current use of any of the drugs listed on the Cautionary Concomitant Med list has to be approved by the Study Chair
• Patients must have adequate hematologic, hepatic and renal function. All laboratory tests must be obtained within 2 weeks from study drug initiation. These include:
• ANC ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• HgB ≥ 9.0 g/dL
• Creatinine clearance ≥ 40 mL/min/1.73 m2
• SGOT, SGPT ≤ 2.5 x ULN if no liver metastasis present; SGOT, SGPT ≤ 4 x ULN if liver metastasis present
• Albumin ≥ 2.0 g/dL
• Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN if known Gilbert's syndrome)
• Potassium within institutional normal limits
• Phosphorus ≤ institutional upper limit of normal
• Prior use of an FGFR inhibitor
• More than 2 lines of chemotherapy in the metastatic setting. No limit on endocrine therapy lines. Prior exposure to CDK4/6 inhibitor acceptable.
• Radiation therapy ≤ 2 weeks prior to study entry. Patients who have received prior radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment (except for alopecia)
• Prior cancer therapy (except for endocrine therapy) must have been discontinued for 1 week prior to initiation of study drugs
• Concurrent anti-cancer therapy other than the ones specified in the protocol is not permitted during study participation. Bisphosphonates or denosumab are allowed
• Major surgery within 4 weeks of enrollment
• Herbal preparations are not allowed throughout the study, and should be discontinued 14 days prior to initiation of study treatment
• Any corneal or retinal abnormality likely to increase the risk of eye toxicity, such as:
• Current corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration
• Uncontrolled glaucoma despite standard of care therapy
• Diabetic retinopathy with macular edema
• Known active wet, age-related macular degeneration (AMD)
• Known central serous retinopathy (CSR) or retinal vascular occlusion (RVO)
• Uncontrolled intercurrent illness including, but not limited to:
• Malabsorption syndrome significantly affecting gastrointestinal function
• Ongoing or active infection requiring antibiotics/antivirals
• Impairment of lung function (COPD > grade 2, lung conditions requiring oxygen therapy)
• Symptomatic congestive heart failure
• Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
• Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse Events, Version 4.03, grade 3]
• QTcF ≥ 480 msec on screening EKG
• Known history of clinically significant QT/QTc prolongation or Torsades de Pointes(TdP)
• ST depression or elevation of ≥ 1.5 mm in 2 or more leads
• Diarrhea of any cause ≥ CTCAE grade 2 that does not resolve within a few days when adequately treated with anti-diarrhea medications
• Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary
• Symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment and be off steroids)
• Known history of chronic liver or chronic renal failure
• Poor wound healing capacity

• Patients must have histologically documented unresectable locally advanced or metastatic non-HER2-positive breast cancer and a known BRCA 1/2 mutation present
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Prior chemotherapy is allowed, including platinum therapy; patients must not have received chemotherapy for 4 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events from any prior chemotherapy (other than alopecia); patients must not have had nitrosoureas or mitomycin C for 6 weeks prior to the initiation of study treatment
• Prior radiation therapy is allowed; patients must not have received minimal radiation therapy (=< 5% of their total marrow volume) within 3 weeks prior to the initiation of study treatment; otherwise, patients must not have received radiation therapy (> 5% of their total marrow volume) within 4 weeks prior to the initiation of study treatment; patients who have received prior radiation to 50% or more of their total marrow volume will be excluded
• Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met: minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose, and no history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4)
• Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) is allowed, provided the following is met: minimum of 2 weeks prior to cycle 1, day 1; patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled; the use of corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
• Prior treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) is allowed, provided the following is met: minimum of 6 weeks prior to cycle 1, day 1
• Patients taking bisphosphonate therapy for symptomatic hypercalcemia are NOT allowed; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
• Prior hormone therapy is allowed; patients must not have received hormone therapy for breast cancer for 2 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events related to these therapies (other than alopecia)
• Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and immunotherapies are allowed; patients must not have received these therapies for 4 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events of these therapies (other than alopecia); prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody is NOT allowed
• Other therapies (e.g. targeted therapy such as cyclin-dependent kinase [CDK] inhibitors): patients should have recovered to =< grade 1 drug related toxicity; they must have completed therapy for either a total of duration equivalent to 5 half-lives of the drug or 28 days, whichever is shorter
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 6 months
• Absolute neutrophil count >= 1,500/mcL
• Leukocytes >= 3,000/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 8 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x upper limit of normal (ULN) if no liver metastasis; =< 5 x upper ULN if liver metastasis present
• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
• Creatinine clearance >= 51 mL/min/1.73 m^2 by Cockcroft-Gault
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
• No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) on peripheral blood smear
• Patients must have tumors determined to be easily accessible for biopsy and must be willing to have serial biopsies (with a third biopsy upon evidence of disease progression)
• Administration of atezolizumab and/or olaparib may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of child-bearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for at least 5 months (150 days) after the last dose of study agent; 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 two highly effective forms of contraception in combination prior to the study, for the duration of study participation, and for at least 5 months (150 days) after completion of atezolizumab and/or olaparib administration; women of child-bearing potential: negative serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1; postmenopausal or evidence of non-childbearing status for women of childbearing potential; postmenopausal is defined as:
• Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-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)
• Ability to understand and the willingness to sign a written informed consent document
• Subject is able to swallow and retain oral medication and does not have uncontrolled emesis or gastrointestinal disorders likely to interfere with absorption of the study medication
• Patients crossing over from monotherapy to combination therapy do not have to be fully rescreened; however, they do need to meet performance status, organ function, and blood parameters and not meet any of the exclusion criteria
• Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:
• A stable regimen of highly active anti-retroviral therapy (HAART)
• No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based test
• Patients with prior allogeneic bone marrow transplantation, double umbilical cord blood transplantation (dUCBT) or prior solid organ transplantation
• Patients with known brain metastases should be excluded from this clinical trial except as those described below, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
• Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
• Evaluable or measurable disease outside the CNS
• No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
• No history of intracranial hemorrhage or spinal cord hemorrhage
• No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
• No neurosurgical resection or brain biopsy within 28 days prior to cycle 1, day 1
• Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
• Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study
• No stereotactic radiation or whole-brain radiation within 28 days prior to cycle 1, day 1
• Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and atezolizumab; patients with a known hypersensitivity to olaparib or any of the excipients of the product
• Prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA
• History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, lichen sclerosis, or glomerulonephritis
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
• Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
• Rash must cover less than 10% of body surface area (BSA)
• Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted if recovered
• Major surgical procedure within 28 days prior to cycle 1, day 1 and patients must have recovered from any effects of any major surgery; anticipation of need for a major surgical procedure during the course of the study
• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab
• Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time during the study
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection; examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression, superior vena cava syndrome, symptomatic congestive heart failure, unstable angina pectoris, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent and would limit compliance with study requirements
• Pregnant women are excluded from this study because olaparib and atezolizumab are have 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 olaparib and atezolizumab, breastfeeding should be discontinued if the mother is treated with olaparib and atezolizumab
• Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1
• Patients with active seizures or a history of uncontrolled seizure disorder, including focal or generalized seizure within the past year
• Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot discontinue it before treatment with atezolizumab
• Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec or family history of long QT syndrome
• Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout p

• Patient has a new, unrated histologic diagnosis of stage IB2 (> 4 cm), II, IIIB or IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix or stage II-IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the vagina not amenable to curative surgical resection alone; the presence or absence of para‐aortic lymph node metastasis will be based on pre-therapy 18F‐FDG PET/CT; NOTE: if the baseline 18F‐FDG PET/CT identifies hypermetabolic para‐aortic disease, such patients will NOT be eligible; the patient must be able to tolerate imaging requirements of an 18F‐FDG PET/CT scan
• Patient must provide study specific informed consent prior to study entry
• Patient must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 or equivalent
• Absolute neutrophil count > 1,500/uL
• Platelets > 100,000/uL
• Hemoglobin > 10 g/dL
• Total bilirubin < 2.0 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
• Prothrombin time (PT)/activated partial thromboplastin time (aPTT) < 1.5 X institutional upper limit of normal
• Creatinine =< 1.5 mg/dL to receive weekly cisplatin
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible for cisplatin if the estimated creatinine clearance (CCr) is >= 30 ml/min; for the purpose of estimating the CCr, the formula of Cockcroft and Gault for females should be used
• Patient does not have uncontrolled diabetes mellitus (i.e., fasting blood glucose > 200 mg/dL)
• Patient has a life expectancy of greater than 20 weeks
• Patient does not have known brain metastases (testing optional)
• Patient does not have known human immunodeficiency virus syndrome (HIV, testing optional); known HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with triapine
• Patient does not have a known allergy to compounds of similar or biologic composition as triapine
• Patient does not have known glucose‐6‐phosphate dehydrogenase (G6PD) deficiency as the condition interferes with triapine antidote metabolism (G6PD testing optional)
• Patient is not actively breastfeeding (or has agreed to discontinue breastfeeding before the initiation of protocol therapy)
• Patient has another concurrent active invasive malignancy
• Patient has had a prior invasive malignancy diagnosed within the last three years (except [1] non-melanoma skin cancer or [2] prior in situ carcinoma of the cervix); patients are excluded if they have received prior pelvic radiotherapy for any reason that would contribute radiation dose that would exceed tolerance of normal tissues at the discretion of the treating physician
• Patient has uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within six months of protocol initiation, cardiac arrhythmia within six months of protocol initiation; known inadequately controlled hypertension; clinically significant pulmonary disease including dyspnea at rest, or patients requiring supplemental oxygen, or poor pulmonary reserve; or clinically significant renal function impairment (baseline serum creatinine > 2 mg/dL); or psychiatric illness/social situations that would limit compliance with study requirements
• Patient is receiving another investigational agent for the treatment of cancer
• Patient is currently pregnant
• Patient does not agree to use two forms of birth control if they are of child-bearing potential
• Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy following radiation as part of their cervical cancer treatment are ineligible
• Patients scheduled to be treated with adjuvant consolidation chemotherapy or other anti-neoplastic therapy at the conclusion of their standard chemoradiation
• Patients with self-reported or known diagnosis of G6PD deficiency
• Patients with vaginal cancer may have previously undergone a hysterectomy for various indications; patients with vaginal cancer who underwent a hysterectomy for treatment of cervical cancer less than five years prior to their diagnosis of vaginal cancer are ineligible

• Patients must have histologically or cytologically confirmed ovarian cancer, peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of either serous or endometrioid cancer based on local histopathological findings; both endometrioid and serous histology should be high-grade for eligibility of non-mutation carriers; patients with clear cell, mixed epithelial, undifferentiated carcinoma, or transitional cell carcinoma histologies are also eligible, provided that the patient has a known deleterious germline BRCA1 or BRCA2 mutation identified through testing at a clinical laboratory
• Note: Due to the long acceptance of BRCA testing through Myriad, Myriad testing will be accepted; if testing for BRCA is done by other organizations, documentation from a qualified medical professional (e.g., ovarian cancer specialty physician involved in the field, high risk genetics physician, genetics counselor) listing the mutation and confirming that the laboratory results showed a recognized germ line deleterious BRCA 1 or BRCA 2 mutation or BRCA rearrangement is required; a copy of Myriad or other BRCA mutational analysis (positive or variants of unknown significance [VUS] or negative) reports will be requested but not required for study enrollment
• Patients should have recurrent platinum-resistant or- refractory disease
•defined as disease that has progressed by imaging while receiving platinum or had recurrence within 6 months of the last receipt of platinum-based chemotherapy; rising CA125 only is not considered as platinum-resistant or refractory disease
• Phase II study: measurable disease by RECIST 1.1 criteria; if archival tumor sample is not available tumor sample from fresh biopsy is acceptable
• Phase III study: evaluable disease
•defined as RECIST 1.1 measurable disease OR non-measurable disease (defined as solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions OR ascites and/or pleural effusion that has been pathologically demonstrated to be disease-related in the setting of a cancer antigen [CA]125 >= 2 x upper limit of normal [ULN])
• No more than 3 prior treatment regimens (including primary therapy; no more than 1 prior non-platinum based therapy in the platinum-resistant/-refractory setting); hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will not count towards this line limit
• Patients may not have had a prior anti-angiogenic agent in the recurrent setting; prior use of bevacizumab in the upfront or upfront maintenance setting is allowed
• Patients may not have previously received a PARP-inhibitor
• Patient must have provided study specific informed consent prior to study entry
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or 2
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 10 g/dL
• Total bilirubin within =< 1.5 times the upper limit of normal (ULN) institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN; if intrahepatic liver metastases are present, AST and ALT must be =< 5 times institutional ULN
• Creatinine =< 1.5 x the institutional ULN
• Urine protein: creatinine ratio urine protein creatinine (UPC) of =< 1 OR less than or equal to 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart; UPC is the preferred test; patients with 2+ proteinuria on dipstick must also have a 24-hour urine collection demonstrating protein of =< 500 mg over 24 hours
• Toxicities of prior therapy (excepting alopecia) should be resolved to less than or equal to grade 1 as per CTCAE; patients with long-standing stable grade 2 neuropathy may be considered after discussion with the study chair.
• Adequately controlled blood pressure (systolic blood pressure [SBP] =< 140; diastolic blood pressure [DBP] =< 90 mmHg) on maximum of three antihypertensive medications; patients must have a BP of =< 140/90 mmHg taken in the clinic setting by a medical professional within 2 weeks prior to starting study; it is strongly recommended that patients who are on three antihypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on protocol; patients must be willing and able to check and record daily blood pressure readings; blood pressure cuffs will be provided to patients randomized to cediranib alone and the combination of olaparib and cediranib arms
• Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and thyroid-stimulating hormone (TSH) within normal limits
• Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib
• Cediranib has been shown to terminate fetal development in the rat, as expected for a process dependent on VEGF signaling; for this reason, women of child-bearing potential must have a negative pregnancy test prior to study entry; women of child-bearing potential must agree to use two reliable forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 weeks after cediranib discontinuation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Olaparib adversely affects embryofetal survival and development in the rat; for this reason, women of child-bearing potential must have a negative pregnancy test prior to study entry; women of child-bearing potential must agree to use must agree to use two reliable forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months after the last dose of olaparib; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of starting treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; patients may not have had hormonal therapy within 2 weeks prior to entering the study; patients receiving raloxifene for bone health as per Food and Drug Administration (FDA) indication may remain on raloxifene absent other drug interactions
• Any other investigational agents within the past 4 weeks
• Prior treatment affecting the VEGF/VEGFR pathway or the angiopoietin pathway in the recurrent setting, including but not limited to thalidomide, bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, nintedanib, and trebananib; bevacizumab used in the upfront setting in conjunction with chemotherapy and/or as maintenance to treat newly diagnosed disease will be allowed
• Prior use of PARP-inhibitors
• CA-125 only disease without Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurable or otherwise evaluable disease
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib
• Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs
• History of intra-abdominal abscess within the past 3 months
• History of gastrointestinal perforation; patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired or has healed, there has been no evidence of fistula for at least 6 months, and patient is deemed to be at low risk of recurrent fistula
• Dependency on IV hydration or total parenteral nutrition (TPN)
• Any concomitant or prior invasive malignancies with the following curatively treated exceptions:
• Treated limited stage basal cell or squamous cell carcinoma of the skin
• Carcinoma in situ of the breast or cervix
• Primary endometrial cancer meeting the following conditions: stage not greater than IA, grade 1 or 2, no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous/serous, clear cell, or other Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions
• Prior cancer treated with a curative intent with no evidence of recurrent disease 5 years following diagnosis and judged by the investigator to be at low risk of recurrence
• Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should not be included on this study, since neurologic dysfunction may confound the evaluation of neurologic and other adverse events; patients with treated brain metastases and resolution of any associated symptoms must demonstrate stable post-therapeutic imaging for at least 6 months following therapy prior to starting study drug
• Patients with any of the following:
• History of myocardial infarction within six months
• Unstable angina
• Resting electrocardiogram (ECG) with clinically significant abnormal findings
• New York Heart Association functional classification of III or IV
• If cardiac function assessment is clinically indicated or performed: left ventricular ejection fraction (LVEF) less than normal per institutional guidelines, or < 55%, if threshold for normal not otherwise specified by institutional guidelines
• Patients with the following risk factors should have a baseline cardiac function assessment:
• Prior treatment with anthracyclines
• Prior treatment with trastuzumab
• Prior central thoracic radiation therapy (RT), including RT to the heart
• History of myocardial infarction within 6 to 12 months (Patients with history of myocardial infarction within 6 months are excluded from the study)
• Prior history of impaired cardiac function
• History of stroke or transient ischemic attack within six months
• Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or aortic dissection)
• Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted
• Evidence suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
• No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUBCT)
• Patients may not use any complementary or alternative medicines including natural herbal products or folk remedies as they may interfere with the effectiveness of the study treatments
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other than atrial fibrillation with controlled ventricular rate), or psychiatric illness/social situations that would limit compliance with study requirements
• Known human immunodeficiency virus (HIV)-positive individuals are ineligible because of the potential for pharmacokinetic interactions with cediranib or olaparib; in addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible
• Strong inhibitors and inducers of UGT/PgP should be used with caution
• Pregnant women are excluded from this study because cediranib and olaparib are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with cediranib and olaparib, breastfeeding should be discontinued if the mother is treated with cediranib or olaparib; these potential risks may also apply to other agents used in this study

• Patient must consent for the appropriate surgery
• Patients with a histologic diagnosis of squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the cervix, stage IA1 (lymph-vascular space invasion [LVSI]+), IA2, and IB1 (tumor size [maximum visible or palpable]) =< 2 cm), any grade
• All patients must have undergone a cone biopsy or loop electrosurgical excision procedure (LEEP); depth of invasion must be =< 10 mm
• Patients must have no evidence of metastasis on positron emission tomography (PET) scan or magnetic resonance imaging (MRI) or computed tomography (CT) scan of the pelvis and chest imaging
• Patients who have met the pre-entry requirements
• Patients must have signed an approved informed consent and authorization permitting release of personal health information
• Patient must have Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
• Patients with stage IA1 disease who are LVSI negative
• Patients with stage IB1 with tumor size (maximum visible or palpable) > 2 cm
• Patients with >= stage IB2 disease
• Patients with clear cell or neuroendocrine cell types
• Patients with depth of invasion > 10 mm on first cone biopsy (or LEEP)
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

• Female ≥ 18 years
• Previously histologically proven diagnosis of a. Endometrial Cancer: recurrent or persistent endometrial carcinoma refractory to conventional therapy or established treatments with the following histologic epithelial cell types i. Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified, mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma b. Ovarian Cancer: recurrent or persistent ovarian or primary peritoneal cancer refractory to established treatments with the following histologic epithelial cell types i. Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified. c. Cervical cancer: squamous cell carcinoma of the cervix refractory to conventional therapy or established treatments with the following histologic epithelial cell types: i. Squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20mm when measured by conventional techniques, including palpation, plain x-ray, CT, and MRI or ≥ 10mm when measured by spiral CT.
• Life expectancy ≥ 3 months
• Able to take orally administered study medication
• Must sign approved informed consent and authorization permitting release of personal health information.
• Patient must have adequate: 1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm^3, equivalent to Common Toxicity Criteria (CTC) grade 1, platelets ≥ 100,000/mm^3 2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN), CTC grade 1. Note: If creatinine is > 1.5 x ULN, creatinine clearance must be > 50 mL/min. 3. Hepatic function: bilirubin ≤ 1.5 x ULN (CTC grade 1) or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 ×ULN. 4. Coagulation profile: PT such that international normalized ratio (INR) is ≤ 1.55 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times control. 5. ECOG performance ≤ 2
• Patient of child-bearing potential must agree to use contraceptive measures starting 1 week before the administration of the first dose of AL3818 until 4 weeks after discontinuing study drug and have a negative serum pregnancy test prior to study entry and cannot be lactating.
• Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.
• Patients with serious, non-healing wound, ulcer or bone fracture.
• Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• Patient with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases or history of cerebrovascular accident (CVA, stroke) transient ischemic attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment on this study. a. Patients with metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy.
• Patients with proteinuria: patients discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate < 1000 mg protein/24 hours to allow participation in the study.
• Patients with clinically significant cardiovascular disease including uncontrolled hypertension, myocardial infarction or unstable angina within 6 months prior to registration. New York Heart Association (NYHA) Grade II or greater congestive heart failure, Serious cardiac arrhythmia requiring medication, Grade II or greater peripheral vascular disease.
• Patients who are pregnant or nursing.
• Women of childbearing potential who are unable to use contraceptive measures during study therapy and for at least 3 months after completion of AL3818 therapy.
• Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• Hemoptysis within 3 months prior to first scheduled dose of AL3818.
• Patients with acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
• Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of AL3818 or a major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to first scheduled dose of AL3818.
• Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 who cannot be switched to other alternative medications .
• Known history of human immunodeficiency virus infection (HIV).
• Subjects with active bacterial infections (other than uncomplicated urinary tract infection) and/or receiving systemic antibiotics.
• Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy.
• History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months that in the opinion of the investigator may place the patient at risk of side effects on an anti-angiogenesis product.
• History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
• Intra-abdominal abscess within the last 3 months.
• Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken at least one hour apart, defined as systolic bloodpressure (BP) >160 mm Hg or diastolic BP > 90 mm Hg pressure.
• QTcF>470 msec on screening ECG.
• A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• The use of concomitant medications that prolong the QT/QTc interval. Baseline echocardiogram (within 2 months) with left ventricular ejection fraction (LVEF) < 50%.
• History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of AL3818.
• History of pancreatitis and/or renal disease or pancreatitis that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.
• Treatment with an investigational agent within the longest time frame of either 5 half- lives or 30 days of initiating study drug.
• Known recreational substance abuse.
• Known hypersensitivity to AL3818 or components of the formulation.

• Participant is a premenopausal female 18 to 49 years of age (inclusive) at the time of Screening.
• Participant has a documented surgical diagnosis (e.g., laparoscopy or laparotomy) of endometriosis established by visualization within 10 years prior to entry into Washout or Screening.
• Participant must agree to use only protocol specified rescue analgesics during the Screening and Treatment Periods for endometriosis-associated pain.
• Participant must have the following documented in the e-Diary during the last 35 days prior to Study Day 1: 1. At least 2 days of "moderate" or "severe" Dysmenorrhea (DYS) AND either 2. At least 2 days of "moderate" or "severe" Non-menstrual pelvic pain (NMPP) and an average NMPP score of at least 1.0, OR 3. At least 4 days of "moderate" or "severe" NMPP and an average NMPP score of at least 0.5.
• Participant has chronic pelvic pain that is not caused by endometriosis, that requires chronic analgesic therapy, which would interfere with the assessment of endometriosis-related pain.
• Participant is using any systemic corticosteroids for over 14 days within 3 months prior to Screening or is likely to require treatment with systemic corticosteroids during the course of the study. Over-the-counter and prescription topical, inhaled or intranasal corticosteroids are allowed.
• Participant has a history of any major depression or post-traumatic stress disorder (PTSD) within 2 years of the screening visit or other major psychiatric disorder at any time.
• Participant has a history of suicide attempts or answered "yes" to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) within the last 1 year at Screening or prior to randomization on Day 1.
• Participant has any history of osteoporosis or other metabolic bone disease or any condition that would interfere with obtaining adequate Dual Energy X-Ray Absorptiometry (DXA) measurements
• Screening DXA results of the lumbar spine (L1-L4), femoral neck or total hip Bone Mineral Density (BMD) corresponding to less than 2.0 or more standard deviations below normal.
• Participant has either: 1. a newly diagnosed, clinically significant medical condition that requires therapeutic intervention (e.g., new onset hypertension), that has not been stabilized 30 days prior to randomization on Day 1 OR 2. a clinically significant medical condition that is anticipated to require intervention during the course of study participation (e.g., anticipated major elective surgery) OR 3. an unstable medical condition that makes the subject an unsuitable candidate for the study in the opinion of the Investigator, (including, but not limited to, uncontrolled diabetes mellitus, uncontrolled hypertension, epilepsy requiring anti-epileptic medication, unstable angina, confirmed inflammatory bowel disease, hyperprolactinemia, clinically significant infection or injury).
• Participant has any conditions contraindicated with use of E2/NETA.

• Women of childbearing potential must not be known to be pregnant or lactating
• Patients must be scheduled for, or have intent to schedule, a screening mammogram
• Patients must be able to tolerate digital breast tomosynthesis and full-field digital mammographic imaging required by protocol, to be performed at an American College of Radiology Imaging Network (ACRIN)-qualified facility
• Patients must be willing and able to provide a written informed consent
• Patients must not have symptoms or signs of benign or malignant breast disease (eg, nipple discharge, breast lump) warranting a diagnostic rather than a screening mammogram, and/or other imaging studies (eg, sonogram); patients with breast pain are eligible as long as other criteria are met
• Patients must not have had a screening mammogram within the last 11 months prior to date of randomization
• Patients must not have previous personal history of breast cancer including ductal carcinoma in situ
• Patients must not have breast enhancements (e.g., implants or injections)
• ANNUAL SCREENING REGIMEN ELIGIBILITY CHECK
• To be eligible for inclusion in the annual screening regimen one of the following three conditions must be met in addition to the eligibility criteria above:
• Patients are pre-menopausal; OR
• Post-menopausal aged 45-69 with any of the following three risks factors:
• Dense breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
• Family history of breast cancer (first degree relative with breast cancer), or, positive genetic testing for any deleterious genes that indicate an increased risk for breast cancer, or
• Currently on hormone therapy; OR
• Post-menopausal ages 70-74 with either of the following two risk factors:
• Dense breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
• Currently on hormone therapy
• Postmenopausal women are defined as those with their last menstrual period more than 12 months prior to study entry; for the purpose of defining menopausal status for women who have had surgical cessation of their periods, women who no longer have menses due to hysterectomy and oophorectomy will be considered postmenopausal; women who no longer have menses due to hysterectomy without oophorectomy will be considered premenopausal until age 52 and postmenopausal thereafter
• All other postmenopausal women are eligible for inclusion in the biennial screening regimen
• For those women who cannot be assigned to annual or biennial screening at the time of study entry and randomization because they are postmenopausal, have no family history or known deleterious breast cancer mutation, are not on hormone therapy AND have not had a prior mammogram, breast density will be determined by the radiologist?s recording of it at the time of interpretation of the first study screening examination, either DM or TM; for those who are randomized to TM, radiologists will assign BI-RADS density through review of the DM or synthetic DM portion of the TM examination; such women cannot be part of the planned stratification by screening frequency and are expected to represent far less than 1% of the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) population
• Breast density will be determined by prior mammography reports, when available; all other risk factors used to determine patient eligibility for annual or biennial screening will be determined by subject self-report

• Written informed consent obtained from subject prior to any protocol related procedures
• Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.
• Body weight > 30 kg
• Must have an average life expectancy of 6 months
• Patient is able and willing to comply with protocol and study procedures for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up visits
• Histological diagnosis of recurrent or metastatic cervical, vaginal, or vulvar cancer or an unknown pelvic malignancy most likely to have arisen from these sites as determined clinically by the treating physicians (i.e. squamous cell carcinoma or adenocarcinoma that is high risk [HR] human papillomavirus positive [HPV]+, but not limited to this example)
• Metastatic disease in at least two distinct lesions (including the index lesion to be treated) with at least one site outside of the radiation field and evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for evaluation of response
• At least one index lesion to be treated measuring 1 cm amenable to hypofractionated radiation therapy
• Staging computed tomography (CT) scans done prior to enrollment
• Have had at least one line of prior platinum-based systemic chemotherapy once diagnosed with recurrence or metastatic disease if primary cervical cancer. If a patient has primary vulvar or vaginal cancer, there is not a requirement.
• May have received 1 prior biologic regimen (i.e. avastin) but not within 4 weeks of enrollment
• Full recovery from the acute effects of prior treatments, defined as effects having resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03 grade 0 or 1 with the exception of alopecia and certain laboratory values as outlined below; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab and tremelimumab may be included (e.g., hearing loss, neuropathy) upon approval of the principal investigator (PI)
• In patients with central nervous system (CNS) metastases, metastases must be asymptomatic at the time of day 1 of the study and meet the following criteria:
• Brain metastases should have been treated with either whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS)/gamma-knife, or surgical resection;
• At least 28 days without progression of CNS metastases as evidenced by magnetic resonance imaging (MRI) or CT from last day of treatment with radiation to the CNS metastases;
• At least 3 months from surgical resection (if had surgery) with stability on MRI brain at enrollment;
• At least 14 days since last dose of corticosteroids;
• Must not have leptomeningeal disease or cord compression
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN); for subjects with liver metastasis, ALT and AST =< 5 x ULN within 3 weeks prior to initial treatment
• Total bilirubin =< 1.5 x ULN except in patients with documented Gilbert's syndrome or liver metastasis, who must have a baseline total bilirubin 3.0 mg/dl within 3 weeks prior to initial treatment
• Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance within 3 weeks prior to initial treatment
• Negative screening test results for hepatitis B, hepatitis C, and human immunodeficiency virus
• Absolute neutrophil count (ANC) >= 1,500 cells/ul without growth factor support prior to initial treatment
• Hemoglobin >= 9 g/dL prior to initial treatment
• Platelet count >= 100,000 platelets/ul prior to initial treatment
• Subjects must either be of non-reproductive potential (ie, post-menopausal by history; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum or urine pregnancy test upon study entry; women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:
• Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
• Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
• Females of childbearing potential who are sexually active with a nonsterilized male partner must use highly effective method of contraception from the time of screening, and must agree to continue using such precautions for 180 days after the final dose of durvalumab and tremelimumab; cessation of contraception after this point should be discussed with a responsible physician; they must also refrain from egg cell donation for 180 days after the final dose of durvalumab and tremelimumab
• Note: A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly; the acceptable methods of contraception include barrier methods (male condom plus spermicide, copper T intrauterine device, levonorgesterel-releasing intrauterine system) or hormonal methods (implants, hormone shot or injection, combined pill, minipill, patch)
• Involvement in the planning and/or conduct of the study
• Previous enrollment in the present study
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy
• Prior treatment with an anti-CTLA-4, including tremelimumab PD-1 or PD-L1 inhibitor, including durvalumab
• Prior oncology vaccine therapy
• Prior radiation treatment to the index lesion to be treated
• Prior radiation which overlaps and precludes hypofractionated treatment to the index lesion
• Treatment with other investigational agent within 4 weeks to the first dose of tremelimumab or durvalumab
• Concomitant therapy with any of the following: interleukin-2 (IL-2), interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; all such therapies must have been discontinued > 4 weeks
• Any unresolved toxicity (CTCAE grade < 2) from previous anti-cancer therapy; (subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
• Any prior grade >= 3 immune-related adverse event (imAE) while receiving any previous immunotherapy agent, or any unresolved imAE > grade 1
• Treatment with a vascular endothelial growth factor (VEGF) inhibitor within the last 6 weeks
• Major surgical procedure (as defined by the treating physician) within 28 days prior to the first dose of durvalumab and tremelimumab or still recovering from prior surgery
• Active cardiac disease defined as unstable angina, uncontrolled hypertension, myocardial infarction in the last six months (unless successfully treated with coronary artery bypass grafting [CABG] or percutaneous transluminal coronary angioplasty [PTCA]), uncontrolled arrhythmia, or symptomatic congestive heart failure; > 3 heart-related hospitalizations in the past year
• Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiogram (ECGs) using Fridericia's correction
• Severe chronic obstructive pulmonary disease (COPD) requiring > 3 hospitalizations in the past year
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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 are exceptions to this criterion:
• Patients with vitiligo or alopecia;
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement;
• Any chronic skin condition that does not require systemic therapy;
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician;
• Patients with celiac disease controlled by diet alone
• Active or prior documented interstitial lung disease
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and tremelimumab with the exceptions of intranasal and inhaled corticosteroids, systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent, or steroids used transiently to control contrast agent allergies for radiographic studies
• History of allogeneic organ transplant
• History of hypersensitivity to durvalumab or tremelimumab or any CTLA4, PD1, or PDL-1 inhibitor
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies); patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
• History of prior bowel fistula, ulcerations, or perforations
• Evidence of progressive or symptomatic central nervous system (CNS) metastases or leptomeningeal disease
• Uncontrolled inter-current illness, including, but not limited to, ongoing or active infection requiring systemic treatment, current or history of prior radiation induced pneumonitis, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement or compromise the ability of the subject to give written informed consent
• Other active invasive malignancy; history of non-invasive malignancies such as ductal carcinoma in situ of the breast, non-melanomatous carcinoma of the skin, is allowed, as is history of other invasive malignancy that is in remission for >= 5 years after treatment with curative intent
• Any medical, psychological, or social condition that, in the opinion of the treating physician would interfere with evaluation of the investigational product or interpretation of subject safety or study results

Pertinent Inclusion criteria: 1. Informed consent prior to any study specific procedures. 2. Male or female ≥18 years of age. 3. Progressive cancer at the time of study entry. 4. Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations 2013. 5. Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting. 6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay. 7. At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1. 8. Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol). 9. ECOG PS 0-1 within 28 days of randomisation. 10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners). 13. Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16 weeks. Pertinent Exclusion criteria: 1. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment. 2. More than 2 prior lines of cytotoxic chemotherapy for metastatic disease (prior treatments with hormonal, non-hormonal, biologics or the combination of an aromatase inhibitor and everolimus are not counted as a prior line of therapy). 3. Previous randomisation in the present study. 4. Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor (unless less than 3 weeks duration and at least 12 months has elapsed between the last dose and randomization). 5. Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomisation. The minimum washout period for immunotherapy shall be 42 days. 6. Patients with second primary cancer (exceptions defined in the protocol). 7. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470 msec/female patients and >450 msec for male patients (as calculated per institutional standards) or congenital long QT syndrome. 8. Any of the following cardiac diseases currently or within the last 6 months: unstable angina pectoris, congestive heart failure ≥ Class 2 as defined by the New York Heart Association, acute myocardial infarction, conduction abnormality not controlled with pacemaker or medication (patients with a conduction abnormality controlled with pacemaker or medication at the time of screening are eligible), significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible). 9. Concomitant use of known strong or moderate cytochrome P (CYP) 3A inhibitors, strong or moderate CYP3A inducers, or sensitive CYP3A4 substrates or CYp3A4 substrates with a narrow therapeutic index. 10. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy. 11. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery. 12. Immunocompromised patients, eg, human immunodeficiency virus (HIV). 13. Patients with known active hepatitis (ie, hepatitis B or C). 14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection. 15. Patients with symptomatic uncontrolled brain metastases. 16. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 17. Patients with a known hypersensitivity to olaparib, adavosertib, AZD6738, or any of the excipients of the products. 18. Pregnant or breast feeding women.

• Signed and dated IRB/IEC-approved informed consent form (ICF) prior to study-specific screening procedures.
• Female patients aged ≥ 18 years old at time of consent.
• Histologic diagnosis of high grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma. Clear cell, mucinous and borderline histologic subtypes are excluded.
• Received at least one line of therapy with progression within 6 months after platinum-based therapy, persistent disease at the completion of primary platinum-therapy, or PD during platinum-based therapy. Patients with primary platinum resistance (progression after first-line chemotherapy) are considered eligible.
• Measurable or non-measurable disease by RECIST v1.1:
• Previously irradiated lesions are not allowed as measurable disease, unless there is documented evidence of progression in the lesions.
• To be eligible with non-measurable disease, patients must have evaluable disease with CA 125 at least twice the upper limit of reference range (of CA-125 ≥ 70 U/mL), along with radiographically evaluable disease by CT/MRI.
• Availability and consent to provide tumor tissue for GR immunohistochemistry (archival or recent biopsy).
• Up to 2 prior chemotherapeutic or myelosuppressive regimens for recurrent disease (not including maintenance therapy such as single-agent bevacizumab).
• Appropriate to treat with nab-paclitaxel, in the opinion of the Investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Adequate organ and bone marrow function meeting the following criteria at the Screening Visit:
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3.
• Platelet count ≥ 100,000/mm3.
• Hemoglobin ≥ 9 g/dL.
• AST or ALT ≤ 2.5 × upper limit of normal (ULN) (or ≤ 5 × ULN in the context of liver metastasis).
• Total bilirubin ≤ 1.5 × ULN.
• Serum creatinine ≤ 1 × ULN; creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Albumin ≥ 3 g/dL (≥ 30 g/L) .
• If patient has undergone surgery of the gastrointestinal or hepatobiliary tract, adequate absorption as evidenced by: albumin ≥ 3.0 g/dL, controlled pancreatic insufficiency (if present), and lack of malabsorption.
• Able to swallow and retain oral medication and does not have uncontrolled emesis.
• Able to comply with protocol requirements.
• Negative pregnancy test for patients of childbearing potential. Patients of childbearing potential must use appropriate precautions to avoid pregnancy, defined as of non-childbearing potential (ie, postmenopausal or permanently sterilized) or using highly effective contraception with low user-dependency, for at least 3 months after the last dose of study drug. A woman is postmenopausal if it is more than 12 months since her last menstruation, without an alternative medical cause. Accepted methods of permanent sterilization methods are hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy. Accepted methods of highly effective contraception with low user-dependency are:
• An IUD, provided that the subject has tolerated its use for at least 3 months before the first dose of study medication and undertakes not to have it removed for 1 month after the last dose.
• Abstinence from heterosexual intercourse, when it is in line with the subject's preferred and usual lifestyle. Periodic abstinence and withdrawal are NOT acceptable.
• Vasectomized partner provided that the partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success.
• Oral hormonal contraceptives are NOT permitted.
• Clinically relevant toxicity from prior systemic anticancer therapies or radiotherapy that in the opinion of the Investigator has not resolved to Grade 1 or less prior to randomization.
• Any major surgery within 4 weeks prior to randomization. If subject received major surgery including (curative or palliative surgery), they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Treatment with the following prior to randomization:
• Concurrent treatment with other anticancer therapy including other chemotherapy, immunotherapy, radiotherapy, chemo-embolization, targeted therapy, an investigational agent or the non-approved use of a drug or device within 28 days before the first dose of study drug.
• Hormonal anticancer therapies within 7 days of the first dose of study drug.
• Systemic, inhaled, or prescription strength topical corticosteroids within 21 days of the first dose of study drug. Short courses (≤ 5 days) for non-cancer-related reasons are allowed if clinically required (such as prophylaxis for CT).
• Received radiation to more than 25% of marrow-bearing areas.
• Toxicities of prior therapies (except alopecia) that have not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 ≤ Grade 1.
• Requirement for treatment with chronic or frequently used oral corticosteroids for medical conditions or illnesses (e.g., rheumatoid arthritis, immunosuppression after organ transplantation).
• History of severe hypersensitivity or severe reaction to either study drug.
• Peripheral neuropathy from any cause > Grade 1.
• Pregnant or lactating patients or patients expecting to conceive children within the projected duration of the trial, starting with screening visit through 90 days after the last dose of trial treatment.
• Human immunodeficiency virus or current chronic/active infection with hepatitis C virus or hepatitis B virus, including:
• Patients with chronic or active hepatitis B as diagnosed by serologic tests are excluded from the study. In equivocal cases, hepatitis B or C polymerase chain reaction may be performed and must be negative for enrollment.
• Patient has a clinically significant uncontrolled condition(s) or which in the opinion of the Investigator may confound the results of the trial or interfere with the patient's participation, including but not limited to:
• Unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction 6 months before study entry.
• Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or diastolic pressure > 100 mmHg despite optimal management). Patients will be considered eligible if hypertension is treated and controlled during Screening.
• Active infection that requires parenteral antibiotics.
• Bowel obstruction or gastric outlet obstruction.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Untreated parenchymal central nervous system metastases.
• Any other concurrent cancer or a history of another invasive malignancy within the last 3 years that has a likelihood of recurrence of > 30% within the next 5 years. Adequately treated non-melanoma skin cancers or non-muscle invasive urothelial cancer or other tumors curatively treated with no evidence of disease are permissible.
• Drugs with a narrow therapeutic ratio that are highly dependent on CYP3A for clearance should be avoided. Caution should be exercised when co-administering known inhibitors of CYP3A with relacorilant. Medicines/food known to strongly inhibit CYP3A should be avoided.
• Concurrent treatment on other investigational treatment studies for the treatment of ovarian, fallopian tube, or primary peritoneal cancer.
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

• Postmenopausal: no menses for >1 year
• Minimum age: 48 years
• Symptomatic apical and/or anterior vaginal wall prolapse, stage 2 or greater
• No estrogen replacement within the last month (may come off current treatment, i.e. wash out, to join the study)
• Medically fit for elective surgery
• Physically able to apply/insert the study drug
• Available for clinic follow-up for minimum 1yr
• Concurrent use of steroid creams for other indications (e.g. lichen sclerosis)
• BMI >35 kg/m2
• Recent history (within last month) of vaginal infection or vaginitis
• Contraindications to estrogen therapy (e.g. spontaneous DVT, stroke, breast or endometrial/ hormone-responsive cancer, genital bleeding of unknown cause)
• History of connective tissue disease
• Any oral or transdermal estrogen, SERM, or other medication impacting vaginal milieu
• History of vaginal irradiation
• Allergy to Premarin or its constituents
• Prior apical repair or use of mesh for prolapse repair
• Current tobacco use

• Pathologically proven primary cervical cancer I-IIA with squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma initially treated with a standard radical hysterectomy with pelvic lymphadenectomy
• Patients with the following characteristics (depth of stromal invasion and lymphovascular space involvement to be pathologically confirmed):
• Positive capillary-lymphovascular space involvement and one of the following:
• Deep third penetration
• Middle third penetration, clinical tumor >= 2 cm
• Superficial third penetration, clinical tumor >= 5 cm
• Negative capillary-lymphatic space involvement
• Middle or deep third penetration, clinical tumor >= 4 cm
• Absolute neutrophil count (ANC) >= 1,500/mcl
• Platelets >= 100,000/mcl
• Creatinine =< upper limit of normal (ULN) or calculated creatinine clearance >= 60 mL/min
• Bilirubin =< 1.5 x normal
• Alkaline phosphate =< 3 x normal
• Serum glutamic oxaloacetic transaminase (SGOT) =< 3 x normal
• Gynecologic Oncology Group (GOG) performance status 0, 1, 2
• Patients should not be randomized less than 3 weeks post-surgery but will not be acceptable for randomization more than 8 weeks post-surgery
• Patients who have met the pre-entry requirements
• Patients must have signed an approved informed consent and authorization permitting release of personal health information
• Patients with tumor in the parametria, pelvic lymph nodes or any other extra uterine site or with positive surgical margins
• Patients with septicemia or severe infection
• Patients with intestinal obstruction or gastrointestinal bleeding
• Patients with postoperative fistula
• Patients with cervix cancer who have received any previous radiation or chemotherapy
• Patients whose circumstances do not permit completion of the study or the required follow-up
• Patients with renal abnormalities requiring modification of radiation field (pelvic kidney, renal transplant, etc.)
• Patients with GOG performance status of 3 or 4
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

• Between 16 and 44 years of age inclusive
• Singleton pregnancy
• Intact membranes
• Between 28-0/7 weeks and 33-6/7 weeks' gestation inclusive
• Reported or documented uterine activity
• Cervical dilation between 2 cm and 4 cm inclusive
• Multifetal gestation
• Less than 28 weeks' gestation
• 34 or more weeks' gestation
• Ruptured membranes
• More than 4 cm dilated
• Previously received a course of corticosteroids for fetal lung maturation
• Oligohydramnios
• Fetal growth restriction
• Chorioamnionitis or temperature of at least 38.0 degrees Celsius
• Fetal death
• Preeclampsia
• Suspected placental abruption or placenta previa
• Lethal fetal malformation or amniotic fluid index at least 35
• Systolic BP < 90 mmHg or diastolic BP < 50 mmHg
• Baseline tachycardia (pulse >120 after 2 consecutive measurements 30 minutes apart)
• Chronic hypertension treated with antihypertensives in pregnancy
• Seizure disorder or HIV
• Maternal allergy to nifedipine
• Known maternal cardiac disease
• Women who have received progesterone therapy in the second or third trimester for prevention of preterm birth

• The patient must sign consent for study participation.
• The patient must be female and have a diagnosis of an invasive or non-invasive breast cancer that was treated surgically by a partial mastectomy.
• The patient must be deemed an appropriate candidate for breast conserving therapy (i.e. not pregnant, never had radiation to the treated breast, breast size would allow adequate cosmesis after volume loss from partial mastectomy).
• Patients with involved lymph nodes are candidates for the study.
• Surgical margins are negative for invasive (no tumor on ink) or non-invasive breast cancer (2 mm negative margin).
• The greatest dimension of the tumor is less than 4cm before surgery.
• Multifocal disease is allowed if it was removed by a single lumpectomy resection and the patient remained a candidate for breast conservation.
• Age 18 years and older.
• Women of childbearing potential (pre-menopausal defined as having a menstrual period within the past 1 year) must have a negative serum pregnancy test or complete a pregnancy waiver form per institutional policy.
• The surgical cavity is clearly visible on CT images. Of note, clips are not required but recommended.
• The patient must weigh less than 150Kg (330lb), which is the limit of the imaging couch.
• The patient must be less than 6'6" in height.
• The patient must feel comfortable in the prone position.
• Diagnosis of prior contralateral breast cancer is allowed.
• Diagnosis of synchronous bilateral cancers is allowed. In this case if bilateral boosts are required, a patient would not have both treatments on the same day.
• Oncoplastic reduction surgery is allowed if the lumpectomy cavity can be clearly visualized.
• Patients with proven multi-centric carcinoma (tumors in different quadrants of the breast or tumor separated by at least 4 cm).
• Prior radiation therapy to that breast or that hemi thorax.
• Unable to fit into the immobilization breast cup with an adequate seal.
• Male gender.
• Patient cannot comfortably be set up in the prone position (i.e. physical disability)
• Unable to fit into the breast immobilization device due to breast size or other anatomical reason.
• Mastectomy is the surgery performed.
• Patient has received prior radiotherapy to the involved breast.
• Tumor bed is less than 3 mm from the skin surface.
• Greater than 50% of the target volume is above the upper border of the table.
• Patients with skin involvement, regardless of tumor size.
• Patients with connective tissue disorders specifically systemic lupus erythematosis, scleroderma, or dermatomyositis.
• Patients with psychiatric or addictive disorders that would preclude obtaining informed consent.
• Patients who are pregnant or lactating due to potential exposure of the fetus to RT and unknown effects of RT to lactating females.
• Patients with breast implants/tissue expanders or flap reconstruction.

1. Histologically or cytologically confirmed recurrent locally advanced or metastatic breast cancer not amenable to treatment with curative intent, meeting all of the criteria for 1 of the following cohorts: A. Cohort 1 i. HR+ HER2- breast cancer harboring an FGFR2 gene amplification. HR+ HER2- breast cancer is defined per the local pathology report as estrogen receptor (ER) >1% and/or progesterone receptor (PR) >1%, HER2-negative per American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines, 2018. ii. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 iii. Has received 1-3 prior endocrine-containing therapies and up to 2 prior chemotherapy regimens for advanced/metastatic disease iv. Has received prior treatment with a CDK4/6 inhibitor or is ineligible for such i. treatment (per Investigator decision) ii. Has experienced disease progression/recurrence within 1 month following the completion of any endocrine therapy for advanced/metastatic breast cancer B. Cohort 2 i. TNBC harboring an FGFR2 gene amplification. TNBC is defined as negative for ER, PR and HER2. Negative for ER and PR includes the following: local pathology report classifies them as negative, Allred Score of 2 or below or <1% staining. HER2-negative per ASCO / CAP guidelines, 2018. ii. Measurable disease per RECIST 1.1 iii. Has received at least 1 prior chemotherapy or chemotherapy/immunotherapy iv. (PD-L1/PD-1 inhibitors) regimen for advanced/metastatic disease Has experienced disease progression/recurrence during or after the most recent prior chemotherapy for advanced/metastatic breast cancer C. Cohort 3 i. TNBC or HR+ HER2- breast cancer (defined as above) harboring an FGFR2 gene amplification ii. Non measurable, evaluable disease per RECIST 1.1. Patients with bone-only disease must have lytic or mixed lytic-blastic lesions iii. Other criteria for either HR+ HER2- breast cancer or TNBC should be met as described for Cohort 1 and 2, respectively D. Cohort 4 i. HR+ HER2- breast cancer (defined as above) harboring an FGFR1 high-level gene amplification ii. Measurable disease per RECIST 1.1 iii. Has received 1-2 prior endocrine-containing therapies and no more than 1 prior chemotherapy regimen for advanced/metastatic disease. Prior treatment with fulvestrant is not permitted. iv. Has received prior treatment with a CDK4/6 inhibitor or is ineligible for such i. treatment (per Investigator decision) ii. Pre/peri-menopausal patients must be on goserelin. Patients must have commenced treatment with goserelin or an alternative GnRH agonist at least 4 weeks prior to the first dose of fulvestrant. If patients have received an alternative GnRH agonist prior to study entry, they must switch to goserelin for the duration of the trial. Postmenopausal is defined as at least one of the following criteria: age ≥60 years; age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle-stimulating hormone level within the laboratory's reference range for postmenopausal females; or documented bilateral oophorectomy. iii. Has experienced disease progression/recurrence within 1 month following the completion of any endocrine therapy for advanced/metastatic breast cancer. 2. Archival or (preferably) fresh tumor tissue must be available for central laboratory confirmation of FGFR amplification. 3. The patient has adequate organ function as defined by the following criteria: 1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × the upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastases, AST and ALT ≤5 × ULN 2. Total bilirubin ≤1.5 × ULN or ≤3 × ULN in case of Gilbert's syndrome 3. Absolute neutrophil count (ANC) ≥1.0 × 109/L without hematopoietic growth factor support 4. Platelet count ≥75 × 109/L without transfusion support (that is, excluding measurements obtained within 3 days after transfusion of platelets) 5. Hemoglobin ≥9.0 g/dL without transfusion support (that is, excluding measurements within 7 days after transfusion of packed red blood cells or whole blood) 6. Serum phosphorus ≤ ULN 7. Creatinine clearance (calculated or measured value): ≥40 mL/min A patient must not meet any of the following exclusion criteria to be eligible for this study: 1. History and/or current evidence of any of the following disorders: 1. Non-tumor related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator 2. Ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the Investigator 3. Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator. 2. Corrected QT interval using Fridericia's formula (QTcF) >470 msec. Patients with an atrioventricular pacemaker or other condition (for example, right bundle branch block) that renders the QT measurement invalid are an exception and the criterion does not apply. 3. Treatment with any of the following within the specified time frame prior to the first dose of TAS-120: 1. Major surgery within 4 weeks (the surgical incision should be fully healed) 2. Radiotherapy for extended field within 4 weeks or limited field radiotherapy within 2 weeks 3. Any prior systemic therapy regardless of the stop date, but the patient must have recovered to eligibility levels from prior toxicity 4. Any investigational agent received within 30 days or 5 half-lives (whichever is shorter) 4. Prior treatment with an FGFR inhibitor 5. Cohort 4 only: Prior treatment with fulvestrant, or known hypersensitivity to fulvestrant. 6. A serious illness or medical condition(s) including but not limited to the following: 1. Known acute systemic infection 2. Myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within the previous 6 months 3. History or current evidence of serious uncontrolled ventricular arrhythmia 4. Chronic diarrhea diseases considered to be clinically significant in the opinion of the Investigator 5. Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death 6. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or TAS-120 administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study 7. Brain metastases that are untreated or clinically or radiologically unstable (that is, have been stable for <1 month) 8. History of another primary malignancy that is currently clinically significant or currently requires active intervention 9. Pregnant or lactating female

1. Nulliparous
•no previous pregnancy beyond 20 weeks 2. Singleton gestation. Twin gestation reduced to singleton, either spontaneously or therapeutically, is not eligible unless the reduction occurred before 14 weeks project gestational age. 3. Gestational age at randomization between 38 weeks 0 days and 38 weeks 6 days inclusive based on clinical information and evaluation of the earliest ultrasound. 1. Project gestational age at date of first ultrasound is > 20 weeks 6 days 2. Plan for induction of labor prior to 40 weeks 5 days 3. Plan for cesarean delivery or contraindication to labor 4. Breech presentation 5. Signs of labor (regular painful contractions with cervical change) 6. Fetal demise or known major fetal anomaly 7. Heparin or low-molecular weight heparin during the current pregnancy 8. Placenta previa, accreta, vasa previa 9. Active vaginal bleeding greater than bloody show 10. Ruptured membranes 11. Cerclage in current pregnancy 12. Known oligohydramnios, defined as AFI < 5 or MVP < 2 13. Fetal growth restriction, defined as EFW < 10th percentile 14. Known HIV positivity because of modified delivery plan 15. Major maternal medical illness associated with increased risk for adverse pregnancy outcome (for example, any diabetes mellitus, lupus, any hypertensive disorder, cardiac disease, renal insufficiency) 16. Refusal of blood products 17. Participation in another interventional study that influences management of labor at delivery or perinatal morbidity or mortality 18. Delivery planned elsewhere at a non-Network site

The participants must meet the following criteria:
• Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
• Women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
• Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20 mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making irregular/absent periods difficult to assess as related to the menopausal transition).
• Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
• Greene Climacteric Scale total scores > 20
• Greene Climacteric Scale sub-score for vasomotor symptoms >3
• 5 or more bothersome hot flashes per week (self-reported)
• Women meeting DSM-5 criteria for current major depressive disorder (assessed by the SCID)
• Baseline HRSD score of ≥ 18
• Subject agrees to abstain from disallowed medications for the duration of the trial The participants must not meet any of the following criteria:
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
• Psychiatric disorder other than MDD that is acute and the primary focus of symptom burden or treatment.
• History of bipolar disorder or psychotic disorder
• Current substance use disorder
• Positive baseline urine drug screen of an illicit substance with the exception of a medication used with a prescription such as an opioid pain medication
• Current eating disorder
• Treatment resistant depression (failure of 2 adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials are defined as within the US FDA approved dosage for the medication and used for at least 6 weeks, with failure described by the patient as <50% improvement based on her subjective experience). )
• High risk for suicidal acts including active suicidal ideation with plan and intent or > 2 suicide attempts in lifetime or any attempt in the past 6 months
• Women who have used psychoactive or centrally acting medications within 2 weeks prior to study screening
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpiderm, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed), and antidepressants within 2 weeks of the baseline visit and randomization.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), natural menopause supplements, episodic sleep medications (chronic, regular, stable-dose benzodiazepines allowed), antidepressants, phytoestrogens, soy-based medications, steroids within 4 weeks of randomization
• Use of any disallowed medications (specified in the Excluded Concomitant Medication section below)
• Women who have received a gonadal hormonal intervention within 1 month prior to study entry (stable thyroid medications are allowed).
• Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period (IUDs, condoms, abstinence are acceptable forms of contraception in this study; due to the possible interactions with the study medication, oral contraceptive pills will be prohibited)
• Uncontrolled hypertension (>160/95mmHg)
• Active Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder
• Any severe, life threatening or unstable medical condition that, based on clinician-judgment, would make participation in the study unsafe or inappropriate
• Personal or first- degree family history of known hormone sensitive tumors
• History of allergic reaction or side effects with prior pregnenolone use
• Clinically significant laboratory, physical examination
• Concurrent enrollment in another clinical trial Exclusion of Concomitant Medications:
• Selective estrogen-receptor modulators (SERMs)
• Hormone replacement therapy
• Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
• Natural menopause or antidepressant supplements
• Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed)
• Antidepressants used at indicated, therapeutic, FDA-approved doses (Note: sub-therapeutic dosages of antidepressants used for other indications will be permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin).
• Phytoestrogens
• Soy-based medications or supplements

• Age 18-50 years
• Parturient in active labor and desires labor epidural for pain relief.
• American Society of Anesthesiologists (ASA) Class I, 2 and 3 parturients, which include normal parturients
• Parturients with morbidities (including obesity) that are not life-threatening,
• Parturient BMI ≥ 25
• History of scoliosis or back surgery
• Patient refusal
• Patient with elevated intracranial pressure
• Any patient with a contraindication for placement of epidural anesthesia, including infection at needle insertion site, or coagulopathy.
• ASA Class 4

• Planning to undergo or have undergone* RF ablation (Acessa) or myomectomy (laparoscopic or abdominal) for treatment of uterine fibroids.
• Able to give informed consent
• Speak English or Spanish
• Women enrolled at contracted clinical sites must enroll prior to their RF ablation treatment
• <21 years of age
• Plan to undergo hysteroscopic myomectomy

• Age ≥ 35 years
• Able to provide informed consent
• BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with metabolic syndrome
• Metabolic syndrome is defined as at least three of the following:3 1. waist circumference > 102 cm (40 in) in men and 88 cm (35 in) in women 2. triglycerides > 150 mg/dL or on treatment for hypertriglyceridemia 3. HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women 4. blood pressure > 130/85 mmHg or on treatment for hypertension 5. fasting glucose > 100 mg/dL
• Treatment with GLP-1 receptor agonists (including liraglutide, exenatide or others as they become available), DPP-4 inhibitors or insulin within the last 3 months.
• Receipt of any anti-obesity drug or supplement within 1 month prior to screening for this trial.
• Self-reported or clinically documented history of significant fluctuations (>5% change) in weight within 3 months prior to screening for this trial.
• History of diabetes mellitus (type 1 or 2) or on treatment with anti-diabetes medication.
• History of chronic pancreatitis or idiopathic acute pancreatitis (current or prior history).
• History of gallbladder disease (cholelithiasis or cholecystitis).
• Chronic kidney disease stage III or greater (eGFR<60 mL/min).
• Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome).
• Current or history of treatment with medications that may cause significant weight gain, within 1 month prior to screening for this trial, including systemic corticosteroids (except for a short course of treatment, i.e., 7- 10 days), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g., imipramine, amitryptiline, mirtazapine, paroxetine, phenelzine, clorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium).
• Diet attempts using herbal supplements or over-the-counter medications within 1 month prior to screening for this trial.
• Current participation in an organized weight reduction program or within the last 1 month prior to screening for this trial.
• Participation in a clinical trial within the last 3 months prior to screening for this trial.
• Familial or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma.
• Personal history of non-familial medullary thyroid carcinoma.
• History of Major Depressive Disorder within the last 2 years.
• History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder.
• Any lifetime history of a suicide attempt.
• A history of any suicidal behavior in the last month prior to randomization.
• Surgery scheduled for the trial duration period, except for minor surgical procedures, at the discretion of the Investigator.
• Known or suspected hypersensitivity to trial product(s) or related product(s).
• Known or suspected abuse of alcohol or narcotics.
• Language barrier, mental incapacity, unwillingness or inability to understand.
• Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods. These include abstinence and the following methods: diaphragm with spermacide, condom with spermacide (by male partner), intrauterine device, sponge, spermacide, Norplant®, Depo-Provera® or oral contraceptives.

1. Patient has a dysfunctional, non-compliant RVOT conduit. 2. The patient/patient's legally authorized representative has been informed of the nature of the study, agrees to its provisions and has provided written informed consent. 1. Inability to tolerate an anticoagulation/antiplatelet regimen 2. Active bacterial endocarditis

•Male or female, age greater than or equal to 45 years at the time of signing informed consent
•Body mass index (BMI) greater than or equal to 27 kg/m^2
•Have established cardiovascular (CV) disease as evidenced by at least one of the following: prior myocardial infarction; prior stroke (ischemic or haemorrhagic stroke); or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) less than 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Exclusion Criteria:
•Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
•HbA1c greater than or equal to 48 mmol/mol (6.5 %) as measured by the central laboratory at screening
•History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)

• Participants with clinical diagnosis of Polycystic Ovary Syndrome (PCOS)
• Participants with a Body Mass Index (BMI) of 18.5 to 38kg/m2 at time of Screening
• Participants with newly diagnosed medical condition requiring intervention that has not been stabilized at least 30 days prior to Baseline
• Participants with a significant medical condition that may require intervention during the course of study participation (such as anticipated major elective surgery)
• Participants with an unstable medical condition (including, but not limited to, uncontrolled hypertension, epilepsy requiring anti-epileptic medicine, unstable angina, confirmed inflammatory bowel disease)
• Participants with surgical history of hysterectomy, unilateral or bilateral oophorectomy, bilateral tubal ligation, bilateral tubal occlusion, or bilateral salpingectomy

• Stage 2 to 4 prolapse
• Prolapse of the vaginal apex or cervix to at least half way into the vaginal canal (POPQ Point C > -TVL/2)
• Vaginal bulge symptoms as indicated by an affirmative response to either questions on the PFDI
• Vaginal surgery for prolapse is planned, including a vaginal apical suspension procedure.
• Stress incontinence symptoms as indicated by an affirmative response to the PFDI Stress incontinence subscale
• Documentation of transurethral stress leakage on an office stress test or urodynamics with or without prolapse reduction within the previous 12 months
• A TVT is planned to treat stress urinary incontinence.
• A PMT visit can be performed at least 2 weeks and not more than 4 weeks before surgery.
• Available for 24-months of follow-up.
• Able to complete study assessments, per clinician judgment
• Able and willing to provide written informed consent
• Contraindication to SSLF, ULS, or TVT in the opinion of the treating surgeon.
• History of previous surgery that included a SSLF or ULS. (Previous vaginal vault suspensions using other techniques or in which the previous technique is unknown are eligible.)
• Pelvic pain or dyspareunia due to levator ani spasm that would preclude a PMT program.
• History of previous synthetic sling procedure for stress incontinence.
• Previous adverse reaction to synthetic mesh.
• Urethral diverticulum, current or previous (i.e., repaired)
• History of femoral to femoral bypass.
• Current cytotoxic chemotherapy or current or history of pelvic radiation therapy.
• History of two inpatient hospitalizations for medical comorbidities in the previous 12 months.
• Subject wishes to retain her uterus. [Both ULS and SLS include removal of the uterus, if not previously removed]