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Testing the Combination of Olaparib and Durvalumab, Cediranib and Durvalumab, Olaparib and Capivasertib, and Cediranib alone in Recurrent or Refractory Endometrial Cancer following the Earlier Phase of the Study That Tested Olaparib and Cediranib in Comparison to Cediranib Alone, and Olaparib Alone

Status
Active
Cancer Type
Uterine Cancer
Trial Phase
Phase II
Eligibility
18 Years and older, Female
Study Type
Treatment
NCT ID
NCT03660826
Protocol IDs
NRG-GY012 (primary)
NRG-GY012
NCI-2017-01672
Study Sponsor
NRG Oncology

Summary

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.

Objectives

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)

EXPLORTORY 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 receive cediranib maleate orally (PO) once daily (QD). Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM II (ENROLLMENT COMPLETE): Patients receive olaparib PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.

ARM III (ENROLLMENT COMPLETE): Patients receive olaparib PO BID and cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.

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.

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.

ARM VI: Patients receive cediranib maleate PO BID on days 1-28 and durvalumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.

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

Eligibility

  1. 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 histology is excluded
  2. Patients must have evaluable 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
  3. Patients must have signed an approved informed consent and authorization permitting release of personal health information
  4. 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
  5. 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
  6. 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
  7. Bevacizumab, or one course of single-agent immune-checkpoint therapy, excluding durvalumab (MEDI4736), is permitted prior to enrollment on this trial
  8. Body weight > 30 kg
  9. Age >= 18
  10. 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
  11. 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
  12. Hemoglobin >= 10 mg/dL with no blood transfusion in the past 28 days (within 28 days prior to administration of study drug)
  13. Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study drug)
  14. Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to administration of study drug)
  15. 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)
  16. Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days prior to administration of study drug)
  17. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (within 28 days prior to administration of study drug)
  18. Urine protein: creatinine (UPC) < 1 or < 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also have UPC < 0.5 on 2 consecutive samples (within 28 days prior to administration of study drug)
  19. Patients must be able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption of cediranib, olaparib, or AZD5363 (capivasertib)
  20. 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
  21. The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
  22. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
  23. 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)
  24. Patients must have a life expectancy of greater than 16 weeks
  25. 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
  26. 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 <>. [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

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