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

NCT ID: NCT01116648

Last Updated: 2025-09-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 155 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-14
• Study Completion Date: 2026-02-13

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 (recurrent). 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 be safe, tolerable and/or effective in treating patients with recurrent ovarian, fallopian tube, or peritoneal cancer or recurrent triple-negative breast cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. Assess the maximum tolerated dose (MTD) of cediranib maleate (cediranib) 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) 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)

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)

TRANSLATIONAL 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) as well as blood sample collection on the trial. Patients may also optionally undergo a tissue biopsy on the trial.

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, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo CT or MRI as well as blood sample collection on the trial. Patients may also optionally undergo a tissue biopsy on the trial.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Conditions

Fallopian Tube Carcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian High Grade Serous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Triple-Negative Breast Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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. Patients undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo CT or MRI as well as blood sample collection on the trial. Patients may also optionally undergo a tissue biopsy on the trial.

Group Type: EXPERIMENTAL

Biopsy Procedure

Intervention Type: PROCEDURE

Undergo optional tissue biopsy

Biospecimen Collection

Intervention Type: PROCEDURE

Undergo blood sample collection

Cediranib Maleate

Intervention Type: DRUG

Given PO

Computed Tomography

Intervention Type: PROCEDURE

Undergo CT

Echocardiography Test

Intervention Type: PROCEDURE

Undergo ECHO

Magnetic Resonance Imaging

Intervention Type: PROCEDURE

Undergo MRI

Multigated Acquisition Scan

Intervention Type: PROCEDURE

Undergo MUGA

Olaparib

Intervention Type: DRUG

Given PO

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. Patients undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo CT or MRI as well as blood sample collection on the trial. Patients may also optionally undergo a tissue biopsy on the trial.

Group Type: ACTIVE_COMPARATOR

Biopsy Procedure

Intervention Type: PROCEDURE

Undergo optional tissue biopsy

Biospecimen Collection

Intervention Type: PROCEDURE

Undergo blood sample collection

Computed Tomography

Intervention Type: PROCEDURE

Undergo CT

Echocardiography Test

Intervention Type: PROCEDURE

Undergo ECHO

Magnetic Resonance Imaging

Intervention Type: PROCEDURE

Undergo MRI

Multigated Acquisition Scan

Intervention Type: PROCEDURE

Undergo MUGA

Olaparib

Intervention Type: DRUG

Given PO

Interventions

Biopsy Procedure

Undergo optional tissue biopsy

Intervention Type: PROCEDURE

Biospecimen Collection

Undergo blood sample collection

Intervention Type: PROCEDURE

Cediranib Maleate

Given PO

Intervention Type: DRUG

Computed Tomography

Undergo CT

Intervention Type: PROCEDURE

Echocardiography Test

Undergo ECHO

Intervention Type: PROCEDURE

Magnetic Resonance Imaging

Undergo MRI

Intervention Type: PROCEDURE

Multigated Acquisition Scan

Undergo MUGA

Intervention Type: PROCEDURE

Olaparib

Given PO

Intervention Type: DRUG

Other Intervention Names

Biopsy; BIOPSY_TYPE; Bx; Biological Sample Collection; Biospecimen Collected; Specimen Collection; AZD2171; AZD2171 Maleate; Recentin; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized axial tomography (procedure); Computerized Tomography; Computerized Tomography (CT) scan; CT; CT Scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; tomography; EC; Echocardiography; Magnetic Resonance; Magnetic Resonance Imaging (MRI); Magnetic resonance imaging (procedure); Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI; MRI Scan; MRIs; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Structural MRI; Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; Gated Heart Pool Scan; MUGA; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Radionuclide Ventriculography; RNV Scan; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; AZD 2281; AZD-2281; AZD2281; KU 0059436; KU-0059436; KU0059436; Lynparza; Olanib; Olaparix; PARP Inhibitor AZD2281

Eligibility Criteria

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
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of cediranib or olaparib in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials
• 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)
• The effects of cediranib and olaparib 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 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, since neurologic dysfunction may confound the evaluation of neurologic and other adverse events; 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 because cediranib and olaparib are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with cediranib and olaparib, breastfeeding should be discontinued if the mother is treated with cediranib or olaparib; these potential risks may also apply to other agents used in this study
• Known human immunodeficiency virus (HIV)-positive individuals are ineligible because of the potential for pharmacokinetic interactions with cediranib or olaparib; in addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joyce F Liu

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Cedars Sinai Medical Center

Los Angeles, California, United States

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States

NorthShore University HealthSystem-Evanston Hospital

Evanston, Illinois, United States

Fort Wayne Medical Oncology and Hematology Inc - Jefferson Boulevard

Fort Wayne, Indiana, United States

Fort Wayne Medical Oncology and Hematology Inc-Parkview

Fort Wayne, Indiana, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

National Cancer Institute

Rockville, Maryland, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Massachusetts General Hospital

Charlestown, Massachusetts, United States

Newton-Wellesley Hospital

Newton, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Countries

United States

References

Gaitskell K, Rogozinska E, Platt S, Chen Y, Abd El Aziz M, Tattersall A, Morrison J. Angiogenesis inhibitors for the treatment of epithelial ovarian cancer. Cochrane Database Syst Rev. 2023 Apr 18;4(4):CD007930. doi: 10.1002/14651858.CD007930.pub3.

Reference Type: DERIVED

PMID: 37185961 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25218906 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23810467 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2012-02938

Identifier Type: REGISTRY

Identifier Source: secondary_id

NCI-2010-01329

Identifier Type: -

Identifier Source: secondary_id

DFCI IRB 09-293

Identifier Type: -

Identifier Source: secondary_id

NCI-2013-00578

Identifier Type: -

Identifier Source: secondary_id

8348

Identifier Type: OTHER

Identifier Source: secondary_id

8348

Identifier Type: OTHER

Identifier Source: secondary_id

N01CM00071

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA006516

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01CA062490

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UM1CA186709

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2012-02938

Identifier Type: -

Identifier Source: org_study_id

NCT01115829

Identifier Type: -

Identifier Source: nct_alias