Research & Innovation

Ovarian Clinical Trials

Clinical Trials

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

Physician

Doctor

Nicholas Taylor, MD

Study Coordinator

Vanessa Shaw, RN

484-526-6038

Vanessa.Shaw@sluhn.org

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Synopsis

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.

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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; 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]) less then 2.5 x institutional
  • Creatinine is less then the institutional uln or creatinine clearance greater then or equal to 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 less then 1 gm protein 24-hour urine collection or a urine protein:creatinine ratio of
  • 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] less then or equal to 140; diastolic blood pressure [dbp] less then 90 mmhg) maximum of three antihypertensive medications; patients must have a bp of less then 140/90 mmhg taken in the clinic setting by a medical professional within 2 weeks prior to starting study; patients who are three antihypertensive medications must be actively followed by a cardiologist or a primary care physician for management of bp while protocol; patients must be willing and able to check and record daily blood pressure
  • 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

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Exclusion Criteria
  • 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 (less than 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 less than 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

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NRG-GY009

A Randomized, Phase II/III Study of Pegylated Liposomal Doxorubicin and CTEP-Supplied Atezolizumab Versus Pegylated Liposomal Doxorubicin/Bevacizumab and CTEP-Supplied Atezolizumab Versus Pegylated Liposomal Doxorubicin/Bevacizumab in Platinum Resistant Ovarian Cancer

Physician & Study Coordinator

Physician

Doctor

Nicholas Taylor, MD

Study Coordinator

Vanessa Shaw, RN

484-526-6038

Vanessa.Shaw@sluhn.org

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Synopsis

Treatment Agent: Atezolizumab, Bevacizumab, Liposomal Doxorubicin 

Synopsis: The purpose of this study is to compare any good and bad effects of adding Atezolizumab to the usual chemotherapy (liposomal doxorubicin) and to the usual chemotherapy with bevacizumab.  Atezolizumab is a PD-L1 inhibitor that may allow the immune system to recognize and destroy tumor cells. It is an experimental medication (not approved by the FDA). The addition of Atezolizumab to the usual chemotherapy or the usual chemotherapy with bevacizumab could shrink your cancer but it could also cause side effects. This study will allow the researchers to know whether the different approaches are better, the same, or worse than the usual approach. To be better, the study drugs should increase life by six months or more compared to the usual approach.

 The purpose of this study is to test three things:

  1. Compare any good and bad effects of adding atezolizumab to the usual chemotherapy (liposomal doxorubicin and atezolizumab) to using the usual chemotherapy with bevacizumab (liposomal doxorubicin and bevacizumab).

  2. Compare any good and bad effects of adding atezolizumab to the usual chemotherapy with bevacizumab (liposomal doxorubicin and bevacizumab plus atezolizumab) to using the usual chemotherapy with bevacizumab (liposomal doxorubicin and bevacizumab).

  3. Compare if either of the two regimens using atezolizumab is better than the other.

 

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 has certain characteristics and will respond to study drug. Tissue from your surgery will be used 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.

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Inclusion Criteria
  • Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up
  • Women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  • Submission of tumor tissue is required for all patients; investigators should check with their site pathology department regarding release of biospecimens before approaching patients about participation in the trial
  • High grade ovarian cancer, including high grade serous; clear cell; endometrioid, grade 3; and others (adenocarcinoma, nitric oxide synthase [NOS]; mixed epithelial carcinoma; undifferentiated carcinoma); NOTE: low grade serous, mucinous and carcinosarcoma histologies are excluded; ovarian cancer = ovarian, fallopian tube or primary peritoneal cancer; required data element: submission of pathology report
  • Recurrent, platinum resistant ovarian cancer (defined as progression within < 6 months from completion of platinum based therapy; the date should be calculated from the last administered dose of platinum therapy)
  • 1-2 prior regimens (including primary therapy); hormonal therapies (e.g., tamoxifen, aromatase inhibitors) will not count toward the prior regimen limit
  • Measurable disease (defined by RECIST v. 1.1) 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 cancer antigen [CA]25 >= 2 x upper limit of normal [ULN])
  • Performance status 0, 1 or 2
  • Within 14 days prior to registration: Absolute neutrophil count (ANC) >= 1,500/mcl
  • Within 14 days prior to registration: Platelets >= 100,000/mcl
  • Within 14 days prior to registration: Hemoglobin (Hgb) >= 8 g/dl
  • Within 14 days prior to registration: Creatinine =< 1.5 x institutional upper limit of normal (ULN)
  • Within 14 days prior to registration: Urine protein creatinine (UPC) ratio must be < 1.0 gm; if UPC ratio >= 1, collection of 24-hour urine measurement of urine protein is recommended (24-hour urine protein level must be < 1000 mg for patient enrollment); UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm
  • Within 14 days prior to registration: Total Bilirubin =< 1.5 x ULN (patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
  • Within 14 days prior to registration: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (or on stable dose of therapeutic anticoagulation, such as low-molecular-weight heparin, warfarin or rivaroxaban)
  • Thyroid-stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid patients on thyroid replacement therapy)
  • The patient or legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

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Exclusion Criteria
  • Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Patients who have had systemic anticancer therapy (e.g., chemotherapy, targeted therapy) within 3 weeks prior to entering the study
  • Patients who have had hormonal therapy (e.g., tamoxifen, aromatase inhibitor) within 1 week prior to entering the study
  • Patients with prior treatment with anti-programmed cell death (PD)-1, anti- programmed cell death ligand (PD-L)1 or anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 therapeutic antibody or other similar agents
  • Patients with prior treatment with bevacizumab (or any other anti vascular therapy, e.g., cediranib) for platinum resistant recurrence; (Note: prior bevacizumab in initial therapy and/or platinum sensitive recurrent setting is allowed)
  • Patients with prior treatment with PLD
  • Prior radiotherapy to the abdomen or pelvis
  • Patients who have not recovered from adverse events to < grade 1 (other than alopecia) due to agents administered more than 3 weeks earlier; however, the following therapies are allowed:
  • Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
  • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1
  • Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1
  • Patients taking bisphosphonate therapy for symptomatic hypercalcemia within the past 28 days; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
  • Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Patients requiring treatment with a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (e.g. denosumab) who cannot discontinue it before treatment with atezolizumab
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
  • History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
  • History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Patients with active tuberculosis (TB) are excluded
  • Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
  • Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  • Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
  • Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab
  • 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
  • Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:
  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years, with the exception of those with a negligible risk of metastases or death, such as carcinoma in situ of the breast or cervix
  • Severe, active co-morbidity defined as follows:
  • Significant cardiovascular or cerebrovascular disease including:
  • History of abdominal/pelvic or tracheoesophageal fistula or gastrointestinal perforation and/or abscess within 6 months prior to initiation of treatment
  • Pregnant or lactating patients

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