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Testing Olaparib for One or Two Years, With or Without Bevacizumab, to Treat Ovarian Cancer

Phase 3
Recruiting
Conditions
Fallopian Tube Endometrioid Adenocarcinoma
Fallopian Tube High Grade Serous Adenocarcinoma
FIGO Stage III Ovarian Cancer 2014
FIGO Stage IV Ovarian Cancer 2014
Ovarian Carcinoma
Ovarian High Grade Endometrioid Adenocarcinoma
Ovarian High Grade Serous Adenocarcinoma
Primary Peritoneal Endometrioid Adenocarcinoma
Primary Peritoneal High Grade Serous Adenocarcinoma
Interventions
Procedure: Biospecimen Collection
Procedure: Computed Tomography
Procedure: Magnetic Resonance Imaging
Registration Number
NCT06580314
Lead Sponsor
NRG Oncology
Brief Summary

This phase III trial compares the effect of olaparib for one year versus two years, with or without bevacizumab, for the treatment of BRCA 1/2 mutated or homologous recombination deficient stage III or IV ovarian cancer. Olaparib is a polyadenosine 5'-diphosphoribose polymerase (PARP) enzyme inhibitor and may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving olaparib for one year with or without bevacizumab may be effective in treating patients with BRCA 1/2 mutated or homologous recombination deficient stage III or IV ovarian cancer, when compared to two years of olaparib.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine investigator assessed progression-free survival using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (non-inferiority) for one versus (vs.) two years of maintenance olaparib.

SECONDARY OBJECTIVES:

I. To evaluate overall survival (OS360) in the modified intent to treat (ITT) population, with time at risk for progression/death starting 360 days after randomization.

II. To evaluate progression-free survival (PFS), PFS2 and overall survival (OS) in the ITT population.

III. To evaluate PFS, PFS2, and OS in the as-treated population. IV. To evaluate toxicity, including rates of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and other secondary malignancies, in the safety population.

EXPLORATORY OBJECTIVE:

I. To evaluate the moderating effect of physician-choice bevacizumab (as stratified) on randomized treatment effect estimates.

TRANSLATIONAL OBJECTIVES:

I. To assess BRCA reversion mutations in circulating tumor deoxyribonucleic acid (ctDNA) as a predictor of poor response in the BRCA mutated (BRCAm) population.

II. To correlate a combined assay assessing quantitative BRCA1 and RAD51C promoter methylation and pathogenic variants in core homologous recombination repair (HRR) genes with clinical homologous recombination deficiency (HRD) testing and outcomes in the BRCA wildtype (BRCAwt) population.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (REFERENCE): Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study.

ARM II (EXPERIMENTAL): Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
880
Inclusion Criteria
  • Patients with newly diagnosed, pathologically confirmed, Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer of the following types:

    • High grade serous
    • High grade endometrioid, and/or
    • Other epithelial ovarian cancer with BRCA1/2 deleterious alteration (germline or somatic)
    • Submission of pathology report is required
    • Ovarian cancer = ovarian, fallopian, or primary peritoneal cancer
  • Patients must have:

    • Documented variant (tumor or germline) in BRCA1 or BRCA2 that is predicted to be pathogenic or suspected pathogenic (deleterious alteration)

      • Submission of testing report is required. OR
    • BRCA 1/2 wildtype AND known HRD deficient tumor determined by any commercial or academic, Clinical Laboratory Improvement Act (CLIA)-certified laboratory (e.g., Myriad MyChoice©)

      • Submission of testing report is required
  • Patient must have undergone cytoreductive surgery (primary or interval)

  • Patients must have completed first line platinum-based therapy prior to registration:

    • Platinum based chemotherapy course must have consisted of a minimum of 4 treatment cycles and a maximum of 9, although it is strongly recommended that patients receive at least 6 cycles unless medically contraindicated

      • For those receiving less than 6 cycles of platinum-based therapy, the reason for this must be documented and could include hematologic toxicity or non-hematologic toxicities directly related to therapy
    • Intravenous, intraperitoneal, or neoadjuvant platinum-based chemotherapy is allowed; for weekly therapy, three weeks are considered one cycle

    • Patients must not have received an investigational agent during their first line course of chemotherapy

  • Patients must have, in the opinion of the investigator, no clinical evidence of disease progression following completion of this chemotherapy course (partial or complete response to platinum-based chemotherapy)

  • Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression following completion of this chemotherapy course (partial or complete response to platinum-based chemotherapy)

  • Patients must be randomized at least 3 weeks and no more than 12 weeks after their last dose of chemotherapy (last dose is the day of the last infusion of platinum agent)

  • No previous treatment with a PARP inhibitor, including olaparib, niraparib, and rucaparib

  • Age ≥ 18

  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

  • Not pregnant and not nursing

  • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3

  • Platelets ≥ 100,000 cells/mm^3

  • Hemoglobin ≥ 9 g/dl

  • Creatinine clearance (CrCL) of > 30 mL/min by the Cockcroft-Gault formula

  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x institutional ULN may be enrolled)

  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional ULN

  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

  • No active infection requiring parental antibiotic(s)

  • No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not diverted), gastrointestinal perforation, gastrointestinal (GI) obstruction, and/or need for drainage nasogastric or gastrostomy tube

  • No current inability to swallow orally administered medication

  • No history of myelodysplastic syndrome and/or acute myeloid leukemia

  • No history of allogeneic bone marrow transplant

  • No concomitant use of strong or moderate CYP3A inducers

  • No known hypersensitivity to olaparib or any of the excipients of the product

Exclusion Criteria

Not provided

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Arm II (olaparib, bevacizumab)Computed TomographyPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm II (olaparib, bevacizumab)Magnetic Resonance ImagingPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm II (olaparib, bevacizumab)OlaparibPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm I (olaparib, bevacizumab)BevacizumabPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm I (olaparib, bevacizumab)Biospecimen CollectionPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm I (olaparib, bevacizumab)Computed TomographyPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm I (olaparib, bevacizumab)Magnetic Resonance ImagingPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm I (olaparib, bevacizumab)OlaparibPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm II (olaparib, bevacizumab)BevacizumabPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Arm II (olaparib, bevacizumab)Biospecimen CollectionPatients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
Primary Outcome Measures
NameTimeMethod
Progression free survival (PFS) at least 360 days after randomization (PFS360)From completing 360 days of maintenance therapy to disease progression (per Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) or death, whichever occurs first, assessed up to 5 years

PFS will be tested using a one-sided, alpha = 0.05 level logrank test. Treatment hazard ratios and their 90% confidence intervals will be estimated using a Cox proportional hazards model specified with a main effect for the randomized treatment assignment and stratified using the stratification factors applied at randomization.

Secondary Outcome Measures
NameTimeMethod
Overall survival (OS) 360From 360 days after randomization to death from any cause, assessed up to 5 years

This endpoint will be supported by the modified intent to treat (ITT) population, which excludes progressions, deaths or withdrawals within 359 days of randomization. Will be summarized using treatment hazard ratio estimates (90% confidence intervals). These estimates will be obtained from outcome-specific Cox-regression models specified with main effects for the randomized treatment and stratified by the factors included in the randomization. OS distributions will be summarized using methods developed by Kaplan-Meier.

PFSFrom randomization to progression or death, whichever occurs first, or date of the last computed tomography scan if neither progression nor death has occurred, assessed up to 5 years

Will be analyzed in the ITT population and serve as a sensitivity analysis for the primary endpoint. Will be summarized using treatment hazard ratio estimates (90% confidence intervals). These estimates will be obtained from outcome-specific Cox-regression models specified with main effects for the randomized treatment and stratified by the factors included in the randomization. PFS distributions will be summarized using methods developed by Kaplan-Meier.

PFS2From randomization to objective tumor progression on next-line treatment or death, assessed up to 5 years

PFS2 may be identified by objective radiological progression using Response Evaluation Criteria in Solid Tumors version (v)1.1., symptomatic deterioration or death. PFS2 will be summarized using treatment hazard ratio estimates (90% confidence intervals). These estimates will be obtained from outcome-specific Cox-regression models specified with main effects for the randomized treatment and stratified by the factors included in the randomization. PFS2 distributions will be summarized using methods developed by Kaplan-Meier.

OSFrom randomization to death, assessed up to 5 years

OS will be summarized using treatment hazard ratio estimates (90% confidence intervals). These estimates will be obtained from outcome-specific Cox-regression models specified with main effects for the randomized treatment and stratified by the factors included in the randomization. OS distributions will be summarized using methods developed by Kaplan-Meier.

Incidence of adverse events (AEs)Up to 30 days after last dose of study treatment

Safety and tolerability will be graded using Common Terminology Criteria for Adverse Events v 5.0. AEs will be summarized by system organ class and preferred term according to the maximum grade observed for each patient.

Trial Locations

Locations (510)

University of Alabama at Birmingham Cancer Center

🇺🇸

Birmingham, Alabama, United States

Anchorage Associates in Radiation Medicine

🇺🇸

Anchorage, Alaska, United States

Alaska Breast Care and Surgery LLC

🇺🇸

Anchorage, Alaska, United States

Alaska Oncology and Hematology LLC

🇺🇸

Anchorage, Alaska, United States

Alaska Women's Cancer Care

🇺🇸

Anchorage, Alaska, United States

Katmai Oncology Group

🇺🇸

Anchorage, Alaska, United States

Providence Alaska Medical Center

🇺🇸

Anchorage, Alaska, United States

Cancer Center at Saint Joseph's

🇺🇸

Phoenix, Arizona, United States

Mercy Hospital Fort Smith

🇺🇸

Fort Smith, Arkansas, United States

CARTI Cancer Center

🇺🇸

Little Rock, Arkansas, United States

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University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States

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