Testing the Combination of Cediranib and Olaparib in Comparison to Each Drug Alone or Other Chemotherapy in Recurrent Platinum-Resistant Ovarian Cancer
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| ClinicalTrials.gov Identifier: NCT02502266 |
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Recruitment Status :
Active, not recruiting
First Posted : July 20, 2015
Last Update Posted : April 4, 2024
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Sponsor:
National Cancer Institute (NCI)
Collaborators:
Canadian Cancer Trials Group
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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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. Chemotherapy drugs 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | Drug: Cediranib Drug: Cediranib Maleate Procedure: Computed Tomography Procedure: Magnetic Resonance Imaging Drug: Olaparib Drug: Paclitaxel Drug: Pegylated Liposomal Doxorubicin Hydrochloride Other: Questionnaire Administration Drug: Topotecan Drug: Topotecan Hydrochloride | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 562 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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) |
| Actual Study Start Date : | May 3, 2016 |
| Estimated Primary Completion Date : | June 30, 2024 |
| Estimated Study Completion Date : | June 30, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Ovarian cancer
Drug Information
available for:
Olaparib
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Phase II Arm I (reference regimen)
Patients undergo physician's choice of standard of care chemotherapy, comprising either paclitaxel IV over 60 minutes on days 1, 8, 15, and 22 every 28 days (Regimen I); pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1 every 28 days (Regimen II); or topotecan hydrochloride IV over 30 minutes 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. Patients also undergo CT and MRI throughout the study. (12/05/2016)
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Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Paclitaxel Given IV
Other Names:
Drug: Pegylated Liposomal Doxorubicin Hydrochloride Given IV
Other Names:
Other: Questionnaire Administration Ancillary studies Drug: Topotecan Given IV
Other Names:
Drug: Topotecan Hydrochloride Given IV
Other Names:
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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. Patients also undergo CT and MRI throughout the study.
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Drug: Cediranib
Given PO
Other Names:
Drug: Cediranib Maleate Given PO
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Olaparib Given PO
Other Names:
Other: Questionnaire Administration Ancillary studies |
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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. Patients also undergo CT and MRI throughout the study.
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Drug: Cediranib
Given PO
Other Names:
Drug: Cediranib Maleate Given PO
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Other: Questionnaire Administration Ancillary studies |
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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. Patients also undergo CT and MRI throughout the study. (In July 2018, the Data Monitoring Committee voted to exclude the olaparib alone regimen).
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Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Olaparib Given PO
Other Names:
Other: Questionnaire Administration Ancillary studies |
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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. Patients also undergo CT and MRI throughout the study. (12/05/2016)
|
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Paclitaxel Given IV
Other Names:
Drug: Pegylated Liposomal Doxorubicin Hydrochloride Given IV
Other Names:
Other: Questionnaire Administration Ancillary studies Drug: Topotecan Given IV
Other Names:
Drug: Topotecan Hydrochloride Given IV
Other Names:
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Experimental: Phase III Arm II (cediranib maleate, olaparib)
Patients receive cediranib maleate PO and olaparib PO as in Phase II Arm II. Patients also undergo CT and MRI throughout the study.
|
Drug: Cediranib
Given PO
Other Names:
Drug: Cediranib Maleate Given PO
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Drug: Olaparib Given PO
Other Names:
Other: Questionnaire Administration Ancillary studies |
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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. Patients also undergo CT and MRI throughout the study.
|
Drug: Cediranib
Given PO
Other Names:
Drug: Cediranib Maleate Given PO
Other Names:
Procedure: Computed Tomography Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Other: Questionnaire Administration Ancillary studies |
Primary Outcome Measures :
- 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 will be assessed using a 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.
Secondary Outcome Measures :
- 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
Other Outcome Measures:
- 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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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 (12/05/2016); 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 (12/05/2016)
- Phase II study: measurable disease by RECIST 1.1 criteria; if archival tumor sample is not available tumor sample from fresh biopsy is acceptable (12/05/2016)
- 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 (12/05/2016)
- 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 (12/05/2016)
- Platelets >= 100,000/mcL (12/05/2016)
- Hemoglobin >= 10 g/dL (12/05/2016)
- Total bilirubin within =< 1.5 times the upper limit of normal (ULN) institutional limits (12/05/2016)
- 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 (12/05/2016)
- Creatinine =< 1.5 x the institutional ULN (12/05/2016)
- 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 (12/05/2016)
- 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 (12/05/2016)
- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and thyroid-stimulating hormone (TSH) within normal limits (12/05/2016)
- Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib
- Age >= 18 years
- 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 (12/05/2016)
- 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 (12/05/2016)
- Dependency on IV hydration or total parenteral nutrition (TPN)
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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 (12/05/2016)
- 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
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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
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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
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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
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- 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
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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 (12/05/2016)
- 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
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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 (12/05/2016)
- 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02502266
Locations
Show 400 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Canadian Cancer Trials Group
NRG Oncology
Investigators
| Principal Investigator: | Jung-min Lee | NRG Oncology |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT02502266 |
| Other Study ID Numbers: |
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 ) |
| First Posted: | July 20, 2015 Key Record Dates |
| Last Update Posted: | April 4, 2024 |
| Last Verified: | March 2024 |
Additional relevant MeSH terms:
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Carcinoma Adenocarcinoma Carcinoma, Transitional Cell Cystadenocarcinoma, Serous Carcinoma, Endometrioid Adenocarcinoma, Clear Cell Recurrence Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Disease Attributes Pathologic Processes Ovarian Neoplasms Neoplasms by Site Ovarian Diseases |
Adnexal Diseases Genital Diseases, Female Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Urogenital Diseases Genital Neoplasms, Female Urogenital Neoplasms Genital Diseases Endocrine System Diseases Gonadal Disorders Cystadenocarcinoma Neoplasms, Cystic, Mucinous, and Serous Endometrial Neoplasms Uterine Neoplasms Paclitaxel |