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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
155
Undergo optional tissue biopsy
Undergo blood sample collection
Given PO
Undergo CT
Undergo ECHO
Undergo MRI
Undergo MUGA
Given PO
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
...and 4 more locations
Number of Participants With Dose Limiting Toxicities of Cediranib Maleate in Combination With Olaparib (Phase I)
Was determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: At 28 days
The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Metastatic Triple-negative Breast Cancer (Phase I)
This trial employed a 3+3 design, escalating on 0/3 or 1/6 DLT, and de-escalating if 2 DLTs were encountered. The MTD (maximum tolerated dose) was the dose at which no more than 1 patient developed a dose-limiting toxicity (DLT) when at least 6 patients had been treated.
Time frame: At 28 Days
Progression-free Survival (PFS) at the Maximum Tolerated Dose/Recommended Phase 2 Dose of Cediranib Maleate With Olaparib Compared to That of Olaparib Alone (Phase II)
Evaluated by Kaplan-Meier analysis and log-rank test for between group comparison, and median survival times reported. PFS is defined as time from randomization to investigator-assessed radiographic progression by RECIST 1.1 criteria or death. Patients alive without evidence of progression were censored at the last disease assessment.
Time frame: Time from start of treatment to time of objective disease progression, assessed up to 5 years
The Maximum Tolerated Dose (MTD) of Cediranib in Combination With Olaparib Tablet Formulation in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T).
The Phase 1-T component of this trial employed a 3+3 design, escalating on 0/3 or 1/6 DLT, and de-escalating if 2 DLTs were encountered. The MTD (maximum tolerated dose) was the dose at which no more than 1 patient developed a DLT when at least 6 patients had been treated.
Time frame: At 28 days
Number of Participants With Treatment-related Toxicities of the Combination of Cediranib Maleate and Olaparib (Phase I)
Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, study-related adverse events observed in \>10% of participants (n=28).
Time frame: Adverse Events monitored for 3 years, mortality assessed up to 5 years
Tumor Response Rate (Objective Response Rate) Defined by Response Evaluation Criteria in Solid Tumors Criteria (Phase II)
The response rates are compared by an exact test and 95% confidence intervals will also be reported. Objective response rate (ORR) is defined as the best confirmed RECIST response, ORR is defined as the number of participants with CR, PR or SD.
Time frame: Up to 5 years
Overall Survival (Phase II)
Will be evaluated by Kaplan-Meier analysis and log-rank test for between-group comparison, and median survival time will be reported.
Time frame: Up to 5 years
Number of Participants With Treatment-related Toxicities of the Combination of Cediranib and Olaparib (Tablet Formulation) in the Treatment of Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer (Phase I-T).
Will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. This outcome reports treatment-related adverse events that occurred in at least 10% of participants.
Time frame: Up to 3 years
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