Ovarian Clinical Trials

Cancer Clinical Trials

NRG-GY004

A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Women With Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN , CCRP
    484-503-4152 

    Robyn.Rex@sluhn.org
  • Treatment Agent: Olaparib, Cediranib

    Synopsis: The purpose of this study is to compare the effect on your cancer of using either olaparib by itself or the combination of cediranib and olaparib to the usual chemotherapy given for your cancer (carboplatin and paclitaxel; carboplatin and gemcitabine; or carboplatin and pegylated liposomal doxorubicin [PLD]). Any of these different approaches could shrink your cancer but could also cause side effects. This study will allow the researchers to learn whether giving olaparib by itself or giving the combination of cediranib and olaparib is better, the same, or worse than the usual chemotherapy by observing both the effect of these treatments on your cancer as well as any side effects that may be experienced.

    Both olaparib and cediranib have already been tested for safety; however, they are not part of the standard approach. Olaparib by itself has been approved by the Food and Drug Administration (FDA) for women with advanced ovarian cancer and a mutation in either BRCA1 or BRCA2 (these are genes in which mutations can be inherited that have been linked to a higher risk of developing cancers, including breast and ovarian cancer) who have received three or more prior treatments for their cancer. The use of olaparib in the setting of platinum-sensitive recurrent ovarian cancer like yours is still being studied and is not FDA-approved. The combination of olaparib and cediranib is still being studied and is not yet FDA-approved.

    Another purpose of this study is for researchers to learn if a biomarker test is helpful to decide whether or not a patient’s tumor will respond to the study drug(s). Tissue from your surgery will be used for the biomarker test. Extra tubes of blood will also be drawn for the biomarker test. Researchers do not know if using the biomarker test is better, the same, or worse than if you enrolled in this study without using the biomarker test.

    • Patients must have platinum-sensitive recurrent high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancers; patients with known deleterious germline BRCA1 or BRCA2 mutation on a clinical assay with an ovarian, primary peritoneal, or fallopian tube cancer of the following other Mullerian histologies are also eligible: clear cell, mixed epithelial, undifferentiated carcinoma, or transitional cell carcinoma; Myriad testing will be accepted; if testing for germline BRCA is done by other organizations, genetic consultation report from a qualified medical professional listing the mutation and confirming that the laboratory results showed a recognized germline deleterious BRCA1 or BRCA2 mutation or BRCA rearrangement is required; please collect a copy of Myriad or other BRCA mutational analysis (positive or VUS or negative) reports
      • Platinum-sensitive disease defined as no disease progression for > 6 months after last receipt of platinum-based therapy
      • Patients must have had a complete response to their prior line of platinum therapy and cannot have had progression through prior platinum-based therapy; patients who have no measurable disease following their initial cytoreductive surgery and have no evidence of disease progression for at least 6 months following their last receipt of platinum-based therapy or their date of surgery (whichever is later) will also be considered eligible
    • Patients must have signed an approved informed consent and authorization permitting release of personal health information
    • Patients must have evaluable disease - defined as one of the following:
      • Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurable disease OR
      • Evaluable 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 125 (CA125) > 2 times upper limit of normal (ULN)
    • Prior therapy:
      • Prior chemotherapy must have included a first-line platinum-based regimen with or without intravenous consolidation chemotherapy
      • Patients may have received an unlimited number of platinum-based therapies in the recurrent setting
      • Patients may have received up to 1 non-platinum-based line of therapy in the recurrent setting; prior hormonal therapy will not be considered to count as this non-platinum-based line
      • 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 poly adenosine diphosphate (ADP) ribose polymerase (PARP)-inhibitor
      • Prior hormonal-based therapy for ovarian, primary peritoneal, or fallopian tube cancer is acceptable
    • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Karnofsky >= 60%)
    • Absolute neutrophil count >= 1,500/mcL
    • Platelets >= 100,000/mcL
    • Hemoglobin >= 10 g/dL
    • Creatinine =< the institutional upper limit of normal (ULN) OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
    • Urine protein: creatinine ratio (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 =< 500 mg over 24 hours
    • Total bilirubin =< 1.5 x the institutional ULN
    • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times institutional ULN
    • Toxicities of prior therapy (excepting alopecia) should be resolved to less than or equal to grade 1 as per National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0); patients with long-standing stable grade 2 neuropathy may be considered after discussion with the overall principal investigator (PI), but may not receive carboplatin and paclitaxel as the reference regimen, if randomized to that arm
    • 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; patients who are on three antihypertensive medications must be actively 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
    • 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
    • Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and thyroid stimulating hormone (TSH) within normal limits
    • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study 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
    • Patients may not be receiving any other investigational agents nor have participated in an investigational trial within the past 4 weeks
    • Patients may not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, pentamidine)
    • Patients may not have received prior treatment affecting the vascular endothelial growth factor (VEGF) pathway (including, but not limited to thalidomide, sunitinib, pazopanib, sorafenib, and nintedanib); bevacizumab used in the upfront setting in conjunction with chemotherapy and/or as maintenance to treat newly diagnosed disease will be allowed
    • Patients may not have previously received a PARP inhibitor
    • CA-125 only disease without RECIST 1.1 measurable or otherwise evaluable disease
    • 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; screening imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated; 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
    • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib or olaparib
    • Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible
    • History of gastrointestinal perforation; patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months, and patient is deemed to be at low risk of recurrent fistula
    • History of intra-abdominal abscess within the past 3 months
    • Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs
    • Dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)
    • Any concomitant or prior invasive malignancies with the following 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, clear cell, or other International Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions
      • Prior cancer treated with a curative intent with no evidence of recurrent disease 3 years following diagnosis and judged by the investigator to be at low risk of recurrence
    • 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 (NYHA) 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
    • Any prior history of hypertensive crisis or hypertensive encephalopathy
    • Clinically significant peripheral vascular disease or vascular disease (including aortic aneurysm or aortic dissection)
    • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib
    • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
    • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cediranib or olaparib
    • Known human immunodeficiency virus (HIV)-positive individuals are ineligible
    • Patients may not use any complementary or alternative medicines including natural herbal products or folk remedies
    • No features 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)

NRG-GY005

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)

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Robyn Rex, RN, OCN , CCRP
    484-523-4152

    Robyn.Rex@sluhn.org
  • Treatment Agent: Cediranib, Olaparib

    Synopsis: This study has two parts: A Phase II part and a Phase III part. You are being asked to participate in the Phase III part of the study. The purpose of the Phase II part of the study is to compare any good and bad effects of using a combination of the experimental drugs cediranib and olaparib, to using the standard chemotherapy, or cediranib alone, or olaparib alone. The Phase III study will follow the Phase II to confirm the effectiveness of a combination of cediranib and olaparib to the standard chemotherapy. One of the experimental drugs, either cediranib or olaparib alone may be compared with the standard chemotherapy for the effectiveness, after reviewing the results from Phase II study. Cediranib is an experimental drug that may help keep cancer cells from growing by affecting their blood supply. Olaparib is a drug that may stop cancer cells from growing abnormally. Olaparib by itself has been approved by the Food and Drug Administration (FDA) for use in women with advanced ovarian cancer with BRCA1 and BRCA2 mutations (defined below) who have been treated with three or more different chemotherapy treatments. The combination of olaparib and cediranib is investigational. These drugs have been used in other research studies in ovarian cancer, and information from those other research studies suggest that these may help to keep cancer from growing. The addition of cediranib to olaparib could shrink your cancer but it could also cause side effects. This study will allow the researchers to know whether this different approach using two study drugs is better, the same, or worse than the usual chemotherapy approach. Standard chemotherapy drugs that are already FDA-approved for use in recurrent ovarian cancer include paclitaxel, topotecan, or pegylated liposomal doxorubicin (PLD).

    Another purpose of this study is for researchers to learn if a biomarker test is helpful to decide whether or not a patient’s tumor will respond to the study drug(s). Tissue from your surgery will be used for the biomarker test. Extra tubes of blood will also be drawn for the biomarker test. Researchers do not know if using the biomarker test is better, the same, or worse than if you enrolled in this study without using the biomarker test.

    The biomarker test will be done to study gene mutations using a sample from the tissue that was collected at the time of your surgery or biopsy and from a blood sample collected before you start treatment. Also, two additional blood samples will be collected before and three days after you begin treatment to study changes in cells that have been shed from the lining of the vascular wall into the blood stream related to blood vessel injury, and to investigate proteins related to tumor growth, blood vessel formation and inflammation.

    • 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; participants with a deleterious germline BRCA-mutation on a commercial Clinical Laboratory Improvement Amendments (CLIA) assay with other high-grade histologies, including mucinous adenocarcinoma, clear cell, transitional cell, undifferentiated adenoca, undifferentiated carcinoma, mixed epithelial andenoca are also eligible
    • Patients should have recurrent platinum-resistant or- refractory disease - defined as disease that has progressed while receiving platinum or had recurrence within 6 months of the last receipt of platinum-based chemotherapy
    • Phase II study: measurable disease by RECIST 1.1 criteria; baseline biopsy for retinitis pigmentosa 2 (RP2) study is optional but highly encouraged
    • 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 2 prior treatment regimens (including primary therapy); 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
    • Patient must have provided study specific informed consent prior to study entry
    • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
    • 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]) < 2.5 x institutional ULN
    • Creatinine < the institutional ULN or creatinine clearance >= 60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
    • Less than or equal to 1+ proteinuria on two consecutive dipsticks taken no less than 1 week apart, or < 1 gm protein on 24-hour urine collection or a urine protein:creatinine ratio of < 1
    • Troponin T or I within normal institutional limits
    • Coagulation parameters (international normalized ration [INR], activated partial thromboplastin time [aPTT]) within 1.25 x ULN institutional limits
    • Toxicities of prior therapy (excepting alopecia) should be resolved to less than or equal to grade 1 as per CTCAE v4.0; patients with long-standing stable grade 2 neuropathy may be considered after discussion with the overall Principal Investigator (PI)
    • 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; patients who are on three antihypertensive medications must be actively 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
    • Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and thyroid-stimulating hormone (TSH) within normal limits
    • Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible; subjects with early-stage 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 are eligible
    • Patients who have the following risk factors are considered to be at increased risk for cardiac toxicities; these patients should have increased monitoring: 1) prior treatment with anthracyclines, 2) prior treatment with trastuzumab, 3) a New York Heart Association classification of II controlled with treatment, 4) prior central thoracic radiation therapy (RT), including RT to the heart, 5) history of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded from the study)
    • Able to tolerate oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib
    • Chemotherapy or radiation therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C); patients must have recovered from adverse events due to agents administered more than 3 weeks earlier; patients may not have had hormonal therapy within 2 weeks prior to entering the study
    • Any other investigational agents within the past 4 weeks
    • Prior use of poly adenosine diphosphate (ADP) ribose polymerase (PARP)-inhibitors; prior treatment affecting the vascular endothelial growth factor (VEGF) pathway in the recurrent setting, including but not limited to thalidomide, bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, and nintedanib; bevacizumab used in the upfront setting in conjunction with chemotherapy and/or as maintenance to treat newly diagnosed disease will be allowed
    • CA-125 only 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 except temporary (< 24 hr) improved with medical management within last 3 months
    • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months
    • Dependency on IV hydration or total parenteral nutrition (TPN)
    • Current pregnancy; patients must be on two forms of birth control if of child-bearing potential
    • 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
      • Patients with corrected QT interval (QTc) prolongation > 470 msec (with Bazett's correction) or familial long QT syndrome
      • 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
    • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
    • Known human immunodeficiency virus (HIV)-positive individuals are ineligible
    • Patients may not use natural herbal products or other "folk remedies" while participating in this study