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Olaparib and Cediranib Maleate in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube 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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02345265
Recruitment Status : Active, not recruiting
First Posted : January 26, 2015
Last Update Posted : June 18, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well olaparib and cediranib maleate work in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent). Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Fallopian Tube Endometrioid Adenocarcinoma Fallopian Tube Serous Adenocarcinoma High Grade Ovarian Serous Adenocarcinoma Ovarian Endometrioid Tumor Primary Peritoneal Serous Adenocarcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Drug: Cediranib Maleate Drug: Olaparib Other: Questionnaire Administration Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 72 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Olaparib and Cediranib for the Treatment of Recurrent Ovarian Cancer
Actual Study Start Date : December 4, 2015
Actual Primary Completion Date : February 11, 2020


Arm Intervention/treatment
Experimental: Treatment (olaparib and cediranib maleate)
Patients receive olaparib PO BID and cediranib maleate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
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

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: Interval from start of treatment to documented disease progression per Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first, assessed up to 1 year ]
    Will be summarized using the Kaplan-Meier product-limit estimator with 95% confidence bands derived using Greenwood's formula.

  2. Objective response rate (platinum-resistant cohort) [ Time Frame: Up to 1 year ]
    Will be defined as confirmed complete response or partial response under Response Evaluation Criteria in Solid Tumors 1.1. Clinical activity will be determined using objective response rate.

  3. Biomarker signature development [ Time Frame: Up to 30 days post-treatment ]
    Will summarize the distribution of all candidate markers using descriptive statistics and non-parametric tests of their association with patient and disease characteristics. Biomarker profiles will be explored using unsupervised hierarchical clustering of all analytes and patients. The association of each candidate marker to progression-free survival will be evaluated by Cox proportional hazard models using a two-sided alpha = 0.05, while estimating the false discovery rate for any sets of identified markers by the Benjamini-Hochberg step-up procedure.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Up to 1 year ]
    Will be summarized using the Kaplan-Meier product-limit estimator with 95% confidence bands derived using Greenwood's formula.

  2. Genetic alterations [ Time Frame: Baseline ]
    Will be detected by the BROCA-homologous recombination assay. Descriptive statistics will be used to summarize the genetic alterations detected by the BROCA-homologous recombination assay and Bioinformatics Pipeline. The prevalence of each genetic alteration will be reported overall, and within stratum defined by platinum-sensitive and platinum-resistant disease using binomial exact 95% confidence intervals. The primary analysis will associate BRCA mutations (germline or somatic) and other homologous recombination gene mutation (as a pooled group) with/against progression-free survival as a time-to-event endpoint, using Kaplan-Meier product-limit estimates and stratified logrank test using a two-sided alpha of 0.05.

  3. Change in circulating endothelial cells/circulating endothelial precursor cells [ Time Frame: Baseline to day 3 ]
    Will determine if there is an association between levels of circulating endothelial cells at baseline, or the change in circulating endothelial cells from baseline to day 3, and progression-free survival in patients receiving cediranib maleate/olaparib trial, and to determine if there are significant changes from baseline to day 3 in the levels of circulating endothelial cells. Will use a paired t-test. In addition, if the paired differences in values are not normally distributed (p < 0.05 by a Shapiro-Wilk test), then a Wilcoxon signed rank test will be used instead of a paired t-test.

  4. Prevalence of genetic alteration using whole exome sequencing [ Time Frame: Baseline ]
    The prevalence of each genetic alteration will be reported overall, and within platinum-sensitive and platinum-resistant cohorts using binomial exact 95% confidence intervals. Exploratory analyses will associate alterations of a single-gene against progression-free survival as a time-to-event endpoint, using Kaplan-Meier product-limit estimates and logrank test using a nominal two-sided alpha of 0.05.


Other Outcome Measures:
  1. Perceived usability and satisfaction of ecediranib-olaparib application from patients [ Time Frame: Up to 1 year ]
    Significance testing of data from patients and healthcare professionals will be done using a one tailed Wilcoxon signed rank test (alpha = 0.05).

  2. Perceived usability and satisfaction of ecediranib-olaparib application from health care professionals [ Time Frame: Up to 1 year ]
    Significance testing of data from patients and healthcare professionals will be done using a one tailed Wilcoxon signed rank test (alpha = 0.05).

  3. Ecediranib-olaparib application web portal metrics [ Time Frame: Up to 1 year ]
    Web portal metrics will be summarized using descriptive statistics. The metrics will include: number of patients who accessed the app, number of diarrhea events reported, % blood pressure values entered compared to the % expected, number of follow-up blood pressure measures entered compared to the number recommended, number and type of blood pressure events reported, average duration of blood pressure event and diarrhea event in days, number of other symptoms reported (headache, change in vision, shortness of breath, chest pain, uncontrolled diarrhea, cramping, blood in stool), number and type of email alerts generated to the study team.

  4. Incidence of ecediranib-olaparib application user support call [ Time Frame: Up to 1 year ]
    User support calls will be summarized including: number of calls and the reason for contacting ecediranib-olaparib application user support (patients and study team).



Information from the National Library of Medicine

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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:

  • Participants must have histologically or cytologically confirmed ovarian cancer, peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of either high grade serous or high grade endometrioid cancer based on local histopathological findings; participants with a deleterious BRCA-mutation on a commercial Clinical Laboratory Improvement Amendments (CLIA) assay with other high-grade histologies are also eligible

    • Due to the long acceptance of BRCA testing through Myriad, Myriad testing will be accepted as documentation of a deleterious mutation; 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 show a recognized germline deleterious BRCA1 or BRCA2 mutation or BRCA rearrangements is required to document the presence of a deleterious mutation
  • Participants must have measurable disease via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Patients may not have received prior poly ADP ribose polymerase (PARP) inhibitors
  • Patients may have received but may not have progressed on prior anti-angiogenic therapy in the upfront setting
  • For platinum sensitive cohort

    • Cancer that has not progressed within 6 months of the last receipt of platinum-based chemotherapy
    • No limit on the number of platinum-based lines
    • No more than one prior non-platinum based line of therapy in the recurrent setting
  • For platinum-resistant or -refractory cohort

    • Disease that has progressed within 6 months of the last receipt of platinum-based chemotherapy
    • No more than 1 prior line of therapy in the platinum-resistant/-refractory setting
    • No limit on number of prior lines received in the platinum-sensitive setting prior to development of platinum-resistance (defined as disease progression within 6 months of platinum-based chemotherapy)
  • Hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will not count towards line limit considerations
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Hemoglobin >= 10 g/dL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • Creatinine less than or equal to the institutional upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • Proteinuria less than or equal to 1+ proteinuria on two consecutive dipsticks taken no less than week apart, or a urine protein:creatinine (UPC) ration of =< 1
  • Coagulation parameters (international normalized ratio [INR], activated partial thromboplastin time [aPTT]) =< 1.25 x ULN institutional limits, except where a lupus anti-coagulant has been confirmed
  • Presence of biopsiable disease and willingness to undergo pre-treatment biopsy
  • The effects of olaparib and cediranib on the developing human fetus are unknown; for this reason, women of child-bearing potential and men 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 up to 3 months after end of treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is 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) less than or equal to the upper limit of normal
  • Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib
  • Ability to understand and the willingness to sign a written informed consent document
  • Willingness to release and confirmed availability of archival tissue sample for research purposes
  • Willingness and ability to check and record daily blood pressure readings; blood pressure cuffs will be provided to patients

Exclusion Criteria:

  • Participants may not have had chemotherapy or radiation therapy (RT) within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and must have recovered to =< grade 1 from adverse events due to agents administered more than 3 weeks earlier; patients should not have received hormonal therapy for treatment of their cancer within 2 weeks of study entry
  • Participants should not have received any other investigational agents nor have participated in an investigational trial within the past 4 weeks
  • Participants may not have had prior use of PARP inhibitors; patients may not have received prior treatment affecting the VEGF pathway in the recurrent setting, including but not limited to thalidomide, bevacizumab, sunitinib, or sorafenib
  • Participants may not have any evidence of ongoing inadequately controlled hypertension (defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic BP of > 90 mmHg); patients with hypertension may not be on more than three antihypertensive medications for management of their blood pressure (medications that combine two anti-hypertensives into one are considered as two medications); it is strongly recommended that patients who require three antihypertensive medications for baseline management of pre-existing hypertension be actively followed by a cardiologist or blood pressure specialist for management of BP while on protocol
  • Participants may not have had any prior history of hypertensive crisis or hypertensive encephalopathy
  • Participants may not have had history of abdominal fistula or gastrointestinal perforation; patients with a history of abdominal fistula will be considered eligible if the fistula has healed or 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
  • Participants may not have had a history of intra-abdominal abscess within the past 3 months
  • Participants may not have current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs
  • Participants may not have a dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)
  • Participants with any concomitant or prior invasive malignancies are ineligible 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 curative intent with no evidence of recurrent disease 3 years following diagnosis and judged by the investigator to be at low risk of recurrence
  • Participants with any of the following:

    • History of myocardial infarction within six months
    • Unstable angina
    • New York Heart Association (NYHA) classification of III or IV
  • If cardiac function assessment is clinically indicated or performed: participants will be ineligible if left ventricular ejection fraction (LVEF) is less than normal per institutional guidelines, or < 55%, if the threshold for normal is not otherwise specified by institutional guidelines
  • Patients with any of 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
    • A NYHA classification of II controlled with treatment
    • Prior history of impaired cardiac function
  • Participants may not have had a history of a stroke or transient ischemic attack within six months
  • Participants should not have clinically significant peripheral vascular disease or vascular disease (including aortic aneurysm or aortic dissection)
  • Participants may not have a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib
  • Participants should not have any 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 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 are ineligible; 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 must demonstrate stable post-therapeutic imaging and resolution of any associated symptoms and must be stably off steroids with no symptoms for at least 6 months following therapy prior to starting study drug
  • Participants may not have a 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) or moderate inhibitors of CYP3A4 are ineligible; the study team should check a frequently-updated medical reference for a list of drugs to avoid or minimize use of; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; dihydropyridine calcium-channel blockers are permitted for management of hypertension
  • Pregnant women are excluded from this study because olaparib and cediranib have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib and cediranib, breastfeeding should be discontinued if the mother is treated with cediranib and olaparib; these potential risks may also apply to other agents used in this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cediranib or olaparib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Participants should not have evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted
  • Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

    • Other anti-cancer therapy while on study treatment
    • Prophylactic use of bisphosphonates in patients without bone disease, except for the treatment of osteoporosis
    • Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, cannabis, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)
    • Raloxifene is allowed for patients taking it for bone health
  • Participants may not have any features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated

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): NCT02345265


Locations
Show Show 20 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Joyce F Liu Dana-Farber - Harvard Cancer Center LAO
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02345265    
Other Study ID Numbers: NCI-2015-00051
NCI-2015-00051 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16-700
9825 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
9825 ( Other Identifier: CTEP )
UM1CA186644 ( U.S. NIH Grant/Contract )
UM1CA186686 ( U.S. NIH Grant/Contract )
UM1CA186690 ( U.S. NIH Grant/Contract )
UM1CA186691 ( U.S. NIH Grant/Contract )
UM1CA186704 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
UM1CA186712 ( U.S. NIH Grant/Contract )
UM1CA186716 ( U.S. NIH Grant/Contract )
UM1CA186717 ( U.S. NIH Grant/Contract )
ZIABC011078 ( U.S. NIH Grant/Contract )
First Posted: January 26, 2015    Key Record Dates
Last Update Posted: June 18, 2020
Last Verified: June 2020
Additional relevant MeSH terms:
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Carcinoma
Adenocarcinoma
Cystadenocarcinoma, Serous
Carcinoma, Endometrioid
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Ovarian Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Endometrial Neoplasms
Uterine Neoplasms
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Cediranib
Maleic acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors