Cediranib Maleate and Olaparib in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Recurrent Triple-Negative Breast Cancer

Tracking Information
First Submitted Date ICMJE	April 29, 2010
First Posted Date ICMJE	May 5, 2010
Last Update Posted Date	March 5, 2018
Actual Study Start Date ICMJE	March 25, 2010
Estimated Primary Completion Date	October 31, 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 2, 2018)	Dose limiting toxicity and maximum tolerated dose of cediranib maleate in combination with olaparib (Phase I) [ Time Frame: At 28 days ]Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0; Progression-free survival at the maximum tolerated dose/recommended phase 2 dose of cediranib maleate with olaparib compared to that of olaparib alone (Phase II) [ Time Frame: Time from start of treatment to time of objective disease progression, assessed up to 3 years ]Will be evaluated by Kaplan-Meier analysis and log-rank test for between group comparison, and median survival times reported.; Dose limiting toxicities and maximum tolerated dose of cediranib maleate in combination with olaparib (tablet formulation) (Phase I-Tablet) [ Time Frame: At 28 days ]Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Original Primary Outcome Measures ICMJE; (submitted: May 4, 2010)	Phase I: Establish the MTD of cediranib in combination with olaparib in the treatment of recurrent papillary-ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer. [ Time Frame: 2 years ]; Phase II: Assess the efficacy of the combination of cediranib and olaparib compared to cediranib alone in recurrent grade 2 or 3 platinum-sensitive papillary-serous ovarian, fallopian tube, or peritoneal cancer, as measured by disease-free progression. [ Time Frame: 2 years ]
Change History	Complete list of historical versions of study NCT01116648 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 2, 2018)	Incidence of toxicities of the combination of cediranib maleate and olaparib (Phase I) [ Time Frame: Up to 3 years ]Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0; Tumor response rate as defined by Response Evaluation Criteria in Solid Tumors criteria (Phase II) [ Time Frame: Up to 3 years ]The response rates will be compared by an exact test and 95% confidence intervals will also be reported.; Clinical benefit rate defined as response or stable disease x 16 weeks, as determined by Response Evaluation Criteria in Solid Tumors 1.1 criteria (Phase II) [ Time Frame: Up to 3 years ]Will be determined by Response Evaluation Criteria in Solid Tumors 1.1 criteria.; Overall survival (Phase II) [ Time Frame: Up to 3 years ]Will be evaluated by Kaplan-Meier analysis and log-rank test for between-group comparison, and median survival time will be reported.; Incidence of toxicities of the combination of cediranib maleate and olaparib (Phase I-Tablet) [ Time Frame: Up to 3 years ]Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Original Secondary Outcome Measures ICMJE; (submitted: May 4, 2010)	Phase I: Assess side effects and toxicity of this drug combination in this patient population, as measured by CTCAE Active Version. [ Time Frame: 2 years ]The type and number of participants with adverse events will be assessed as a measure of safety and tolerability; Phase I: Assess clinical benefit, progression-free survival, and overall survival for this patient population. [ Time Frame: 5 years ]; Phase II: Assess tumor response, clinical response benefit, and overall survival for patients treated with cediranib and olaparib as compared with patients receiving olaparib alone. [ Time Frame: 5 years ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Cediranib Maleate and Olaparib in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Recurrent Triple-Negative Breast Cancer
Official Title ICMJE	Phase I/II Study of Cediranib and Olaparib in Combination for Treatment of Recurrent Papillary-Serous Ovarian, Fallopian Tube, or Peritoneal Cancer or for Treatment of Recurrent Triple-Negative Breast Cancer
Brief Summary	This partially randomized phase I/II trial studies the side effects and the best dose of cediranib maleate and olaparib and to see how well they work compared to olaparib alone in treating patients with ovarian, fallopian tube, peritoneal, or triple-negative breast cancer that has returned after a period of improvement. Cediranib maleate may help keep cancer cells from growing by affecting their blood supply. Olaparib may stop cancer cells from growing abnormally. The combination of cediranib maleate and olaparib may help to keep cancer from growing.
Detailed Description	PRIMARY OBJECTIVES: I. Assess the maximum tolerated dose (MTD) of cediranib (cediranib maleate) in combination with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer. (Phase I) II. Assess the efficacy (as measured by progression-free survival [PFS]) of the combination of cediranib and olaparib compared to olaparib alone in recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer. (Phase II) III. Assess the MTD of cediranib in combination with olaparib tablet formulation in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer. (Phase I-T) SECONDARY OBJECTIVES: I. Assess the toxicities of the combination of cediranib and olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast cancer. (Phase I) II. Assess clinical benefit, progression-free survival, and overall survival for patients treated with cediranib and olaparib. (Phase I) III. Assess tumor response, clinical response benefit (response or stable disease as defined by Response Evaluation Criteria in Solid Tumors [RECIST] response criteria x 16 weeks), and overall survival (OS) for patients treated with cediranib and olaparib at the recommended phase II dose (RP2D) as compared with patients receiving olaparib alone. (Phase II) IV. Assess the toxicities of the combination of cediranib and olaparib (tablet formulation) in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer. (Phase I-T) V. Assess clinical benefit, progression-free survival, and overall survival for patients treated with cediranib and olaparib (tablet formulation). (Phase I-T) VI. Assess the pharmacokinetic profile of cediranib and olaparib (tablet formulation) when administered in combination. (Phase I-T) TERTIARY OBJECTIVES: I. To evaluate the prognostic and predictive role of measured changes in functional vascular imaging using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) between pre-study and day 3. (Phase II) II. To evaluate in an exploratory fashion the predictive or prognostic value of single nucleotide polymorphisms (SNPs) in key genes involved in angiogenesis and deoxyribonucleic acid (DNA) repair. (Phase II) III. To evaluate the predictive value of baseline peripheral blood mononuclear cells (PBMC) poly adenosine diphosphate (ADP) ribose (PAR) incorporation on response to therapy. (Phase II) IV. To measure early changes in vascular cytokine production and evaluate in an exploratory fashion that these changes may be predictive or prognostic, or differentially affected by the combination of agents. (Phase II) V. To evaluate early changes to circulating endothelial cells and if these changes are predictive or prognostic. (Phase II) VI. To assess changes in measures of DNA damage and repair and angiogenesis in tumor cells (tissue and/or malignant effusions) and correlate to drug/drug/combination. (Phase II) OUTLINE: This is a phase I, dose-escalation study followed by a randomized phase II study. PHASE I: Patients receive cediranib maleate orally (PO) once daily (QD) and olaparib PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28. ARM II: Patients receive olaparib PO BID on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for up to 3 years.
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Deleterious BRCA1 Gene Mutation; Deleterious BRCA2 Gene Mutation; Estrogen Receptor Negative; HER2/Neu Negative; Ovarian Endometrioid Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Triple-Negative Breast Carcinoma
Intervention ICMJE	Drug: Cediranib Maleate Given PO Other Names: AZD2171 AZD2171 Maleate Recentin; Other: Laboratory Biomarker Analysis Correlative studies; Drug: Olaparib Given PO Other Names: AZD2281 KU-0059436 Lynparza PARP Inhibitor AZD2281; Other: Pharmacological Study Correlative studies
Study Arms	Experimental: Arm I (cediranib maleate and olaparib) Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Interventions: Drug: Cediranib Maleate Other: Laboratory Biomarker Analysis Drug: Olaparib Other: Pharmacological Study; Active Comparator: Arm II (olaparib) Patients receive olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Interventions: Other: Laboratory Biomarker Analysis Drug: Olaparib Other: Pharmacological Study
Publications *	Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel B, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014 Oct;15(11):1207-14. doi: 10.1016/S1470-2045(14)70391-2. Epub 2014 Sep 10.; Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, Lee H, Whalen C, Tyburski K, Winer E, Ivy P, Matulonis UA. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013 Sep;49(14):2972-8. doi: 10.1016/j.ejca.2013.05.020. Epub 2013 Jun 27.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Estimated Enrollment ICMJE; (submitted: May 20, 2015)	162
Original Estimated Enrollment ICMJE; (submitted: May 4, 2010)	90
Study Completion Date	Not Provided
Estimated Primary Completion Date	October 31, 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: PHASE I: Participants must have histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal serous cancer, fallopian tube cancer, or triple-negative breast cancer; PHASE II: Participants must have histologically or cytologically grade 2 or 3 (high-grade) papillary-serous or endometrioid epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer; participants with epithelial ovarian, primary peritoneal, or fallopian tube cancers of other high-grade histologies who carry a known deleterious breast cancer gene (BRCA) germline mutation by standard clinical testing (Myriad BRAC Analysis) will also be considered eligible; PHASE I-T: Participants must have histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer; Ovarian cancer, primary peritoneal, and fallopian tube participants in the Phase 1 and Phase 1-T portions of this trial must have either measurable cancer by RECIST 1.1 criteria or an elevated cancer antigen (CA)125 level at least twice the upper limit of normal on two separate occasions at least 1 day but not more than 3 months apart; at least one of the samples should be within 1 week of starting treatment; patients with both an elevated CA125 and measurable cancer will be followed by RECIST 1.1 criteria; patients with only an elevated CA125 level will be followed by modified Gynecologic Cancer Intergroup (GCIG) criteria; Participants in the Phase II portion of the trial must have measurable disease by RECIST 1.1 criteria; Breast cancer participants must have measurable disease by RECIST criteria; PRIOR THERAPY PHASE I and PHASE I-T: Prior chemotherapy for ovarian cancer patients must have included a first-line platinum-based regimen with or without intravenous consolidation chemotherapy Breast cancer patients must have recurred post both an Adriamycin- and taxane-containing regimen Prior hormonal-based therapy for ovarian, primary peritoneal serous, fallopian tube cancer, or breast cancer is acceptable Patients may not have had a prior PAR polymerase (PARP)-inhibitor in the recurrent or metastatic setting; prior treatment with BSI-201 (iniparib) is allowed Patients may not have had a prior anti-angiogenic agent in the recurrent or metastatic setting; PRIOR THERAPY PHASE II: Prior chemotherapy must have included a first-line platinum-based regimen with or without intravenous consolidation chemotherapy Prior hormonal-based therapy for ovarian, primary peritoneal serous, or fallopian tube cancer is acceptable Patients may not have previously received a PARP-inhibitor; prior treatment with BSI-201 is allowed Patients may not have had a prior anti-angiogenic agent in the recurrent setting Patients may have received up to 1 non-platinum-based line of therapy in the recurrent setting Patients may have received an unlimited number of platinum-based therapies in the recurrent setting Patients should have platinum-sensitive disease, where platinum-sensitive disease is defined as having had a > 6 month interval since last receiving platinum therapy prior to disease recurrence; patients must have had a prior response while on the platinum-containing regimen and cannot have experienced disease progression while receiving platinum; Subjects may begin cediranib and olaparib at least 3 weeks after their last dose of chemotherapy or hormonal therapy, assuming they are otherwise eligible; Estimated life expectancy of greater than 6 months; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky > 60%); Absolute neutrophil count >= 1,500/mcL; Platelets >= 100,000/mcL; Hemoglobin > 9 g/dL For patients enrolled to the Phase 1-T portion of the protocol, the hemoglobin should be >= 10 g/dL; Total bilirubin within 1.5 times the upper limit of normal institutional limits; Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal; Creatinine =< the institutional upper limit of normal 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 ratio [INR], activated partial thromboplastin time [aPTT]) within 1.25 x upper limit of normal institutional limits, except where a Lupus anti-coagulant has been confirmed; Toxicities of prior therapy (except 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); Subjects 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 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 are eligible; subjects with any other concomitant or prior invasive malignancies are ineligible; Patients who have the following risk factors are considered to be at increased risk for cardiac toxicities; these patients should have increased monitoring: Prior treatment with anthracyclines Prior treatment with trastuzumab A New York Heart Association classification of II controlled with treatment Prior central thoracic radiation therapy (RT), including RT to the heart History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded from the study); 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 for 3 months following treatment discontinuation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; Ability to understand and the willingness to sign a written informed consent; Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib; Patients must be willing and able to check and record daily blood pressure readings Exclusion Criteria: Participants who have had chemotherapy or radiotherapy within 3 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 3 weeks earlier; Participants may not be receiving any other investigational agents nor have participated in an investigational trial within the past 4 weeks; subjects may not have received prior treatment affecting the vascular endothelial growth factor (VEGF) pathway in the recurrent setting, including thalidomide, bevacizumab, sunitinib, or sorafenib; in the Phase I portion of the trial, subjects may not have received prior treatment with oregovomab (OvaRex) or any other antibodies that may interfere with CA-125 measurements; Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or 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 maleate 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; dihydropyridine calcium-channel blockers are permitted for management of hypertension; Patients with any of the following: History of myocardial infarction within six months Patients with corrected QT (QTc) prolongation > 500 msec or other significant electrocardiogram (ECG) abnormality noted within 14 days of treatment For patients enrolled in the Phase 1-T portion of the protocol, the QTc should not exceed 470 msec 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 Condition requiring concurrent use of drugs or biologics with pro-arrhythmic potential; History of stroke or transient ischemic attack within six months; Patients may not have any evidence of pre-existing inadequately controlled hypertension (defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic BP of > 90 mmHg), and must have a normal blood pressure (=< 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; Any prior history of hypertensive crisis or hypertensive encephalopathy; Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or aortic dissection); Unstable angina; Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib; History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess; Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs; Current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN); Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted; 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 natural herbal products or other "folk remedies" while participating in this study; No features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01116648
Other Study ID Numbers ICMJE	NCI-2012-02938; NCI-2012-02938 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); DFCI IRB 09-293; NCI-2010-01329; NCI-2013-00578; 8348 ( Other Identifier: Dana-Farber Cancer Institute ); 8348 ( Other Identifier: CTEP ); N01CM00071 ( U.S. NIH Grant/Contract ); P30CA006516 ( U.S. NIH Grant/Contract ); U01CA062490 ( U.S. NIH Grant/Contract ); UM1CA186709 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Cancer Institute (NCI)
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Joyce Liu Dana-Farber Cancer Institute
PRS Account	National Cancer Institute (NCI)
Verification Date	November 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP