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Cediranib Maleate and Olaparib or Standard Chemotherapy in Treating Patients With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02502266
Recruitment Status : Recruiting
First Posted : July 20, 2015
Last Update Posted : February 20, 2020
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 17, 2015
First Posted Date  ICMJE July 20, 2015
Last Update Posted Date February 20, 2020
Actual Study Start Date  ICMJE February 5, 2016
Estimated Primary Completion Date June 30, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2019)
  • Progression-free survival (PFS) (Phase II and Phase III) [ Time Frame: Time from study enrollment to the onset of progression as determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) criteria, or death due to any cause, whichever occurs first, assessed up to 5 years ]
    Progression-free survival will be assessed. The primary analysis of PFS proportional hazards model with patients analyzed according to the arm to which they were randomized, regardless of whether treatment is received.
  • Overall survival (OS) (Phase III) [ Time Frame: Time from study enrollment to death due to any cause, assessed up to 5 years ]
    Overall survival will be evaluated. To allow for better understanding of time to subsequent therapy and OS, patients on experimental study drug(s) or standard chemotherapy arm will be followed after progression, with data capture to include the date of initiation of the subsequent therapy, detailed information on the type of subsequent therapy received, and time to progression on the subsequent therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: July 17, 2015)
  • OS (Phase III) [ Time Frame: Time from study enrollment to death due to any cause, assessed up to 5 years ]
  • PFS (Phase II) [ Time Frame: Time from study enrollment to the onset of progression as determined by RECIST v1.1 criteria, or death due to any cause, whichever occurs first, assessed up to 5 years ]
Change History Complete list of historical versions of study NCT02502266 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2019)
  • Objective response rate (partial or complete response) (Phase II and Phase III) [ Time Frame: Up to 5 years ]
    Objective response rate will be defined by RECIST 1.1.
  • Incidence of adverse events (Phase II and Phase III) [ Time Frame: Up to 5 years ]
    Frequency and severity of adverse events measured by Common Terminology Criteria for Adverse Events version 4.0
Original Secondary Outcome Measures  ICMJE
 (submitted: July 17, 2015)
  • Frequency and severity of adverse events by CTCAE v.4.0 (Phase II) [ Time Frame: Up to 5 years ]
  • Frequency and severity of adverse events by CTCAE v.4.0 (Phase III) [ Time Frame: Up to 5 years ]
  • ORR (partial or complete response), defined by RECIST v1.1 criteria (Phase II) [ Time Frame: Up to 5 years ]
  • ORR (partial or complete response), defined by RECIST v1.1 criteria (Phase III) [ Time Frame: Up to 5 years ]
  • Patient-reported scores of disease-related symptoms, measured by the NFOSI-DRS9 (Phase III) [ Time Frame: Up to 2 years ]
    A mixed-effects model will be used to estimate and compare the mean NFOSI-DRS scores for the treatment groups at each of the follow-up assessment times. Model covariates will include the patients' randomly assigned study treatment, age at enrollment onto the study, initial performance status, pre-treatment NFOSI-DRS score, assessment time and a term for the interaction between time and treatment.
  • PFS (Phase III) [ Time Frame: Time from study enrollment to the onset of progression as determined by RECIST v1.1 criteria, or death due to any cause, whichever occurs first, assessed up to 5 years ]
Current Other Pre-specified Outcome Measures
 (submitted: October 2, 2019)
  • Patient-reported scores of disease-related symptoms [ Time Frame: Up to 5 years ]
    Measured by the 9-item Disease Related Symptoms (DRS-9) subscale of the National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) Ovarian Symptom Index (NFOSI-18).
  • Gene mutations assessed BROCA-HR [ Time Frame: Up to 5 years ]
    A single proportional hazards model will be used to estimate the treatment hazard ratios (and variances) for each of the experimental treatments selected for phase III evaluation relative to the reference treatment (chemotherapy) group. The model will include adjustments for prior platinum-free interval, prior bevacizumab treatment, age at study enrollment, randomly assigned study treatment and BROCA-HR status. The estimated hazard ratio(s) for BROCA-HR and the corresponding confidence intervals will be depicted with a forest plot, and assessed for qualitative interaction(s).
  • Change in circulating endothelial cell levels [ Time Frame: Baseline up to 5 years ]
    A proportional hazards model will be used to assess a linear association between the change in circulating endothelial cell values and the log relative hazard of death within each treatment group. Sensitivity analyses will include known prognostic factors in the model. A plot of the martingale residuals or estimated relative hazards by change in circulating endothelial cell quintiles will be used to qualitatively assess the assumption of a linear relationship between the change in circulating endothelial cell values and the log relative hazard.
  • Biomarkers in plasma angiome [ Time Frame: Up to 5 years ]
    A proportional hazards model will be used to assess whether the pretreatment values of any of these analytes have a prognostic association with overall survival. The model will include clinical covariates: age, performance status, and the randomly assigned study treatment. Proportional hazards models will be used to assess the relationship between patients' analyte values and log hazard. A proportional hazards model will be used to assess the potential predictive associations between analytes, treatment and survival.
Original Other Pre-specified Outcome Measures
 (submitted: July 17, 2015)
  • BROCA-HR assay result (positive or negative) (Phase III) [ Time Frame: Baseline ]
    A single proportional hazards model will be used to estimate the treatment hazard ratios and variances for each experimental treatment relative to the reference treatment group. The model will include adjustments for prior platinum-free interval, prior bevacizumab treatment, and age at study enrollment; indicator variable(s) for the randomly assigned treatment; and BROCA-HR status, as well as term(s) for interactions. Kaplan-Meier plots will be used to depict the estimated probability of survival in each treatment group by marker status.
  • Change in level of CECs (Phase III) [ Time Frame: Baseline to day 3 of course 1 ]
    The distributions for each treatment group selected for phase III will be visually assessed using histograms, rug-plots or box-plots. One analysis of covariance (ANCOVA) model will be used to assess if the 3-day CEC levels are independent of treatment. A proportional hazards model will be used to assess a linear association between the change in CEC values and the log relative hazard of death. A plot of the martingale residuals or estimated relative hazards by CEC quintiles will be used to qualitatively assess the assumption of a linear relationship between CEC values and the log hazard.
  • Cost-effectiveness (Phase III) [ Time Frame: Up to 5 years ]
    Assessed with the use of OS, Euroqol 5D, and healthcare resource utilization collection.
  • Patient-reported function/well-being, as measured by NFOSI Function/Well-Being (Phase III) [ Time Frame: Up to 2 years ]
  • Patient-reported general quality of life, as measured by Euroqol EQ-5D (Phase III) [ Time Frame: Up to 2 years ]
  • Patient-reported treatment side effects, as measured by NFOSI TSE (Phase III) [ Time Frame: Up to 2 years ]
  • Values of angiogenic biomarkers in the plasma angiome (Phase III) [ Time Frame: Baseline ]
    Pretreatment biologic specimens will be quantified. Descriptive statistics and histograms will be used to assess the center and dispersion of values for each analyte, and identify outliers. Scattergrams and Spearman's rank correlation will be used to assess the associations between analyte pairs. A proportional hazards model will be used to assess whether pretreatment values of any of the analytes have a prognostic association with overall survival. Kaplan-Meier plots and forest plots will be used to summarize the associations between analytes and overall survival and relative risk of death.
 
Descriptive Information
Brief Title  ICMJE Cediranib Maleate and Olaparib or Standard Chemotherapy in Treating Patients With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Official Title  ICMJE A Randomized Phase II/III Study of the Combination of Cediranib and Olaparib Compared to Cediranib or Olaparib Alone, or Standard of Care Chemotherapy in Women With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (COCOS)
Brief Summary This randomized phase II/III trial studies how well cediranib maleate and olaparib work when given together or separately, and compares them to standard chemotherapy in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has returned (recurrent) after receiving chemotherapy with drugs that contain platinum (platinum-resistant) or continued to grow while being treated with platinum-based chemotherapy drugs (platinum-refractory). Cediranib maleate and olaparib may stop the growth of tumor cells by blocking enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving cediranib maleate and olaparib together may cause more damage to cancer cells when compared to either drug alone or standard chemotherapy.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the efficacy and identify (in)active arm(s) of the combination of cediranib maleate (cediranib) and olaparib, cediranib alone, olaparib alone, and physician's choice standard of care chemotherapy, as measured by progression-free survival (PFS) in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase II) II. To assess the efficacy of the combination of cediranib and olaparib, and cediranib monotherapy, as measured by overall survival (OS) and PFS, as compared to physician's choice standard of care chemotherapy in women with recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)

SECONDARY OBJECTIVES:

I. To assess the efficacy of the combination of cediranib and olaparib, cediranib alone, olaparib alone, and physician's choice standard of care chemotherapy, as measured by objective response rate (ORR: partial or complete response) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase II) II. To assess safety endpoints, as measured by frequency and severity of adverse events by Common Terminology Criteria for Adverse Events (CTCAE). (Phase II and Phase III) III. To assess the efficacy of the combination of cediranib and olaparib, and cediranib monotherapy, as measured by ORR as compared to physician's choice standard of care chemotherapy in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)

OBJECTIVES WITH INTEGRATED BIOMARKERS:

I. To assess correlation of homologous recombination deficiency (HRD) status, as assessed via BROCA-HR assay with response, as measured by PFS and ORR. (Phase II) II. To evaluate the prognostic and predictive role of circulating endothelial cells (CEC) on comparative effectiveness of targeted therapies and reference chemotherapy. (Phase II) III. To evaluate quality of life data compliance, as measured by the 9-item Disease Related Symptoms (DRS-9) subscale of the National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) Ovarian Symptom Index (NFOSI) for utilization and analysis in the Phase III study. (Phase II) IV. To assess correlation of HRD status, as assessed via BROCA-HR assay with response, as measured by OS, PFS and ORR. (Phase III) V. To evaluate the prognostic and predictive role of circulating endothelial cells (CEC) on comparative effectiveness of targeted therapies and reference chemotherapy. (Phase III) VI. To assess the effect on disease-related symptoms (DRS) as measured by the 9-item DRS-P subscale of the NCCN-FACT Ovarian Symptom Index-18 (NFOSI-18), of single agent cediranib and cediranib/olaparib combination, compared to standard chemotherapy, in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)

EXPLORATORY OBJECTIVES:

I. To assess exploratory biomarkers of potential HRD, including genomic scarring, BRCA1 methylation, BRCA1 protein expression, and mutations in NHEJ, and other genes that might modify HRD. (Phase II and Phase III) II. To evaluate the prognostic and predictive role of angiogenic biomarkers, as assessed by the Duke plasma angiome. (Phase II and Phase III) III. To assess the effect on secondary measures of quality of life, as assessed by the treatment side effects (TSE) and function/well-being (F/WB) subscales of the NFOSI-18, sensory neuropathy as measured by the FACT/GOG-Ntx-4, and health utility as measured by the EQ-5D, of single agent cediranib and cediranib/olaparib combination, compared to standard chemotherapy, in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)

OUTLINE:

PHASE II: Patients are randomized to 1 of 4 treatment arms.

ARM I (REFERENCE REGIMEN): Patients undergo physician's choice of standard of care chemotherapy, comprising either paclitaxel intravenously (IV) on days 1, 8, 15, and 22 every 28 days (Regimen I); pegylated liposomal doxorubicin hydrochloride IV on day 1 every 28 days (Regimen II); or topotecan hydrochloride IV on days 1, 8, and 15 every 28 days or days 1-5 every 21 days (Regimen III). Treatment continues in the absence of disease progression or unacceptable toxicity. No modification of the assigned regimens, such as additional drugs (gemcitabine, or bevacizumab) is allowed. (12/05/2016)

ARM II (CEDIRANIB MALEATE AND OLAPARIB): Patients receive cediranib maleate orally (PO) once daily (QD) and olaparib PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III (CEDIRANIB): Patients receive cediranib maleate PO daily continuously. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IV (OLAPARIB): Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (In July 2018, the Data Monitoring Committee voted to exclude the olaparib alone regimen).

PHASE III: Patients are randomized to 1 of 3 treatment arms.

ARM I (REFERENCE REGIMEN): Patients undergo physician's choice standard of care chemotherapy as in Phase II Arm I. No modification of the assigned regimens, such as additional drugs (gemcitabine or bevacizumab) is allowed. (12/05/2016)

ARM II (CEDIRANIB AND OLAPARIB): Patients receive cediranib maleate PO and olaparib PO as in Phase II Arm II.

ARM III (SINGLE AGENT): Patients receive cediranib maleate PO as determined by the Phase II study. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • Fallopian Tube Serous Adenocarcinoma
  • Fallopian Tube Transitional Cell Carcinoma
  • Fallopian Tube Undifferentiated Carcinoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Ovarian Seromucinous Carcinoma
  • Ovarian Serous Adenocarcinoma
  • Ovarian Transitional Cell Carcinoma
  • Ovarian Undifferentiated Carcinoma
  • Primary Peritoneal Serous Adenocarcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
Intervention  ICMJE
  • 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
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Drug: Pegylated Liposomal Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • ATI-0918
    • Caelyx
    • DOX-SL
    • Doxil
    • Doxilen
    • Doxorubicin HCl Liposomal
    • Doxorubicin HCl Liposome
    • Doxorubicin Hydrochloride Liposome
    • Duomeisu
    • Evacet
    • LipoDox
    • Lipodox 50
    • Liposomal Adriamycin
    • liposomal doxorubicin hydrochloride
    • Liposomal-Encapsulated Doxorubicin
    • Pegylated Doxorubicin HCl Liposome
    • S-Liposomal Doxorubicin
    • Stealth Liposomal Doxorubicin
    • TLC D-99
  • Other: Questionnaire Administration
    Ancillary studies
  • Drug: Topotecan
    Given IV
    Other Names:
    • Hycamptamine
    • Topotecan Lactone
  • Drug: Topotecan Hydrochloride
    Given IV
    Other Names:
    • Hycamptamine
    • Hycamtin
    • SKF S-104864-A
    • Topotecan HCl
    • topotecan hydrochloride (oral)
Study Arms  ICMJE
  • Active Comparator: Phase II Arm I (reference regimen)
    Patients undergo physician's choice of standard of care chemotherapy, comprising either paclitaxel IV on days 1, 8, 15, and 22 every 28 days (Regimen I); pegylated liposomal doxorubicin hydrochloride IV on day 1 every 28 days (Regimen II); or topotecan hydrochloride IV on days 1, 8, and 15 every 28 days or days 1-5 every 21 days (Regimen III). Treatment continues in the absence of disease progression or unacceptable toxicity. No modification of the assigned regimens, such as additional drugs (gemcitabine, or bevacizumab) is allowed. (12/05/2016)
    Interventions:
    • Drug: Paclitaxel
    • Drug: Pegylated Liposomal Doxorubicin Hydrochloride
    • Other: Questionnaire Administration
    • Drug: Topotecan
    • Drug: Topotecan Hydrochloride
  • Experimental: Phase II Arm II (cediranib maleate, olaparib)
    Patients receive cediranib maleate PO QD and olaparib PO BID. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cediranib
    • Drug: Cediranib Maleate
    • Drug: Olaparib
    • Other: Questionnaire Administration
  • Experimental: Phase II Arm III (cediranib maleate)
    Patients receive cediranib maleate PO daily continuously. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cediranib
    • Drug: Cediranib Maleate
    • Other: Questionnaire Administration
  • Experimental: Phase II Arm IV (olaparib)
    Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (In July 2018, the Data Monitoring Committee voted to exclude the olaparib alone regimen).
    Interventions:
    • Drug: Olaparib
    • Other: Questionnaire Administration
  • Active Comparator: Phase III Arm I (reference regimen)
    Patients undergo physician's choice standard of care chemotherapy as in Phase II Arm I. No modification of the assigned regimens, such as additional drugs (gemcitabine or bevacizumab) is allowed. (12/05/2016)
    Interventions:
    • Drug: Paclitaxel
    • Drug: Pegylated Liposomal Doxorubicin Hydrochloride
    • Other: Questionnaire Administration
    • Drug: Topotecan
    • Drug: Topotecan Hydrochloride
  • Experimental: Phase III Arm II (cediranib maleate, olaparib)
    Patients receive cediranib maleate PO and olaparib PO as in Phase II Arm II.
    Interventions:
    • Drug: Cediranib
    • Drug: Cediranib Maleate
    • Drug: Olaparib
    • Other: Questionnaire Administration
  • Experimental: Phase III Arm III (single-agent cediranib maleate)
    Patients receive cediranib maleate PO as determined by the Phase II study. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cediranib
    • Drug: Cediranib Maleate
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 17, 2015)
680
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date June 30, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Canada,   Japan,   Korea, Republic of,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02502266
Other Study ID Numbers  ICMJE NCI-2015-00651
NCI-2015-00651 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GY005
s16-01681
NRG-GY005 ( Other Identifier: NRG Oncology )
NRG-GY005 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Jung-min Lee NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP