Cediranib Maleate and Olaparib or Standard Chemotherapy in Treating Patients With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Official Title

A Randomized Phase II/III Study of the Combination of Cediranib and Olaparib Compared to Cediranib or Olaparib Alone, or Standard of Care Chemotherapy in Women With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (COCOS)

Summary:

This randomized phase II/III trial studies how well cediranib maleate and olaparib work when given together or separately, and compares them to standard chemotherapy in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has returned after receiving chemotherapy with drugs that contain platinum (platinum-resistant) or continued to grow while being treated with platinum-based chemotherapy drugs (platinum-refractory). Cediranib maleate and olaparib may stop the growth of tumour cells by blocking enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving cediranib maleate and olaparib together may cause more damage to cancer cells when compared to either drug alone or standard chemotherapy.

Trial Description

Primary Outcome:

  • OS (Phase III)
  • PFS (Phase II and Phase III)
Secondary Outcome:
  • Frequency and severity of adverse events by CTCAE v.4.0 (Phase II and Phase III)
  • ORR (partial or complete response), defined by RECIST v1.1 criteria (Phase II and Phase III)
PRIMARY OBJECTIVES:
  • To assess the efficacy and identify (in)active arm(s) of the combination of cediranib (cediranib maleate) and olaparib, cediranib alone, olaparib alone, and physician's choice standard of care chemotherapy, as measured by progression-free survival (PFS) in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase II)
  • To assess the efficacy of the combination of cediranib and olaparib, and active monotherapy experimental arm(s) from Randomized Phase II, as measured by overall survival (OS) and PFS, as compared to physician's choice standard of care chemotherapy in women with recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)
SECONDARY OBJECTIVES:
  • To assess the efficacy of the combination of cediranib and olaparib, cediranib alone, olaparib alone, and physician's choice standard of care chemotherapy, as measured by objective response rate (ORR: partial or complete response) by Response Evaluation Criteria in Solid Tumours (RECIST) criteria, in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase II)
  • To assess safety endpoints, as measured by frequency and severity of adverse events by Common Terminology Criteria for Adverse Events (CTCAE) version (v).4.0. (Phase II and Phase III)
  • To assess the efficacy of the combination of cediranib and olaparib, and active monotherapy experimental arm(s) from Randomized Phase II, as measured by ORR, as compared to physician's choice standard of care chemotherapy in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)
TERTIARY OBJECTIVES:
  • To assess correlation of homologous recombination deficiency (HRD) status, as assessed via BROCA-HR assay with response, as measured by PFS and ORR. (Phase II)
  • To evaluate the prognostic and predictive role of circulating endothelial cells (CEC) on comparative effectiveness of targeted therapies and reference chemotherapy. (Phase II)
  • To evaluate quality of life data compliance, as measured by the 9-item Disease Related Symptoms (DRS-9) subscale of the National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) Ovarian Symptom Index (NFOSI) for utilization and analysis in the Phase III study. (Phase II)
  • To assess exploratory biomarkers of potential HRD, including genomic scarring, BRCA1 methylation, BRCA1 protein expression, and mutations in NHEJ, and other genes that might modify HRD. (Phase II and Phase III)
  • To evaluate the prognostic and predictive role of angiogenic biomarkers, as assessed by the Duke plasma angioma. (Phase II and Phase III)
  • To assess correlation of HRD status, as assessed via BROCA-HR assay with response, as measured by OS, PFS and ORR. (Phase III)
  • To evaluate the prognostic and predictive role of circulating endothelial cells (CEC) on comparative effectiveness of targeted therapies and reference chemotherapy. (Phase III)
  • To assess the effect on disease-related symptoms (DRS) as measured by the 9-item DRS-P subscale of the NCCN-FACT Ovarian Symptom Index-18 (NFOSI-18), of single agent olaparib or cediranib and combination, compared to standard chemotherapy, in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)
  • To assess the effect on secondary measures of quality of life, as assessed by the treatment side effects (TSE) and function/well-being (F/WB) subscales of the NFOSI-18, sensory neuropathy as measured by the FACT/GOG-Ntx-4, and health utility as measured by the EQ-5D, of single agent olaparib or cediranib and combination, compared to standard chemotherapy, in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)
OUTLINE:

PHASE II: Patients are randomized to 1 of 4 treatment arms.

ARM I (REFERENCE REGIMEN): Patients undergo physician's choice of standard of care chemotherapy, comprising either paclitaxel intravenously (IV) on days 1, 8, 15, and 22 every 28 days (Regimen I); pegylated liposomal doxorubicin hydrochloride IV on day 1 every 28 days (Regimen II); or topotecan hydrochloride IV on days 1, 8, and 15 every 28 days or days 1-5 every 21 days (Regimen III). Treatment continues in the absence of disease progression or unacceptable toxicity.

ARM II (CEDIRANIB MALEATE AND OLAPARIB): Patients receive cediranib maleate orally (PO) and olaparib PO as determined from an ongoing Phase I study. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III (CEDIRANIB): Patients receive cediranib maleate PO daily continuously. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IV (OLAPARIB): Patients receive olaparib PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE III: Patients are randomized to 1 of 3 treatment arms. ARM I (REFERENCE REGIMEN): Patients undergo physician's choice standard of care chemotherapy as in Phase II Arm I.

ARM II (CEDIRANIB AND OLAPARIB): Patients receive cediranib maleate PO and olaparib PO as in Phase II Arm II.

ARM III (SINGLE AGENT): Patients receive either olaparib maleate PO or cediranib PO, as determined by the Phase II study. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for up to 3 years.

View this trial on ClinicalTrials.gov

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