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

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase ITreatment18 and over09-293
NCI-2012-02938, DFCI IRB 09-293, NCI-2010-01329, NCI-2013-00578, NCT01115829, 8348, NCT01116648

Trial Description

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 cediranib maleate and olaparib 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.

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

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

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

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

Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib

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

Hemoglobin > 9 g/dL

For patients enrolled to the Phase 1-T portion of the protocol, the hemoglobin should be >= 10 g/dL

Patients must be willing and able to check and record daily blood pressure readings

Ability to understand and the willingness to sign a written informed consent

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

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)

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

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)

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

Troponin T or I within normal institutional limits

Total bilirubin within 1.5 times the upper limit of normal institutional limits

Absolute neutrophil count >= 1,500/mcL

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky > 60%)

Estimated life expectancy of greater than 6 months

Subjects may begin cediranib and olaparib at least 3 weeks after their last dose of chemotherapy or hormonal therapy, assuming they are otherwise eligible

Breast cancer participants must have measurable disease by RECIST criteria

Participants in the Phase II portion of the trial must have measurable disease by RECIST 1.1 criteria

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

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: Participants must have histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal serous cancer, fallopian tube cancer, or triple-negative breast cancer

Platelets >= 100,000/mcL

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

PHASE I-T: Participants must have histologically or cytologically confirmed epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer

Exclusion Criteria:

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cediranib or olaparib

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

No features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated

Patients may not use natural herbal products or other “folk remedies” while participating in this study

Known human immunodeficiency virus (HIV)-positive individuals are ineligible

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

Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted

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

History of stroke or transient ischemic attack within six months

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

History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib maleate or olaparib

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

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

Current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)

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

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
Joyce Fu Liu, Principal Investigator

Trial Sites

U.S.A.

California
Los Angeles

Cedars-Sinai Medical Center

Bobbie Jo Rimel
Ph: 310-423-1126
Email: bobbie.Rimel@cshs.org

Bobbie Jo Rimel
Principal Investigator

Illinois
Chicago

University of Chicago Comprehensive Cancer Center

Gini F. Fleming
Ph: 773-702-6712
Email: gfleming@medicine.bsd.uchicago.edu

Gini F. Fleming
Principal Investigator

Evanston

NorthShore University HealthSystem-Evanston Hospital

Jean A. Hurteau
Ph: 847-570-2639
Email: jhurteau@uchicago.edu

Jean A. Hurteau
Principal Investigator

Indiana
Fort Wayne

Fort Wayne Medical Oncology and Hematology Inc - Jefferson Boulevard

Sreenivasa R. Nattam
Ph: 260-484-8830
Email: ledgar@fwmoh.com

Sreenivasa R. Nattam
Principal Investigator

Fort Wayne Medical Oncology and Hematology Inc-Parkview

Sreenivasa R. Nattam
Ph: 260-484-8830
Email: ledgar@fwmoh.com

Sreenivasa R. Nattam
Principal Investigator

Maryland
Baltimore

Johns Hopkins University/Sidney Kimmel Cancer Center

Deborah Kay Armstrong
Ph: 410-614-2743
Email: darmstro@jhmi.edu

Deborah Kay Armstrong
Principal Investigator

Rockville

National Cancer Institute

Jung-min Lee
Ph: 301-443-7735
Email: leej6@mail.nih.gov

Jung-min Lee
Principal Investigator

Massachusetts
Boston

Beth Israel Deaconess Medical Center

Mary Kathleen Buss
Ph: 617-667-1395
Email: mbuss@bidmc.havard.edu

Mary Kathleen Buss
Principal Investigator

Dana-Farber Cancer Institute

Joyce Fu Liu
Ph: 617-632-5269
Email: joyce_liu@dfci.harvard.edu

Joyce Fu Liu
Principal Investigator

Massachusetts General Hospital Cancer Center

Michael James Birrer
Ph: 617-724-4800
Email: mbirrer@partners.org

Michael James Birrer
Principal Investigator

Charlestown

Massachusetts General Hospital

Michael James Birrer
Ph: 617-724-4800
Email: mbirrer@partners.org

Michael James Birrer
Principal Investigator

Michigan
Ann Arbor

University of Michigan Comprehensive Cancer Center

Ronald J. Buckanovich
Ph: 734-764-2395
Email: ronaldbu@umich.edu

Ronald J. Buckanovich
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01116648

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.