This phase II trial studies the effects of the combination of olaparib and durvalumab, cediranib and durvalumab, olaparib and capivasertib, and cediranib alone in treating patients with endometrial cancer that has come back (recurrent) or does not respond to treatment (refractory). Olaparib, cediranib, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Testing the combinations may lower the chance of endometrial cancer growing or spreading compared to usual care.

PRIMARY OBJECTIVES:

I. To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms that may be added by subsequent amendment) versus single agent cediranib as measured by progression free survival (PFS), in patients with recurrent, persistent or metastatic endometrial cancer.

II. To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and durvalumab (MEDI4736) versus single agent cediranib as measured by progression free survival (PFS), in patients with recurrent, persistent or metastatic endometrial cancer.

SECONDARY OBJECTIVES:

I. To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms that may be added by subsequent amendment) versus single-agent cediranib as measured by overall survival (OS) in patients with recurrent, persistent or metastatic endometrial cancer.

II. To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and durvalumab (MEDI4736) versus single agent cediranib as measured by overall survival (OS), in patients with recurrent, persistent or metastatic endometrial cancer.

III. To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment versus single-agent cediranib as measured by response rate in patients with recurrent, persistent or metastatic endometrial cancer.

IV. To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and durvalumab (MEDI4736) versus single agent cediranib as measured by response rate in patients with recurrent, persistent or metastatic endometrial cancer.

V. To assess the safety and tolerability of single-agent cediranib, single-agent olaparib, and the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment).

VI. To assess the safety and tolerability of the combination of olaparib and AZD5363 (capivasertib), and the combination of olaparib and durvalumab (MEDI4736), and the combination of cediranib and durvalumab (MEDI4736).

VII. To assess if mutations in deoxyribonucleic acid (DNA) homologous repair genes (assayed prior to all treatment and prior to the study treatment) are predictive of response to olaparib alone or in combination with cediranib. (Integrated Biomarker) VIII. To assess if markers of angiogenesis in serial plasma samples are associated with response to cediranib alone or in combination with olaparib. (Integrated Biomarker)

EXPLORATORY OBJECTIVE:

I. To compare the efficacy of the combination of olaparib and cediranib versus single agent olaparib as measured by PFS, response rate and OS, if and only if the combination is superior to the single-agent cediranib arm.

OUTLINE: Patients are randomized to 1 of 6 arms.

ARM I: Patients in reference group 1 receive cediranib maleate orally (PO) once daily (QD). Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, computed tomography (CT), echocardiography (Echo) or multigated acquisition scan (MUGA) on study.

ARM II: Patients receive olaparib PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

ARM III: Patients receive olaparib PO BID and cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

ARM IV: Patients receive olaparib PO BID on days 1-28 and capivasertib PO BID on days 1-4 each week. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

ARM V: Patients receive olaparib PO BID on days 1-28 and durvalumab intravenously (IV) on day 1. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

ARM VI: Patients receive cediranib maleate PO QD on days 1-5 each week and durvalumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

ARM VII: Patients in reference group 1 receive cediranib maleate PO QD during 08/16/2021 - 06/28/2023). Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Inclusion Criteria:

• Patients must have recurrent or persistent endometrial carcinoma, which is refractory to curative therapy or established treatments; histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.); NOTE: clear cell and carcinosarcoma histology is excluded.

• Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or non-measurable (detectable) disease

  • Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or MRI; patients with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST version 1.1; tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy

  • Non-measurable (detectable) disease in a patient is defined in this protocol as one who does not have measurable disease but has at least one of the following conditions:

    • Ascites and/or pleural effusion attributed to tumor;
    • Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions.

• Patients must have signed an approved informed consent and authorization permitting release of personal health information.

• Patients must have had one prior chemotherapeutic regimen for management of endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy; chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen.

• Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease according to the following definition: cytotoxic regimens include any agent that targets the genetic and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to the bone marrow and/or gastrointestinal mucosa; Note: patients on this non-cytotoxic study are allowed to receive one additional cytotoxic chemotherapy regimen for management of recurrent or persistent disease, as defined above; however, patients are encouraged to enroll on second-line non-cytotoxic studies prior to receiving additional cytotoxic therapy.

• Patients may have received non cytotoxic therapy including immunotherapy (1 prior line in either upfront or recurrent setting) but excluding cediranib, olaparib, AZD5363 (capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and pembrolizumab for the management of recurrent or persistent disease; prior hormonal therapy is allowed; hormonal therapy for grade 1 endometrial cancers with low volume or indolent disease is encouraged.

• Bevacizumab, or one course of single-agent immune-checkpoint therapy, excluding durvalumab (MEDI4736), is permitted prior to enrollment on this trial.

• Body weight > 30 kg.

• Age >= 18.

• The trial is open to females only (including women with an intact uterus with uterine cancer); fertile females of childbearing potential need to agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, and have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment.

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2 (Karnofsky >= 60%) within 7 days prior to registration; patients should have no deterioration over the previous two weeks.

• Hemoglobin >= 10 mg/dL with no blood transfusion in the past 28 days (within 28 days prior to administration of study drug).

• Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study drug).

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to administration of study drug).

• Patients must have creatinine clearance estimated of >= 51 mL/min using the Cockcroft Gault equation or based on a 24-hour urine test (within 28 days prior to administration of study drug).

• Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days prior to administration of study drug).

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (within 28 days prior to administration of study drug).

• Urinalysis (dipstick) =< 1+ proteinuria OR urine protein creatinine ratio (UPCR) < 1 (within 28 days prior to administration of study drug).

• Patients must be able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption of cediranib, olaparib, or AZD5363 (capivasertib).

• Patients must have adequately controlled blood pressure (BP), with a BP no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; 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; patients with hypertension may be managed with up to a maximum of three antihypertensive medications; it is strongly recommended that patients who are on three antihypertensive medications be followed by a cardiologist or blood pressure specialist for management of blood pressure while on protocol.

  • Note: Patients must be willing and able to check and record daily blood pressure readings.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Adequately controlled thyroid function, with no symptoms of thyroid dysfunction.

• Postmenopausal or evidence of non-childbearing status for women of childbearing potential as confirmed by a negative urine or serum pregnancy test within 7 days prior to start of investigational products (IPs); postmenopausal is defined as:

  • Age >= 60 years, or

  • Age < 60 with any one or more of the conditions below:

    • Amenorrheic for >= 1 year in the absence of chemotherapy and/or hormonal treatments,
    • Luteinizing hormone and/or follicle stimulating hormone and/or estradiol levels in the post-menopausal range
    • 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).

• Patients must have a life expectancy of greater than 16 weeks.

• Patients with a previous diagnosis of immune or inflammatory colitis or chronic diarrhea > 1 month without immune or inflammatory colitis are eligible with adequately controlled colitis (no diarrhea greater than grade 1 for at least 28 days) and in the absence of symptoms related to colonic dysfunction; patients who required steroids for prior immune related colitis are not eligible.

• Females of child-bearing potential should use two forms of highly reliable methods of contraception from the time of screening until 4 weeks after discontinuing study treatment.

  • Acceptable methods of contraception include:

    • Established use of oral, injected or implanted hormonal methods of contraception.
    • Placement of an intrauterine device or intrauterine system.
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
    • Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
    • True abstinence (i.e., not engaging in sexual activity for the total duration of study treatment and the treatment washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control).
    • Bilateral tubal occlusion or salpingectomy

  • Acceptable non-hormonal birth control methods include:

    • Total/True abstinence: When the patient refrains from any form of sexual intercourse and this is in line with their usual and/or preferred lifestyle; this must continue for the total duration of the trial and for at least 1 month after the last dose of study drug <<for 3 months after last dose for male patients>>. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, or declaration of abstinence solely for the duration of a trial) and withdrawal are not acceptable methods of contraception]
    • Vasectomised sexual partner PLUS male condom. With participant assurance that partner received post-vasectomy confirmation of azoospermia.
    • Tubal occlusion PLUS male condom
    • Intrauterine device (IUD) PLUS male condom. Provided coils are copper-banded.

  • Acceptable hormonal methods:

    • Normal and low dose combined oral pills PLUS male condom.
    • Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly efficacious progesterone-based pill.
    • Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom.
    • Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom.
    • Norelgestromin/EE transdermal system PLUS male condom
    • Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena) PLUS male condom.
    • Intravaginal device (e.g., EE and etonogestrel) PLUS male condom.

Exclusion Criteria:

• Prior enrollment into a clinical trial including cediranib or olaparib; Note: prior bevacizumab is not an exclusion criterion.

• Prior enrollment into a clinical trial including cediranib, olaparib, AZD5363 (capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and pembrolizumab. Note: Prior bevacizumab or single-agent immune checkpoint blockade, excluding durvalumab (MEDI4736), is not an exclusion criterion.

• Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within 4 weeks.

• More than one prior line of treatment with immune checkpoint blockade therapy.

• Current signs/symptoms of bowel obstruction and/or signs/symptoms of bowel obstruction within the preceding 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.

• Uncontrolled intercurrent illness including, but not limited to known ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or psychiatric illness/social situations that would limit compliance with study requirements.

• Concomitant use of known strong cytochrome (CYP) 3A 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 period prior to starting study treatments is 2 weeks for strong inhibitors, and at least 1 week for moderate inhibitors.

• Concomitant use of potent inhibitors or inducers of CYP3A4 within 2 weeks before the start of study treatment (3 weeks for St John's wort), or sensitive substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week before the start of study treatment. Concomitant use of drugs known to prolong the QT interval within 5 half-lives of the first dose of study treatment.

• 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; for women of childbearing capacity a negative pregnancy test is required.

• Known human immunodeficiency virus (HIV)-positive individuals are ineligible because of the potential for pharmacokinetic interactions between many anti-HIV drugs and cediranib, olaparib, and/or AZD5363 (capivasertib); in addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy.

• Known active hepatitis B or hepatitis C infection on antiviral treatment.

• Prior history of stroke or transient ischemic attack within the last 6 months.

• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per institutional guidelines, or < 55%, if threshold for normal not otherwise specified by institutional guidelines, for patients with the following risk factors:

  • Prior treatment with anthracyclines
  • Prior treatment with trastuzumab
  • Prior central thoracic radiation therapy (RT), including exposure of heart to therapeutic doses of ionizing RT
  • History of myocardial infarction within 6-12 months prior to start of IPs
  • Prior history of other significant impaired cardiac function.

• Patients with any of the following:

  • History of myocardial infarction within 6 months prior to starting treatment
  • Unstable angina
  • Resting electrocardiogram (ECG) with clinically significant abnormal findings or with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • New York Heart Association functional classification of III or IV.

• Prior history of hypertensive crisis or hypertensive encephalopathy.

• Major surgical procedure within 4 weeks prior to starting treatment; patients must have recovered from any effects of any major surgery and surgical wound should have healed prior to starting treatment.

• History of intra-abdominal abscess within 3 months prior to starting treatment.

• 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.

• No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUBCT).

• Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable).

• Patients with myelodysplastic syndrome (MDS)/treatment-related acute myeloid leukemia (t-AML) or with features suggestive of MDS/AML.

• Central nervous system metastases:

  • Symptomatic uncontrolled brain metastases requiring corticosteroid treatment; history of spinal cord compression unless after definitive treatment the patient has clinically stable disease (SD) for at least 28 days prior to starting IPs; in the absence of these features and in an asymptomatic patient a scan to confirm the absence of brain metastases is not required.

• Other malignancy within the last 5 years except for:

  • Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial carcinoma
  • Curatively treated other solid tumors including lymphomas (without bone marrow involvement) with no evidence of disease for >= 5 years prior to start of IPs.

• Persisting >= grade 2 Common Terminology Criteria for Adverse Events (CTCAE) toxicity (except alopecia and grade 2 peripheral neuropathy) from previous anti-cancer treatment(s).

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib, olaparib, AZD5363 (capivasertib), or durvalumab (MEDI4736).

• Pneumonitis or moderate-severe pre-existing pulmonary disease.

• Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of enrollment.

  • Premedication with steroids for CT scan contrast is allowed.
  • Inhaled or topical corticosteroids are allowed.
  • The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
  • The use of physiologic doses of corticosteroids may be approved after consultation with the study chair.

• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. This includes, but is not limited to, patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.

• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.

• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice).