Olaparib and Cediranib Maleate in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer

• ClinicalTrials.gov Identifier: NCT03660826
• Recruitment Status: Suspended
• First Posted: September 7, 2018
• Last Update Posted: January 6, 2021
• Sponsor: National Cancer Institute (NCI)
• Collaborator: NRG Oncology
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: September 6, 2018
• First Posted Date: September 7, 2018
• Last Update Posted Date: January 6, 2021
• Actual Study Start Date: September 4, 2018
• Estimated Primary Completion Date: September 4, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 9, 2018)

Progression-free survival [ Time Frame: From the date of study enrollment to the investigator-determined date of progression, or death due to any cause, whichever occurs first, assessed up to 5 years ]

Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Will be tested using pairwise log-rank tests stratified by the factors.

Original Primary Outcome Measures (submitted: September 6, 2018)

Progression-free survival [ Time Frame: Time from the date of study enrollment to the investigator-determined date of progression, or death due to any cause, whichever occurs first, assessed up to 5 years ]

Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Will be tested using pairwise log-rank tests stratified by the factors.

Current Secondary Outcome Measures (submitted: November 9, 2018)

• Overall survival [ Time Frame: From the date of study enrollment to the date of death regardless of the cause, assessed up to 5 years ]
  Will be tested using pairwise log-rank tests stratified by the factors.
• Objective tumor response [ Time Frame: Up to 5 years ]
  Will be assessed by RECIST version 1.1. Will be tested using pairwise Cochran-Mantel-Haenszel tests stratified by the factors.

Original Secondary Outcome Measures (submitted: September 6, 2018)

• Overall survival [ Time Frame: Time from the date of study enrollment to the date of death regardless of the cause, assessed up to 5 years ]
  Will be tested using pairwise log-rank tests stratified by the factors.
• Objective tumor response [ Time Frame: Up to 5 years ]
  Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Will be tested using pairwise Cochran-Mantel-Haenszel tests stratified by the factors.

Current Other Pre-specified Outcome Measures (submitted: November 9, 2018)

• Incidence of adverse events [ Time Frame: Up to 5 years ]
  Will be assessed by Common Terminology Criteria for Adverse Events version 5.0.
• Mutations in deoxyribonucleic acid (DNA) homologous repair genes [ Time Frame: Up to 5 years ]
  Will be assessed.
• Angiogenesis markers [ Time Frame: Up to 5 years ]
  Will be determined by immunohistochemistry (IHC) including VEGFR1, VEGFR2 and microvessel density using CD31, as well as serum enzyme-linked immunosorbent assay (ELISA) for VEGFA
• Loss of function of ARID1A [ Time Frame: Up to 5 years ]
  Will be assessed by immunohistochemistry (IHC) and mutational profiles.
• Phosphatase and tensin homolog (PTEN) loss [ Time Frame: Up to 5 years ]
  Will be assessed by IHC.
• Loss of DNA mismatch repair protein [ Time Frame: Up to 5 years ]
  Will be assessed by IHC. If results are equivocal microsatellite instability (MSI) may be performed.
• TP53 mutation status [ Time Frame: Up to 5 years ]
  Will be assessed by IHC.
• P53 expression [ Time Frame: Up to 5 years ]
  Will be assessed by IHC.
• Surrogate markers for the TCGA molecular subgroups [ Time Frame: Up to 5 years ]
  Will assess p53 IHC, MSI and mutational status of the exonuclease domain of polymerase-epsilon (POLE).

Original Other Pre-specified Outcome Measures (submitted: September 6, 2018)

• Incidence of adverse events [ Time Frame: Up to 5 years ]
  Will be assessed by Common Terminology Criteria for Adverse Events version 4.0.
• Loss of function of ARID1A [ Time Frame: Up to 5 years ]
  Will be assessed by immunohistochemistry (IHC) and mutational profiles.
• Mutations in DNA homologous repair genes [ Time Frame: Up to 5 years ]
  Will be assessed.
• Phosphatase and tensin homolog (PTEN) loss [ Time Frame: Up to 5 years ]
  Will be assessed by IHC.
• Loss of DNA mismatch repair protein [ Time Frame: Up to 5 years ]
  Will be assessed by IHC. If results are equivocal microsatellite instability (MSI) may be performed.
• TP53 mutation status [ Time Frame: Up to 5 years ]
  Will be assessed by IHC.
• P53 expression [ Time Frame: Up to 5 years ]
  Will be assessed by IHC.
• Angiogenesis markers [ Time Frame: Up to 5 years ]
  Will be determined by IHC including VEGFA, VEGF R1, VEGFR2 and microvessel density using CD31.
• Mutations in WEE1-related genes [ Time Frame: Up to 5 years ]
  Will assess KRAS, MYC, cyclin E, CDKN2A, cyclin D3 in addition to p53 HRD genes.
• Surrogate markers for the TCGA molecular subgroups [ Time Frame: Up to 5 years ]
  Will assess p53 IHC, MSI and mutational status of the exonuclease domain of polymerase-epsilon (POLE).

Descriptive Information

• Brief Title: Olaparib and Cediranib Maleate in Treating Patients With Recurrent, Refractory, or Metastatic Endometrial Cancer
• Official Title: A Randomized Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, and the Combination of Cediranib/Olaparib in Women With Recurrent, Persistent or Metastatic Endometrial Cancer
• Brief Summary: This phase II trial studies how well olaparib and cediranib maleate work in treating patients with endometrial cancer that has come back (recurrent), does not respond to treatment (refractory), or has spread to other places in the body (metastatic). Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

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.

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 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.

III. 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).

IV. 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) V. 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 OBJECTIVES:

I. To compare the efficacy of the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment) 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.

II. To assess if phosphatase and tensin homolog (PTEN) loss as assessed by immunohistochemistry (IHC) is predictive of response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) III. To assess if loss of function of ARID1A assessed by immunohistochemistry (IHC) and mutational profile is predictive of response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) IV. To assess if TP53 mutation status and p53 expression as assessed by IHC is associated with response to olaparib or in combination with cediranib. (Exploratory Biomarker) V. To assess if markers of angiogenesis in tissue are associated with response to cediranib alone or in combination with olaparib. (Exploratory Biomarker) VI. To assess if microsatellite instability (MSI) as assessed by loss of DNA mismatch repair (MMR) proteins is associated with response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) VII. To assess if surrogate markers for the TCGA molecular subgroups p53 IHC, MSI, and mutational status of the exonuclease domain of polymerase-epsilon (POLE) are associated with response to treatment in all arms. (Exploratory Biomarker) VIII. To examine the association of the change in mutant allele frequency with response to treatment and to identify resistance mutations at the time of recurrence using circulating tumor (ct)DNA. (Exploratory Biomarker)

OUTLINE: Patients are randomized to 1 of 3 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: Patients receive olaparib PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.

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.

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

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Endometrial Undifferentiated Carcinoma
• Endometrioid Adenocarcinoma
• Recurrent Endometrial Serous Adenocarcinoma
• Recurrent Uterine Corpus Cancer
• Stage IV Uterine Corpus Cancer AJCC v7
• Stage IVA Uterine Corpus Cancer AJCC v7
• Stage IVB Uterine Corpus Cancer AJCC v7

Intervention

• Drug: Cediranib
  Given PO
  Other Name: AZD2171
• Drug: Cediranib Maleate
  Given PO
  Other Names:

  • AZD2171
  • AZD2171 Maleate
  • Recentin
• Drug: Olaparib
  Given PO
  Other Names:

  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Study Arms

• Experimental: Arm I (cediranib maleate)
  Patients receive cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  Interventions:

  • Drug: Cediranib
  • Drug: Cediranib Maleate
• Experimental: Arm II (olaparib)
  Patients receive olaparib PO BID. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  Intervention: Drug: Olaparib
• Experimental: Arm III (cediranib maleate, olaparib)
  Patients receive olaparib PO BID and cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  Interventions:

  • Drug: Cediranib
  • Drug: Cediranib Maleate
  • Drug: Olaparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Suspended
• Estimated Enrollment (submitted: November 9, 2018): 120
• Original Estimated Enrollment (submitted: September 6, 2018): 160
• Estimated Study Completion Date: September 4, 2022
• Estimated Primary Completion Date: September 4, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 histology is excluded

• 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
• 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 but excluding cediranib and olaparib for 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
• 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
• 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)
• Creatinine clearance >= 51 mL/min (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)
• 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)
• Patients must be able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption of cediranib or olaparib

• 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

  • 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

Exclusion Criteria:

• Prior enrollment into a clinical trial including cediranib or olaparib; Note: prior bevacizumab is not an exclusion criterion
• Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within 4 weeks
• 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 known strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil); the required washout period prior to starting study treatments is 5 weeks for enzalutamide or phenobarbital and 4 weeks for other agents
• 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 child bearing capacity a negative pregnancy test is required
• 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
• 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 2 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 or olaparib

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03660826
• Other Study ID Numbers: NCI-2017-01672; NCI-2017-01672 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NRG-GY012 ( Other Identifier: NRG Oncology ); NRG-GY012 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: NRG Oncology

Investigators

• Principal Investigator: Helen J Mackay; NRG Oncology

• PRS Account: National Cancer Institute (NCI)
• Verification Date: September 2020