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A Study to Evaluate the Efficacy and Safety of Niraparib Novel Treatment Combinations in Participants With Recurrent Ovarian Cancer (OPAL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03574779
Recruitment Status : Active, not recruiting
First Posted : July 2, 2018
Last Update Posted : October 27, 2020
Information provided by (Responsible Party):
Tesaro, Inc.

Brief Summary:
Niraparib is an orally available, potent, highly selective poly adenosine diphosphate-ribose polymerase (PARP) 1 and PARP2 inhibitor. This study is to evaluate the efficacy and safety of niraparib novel treatment combinations in participants with advanced, relapsed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The purpose of this study is to evaluate the efficacy and safety of novel combinations of niraparib with other agents with strong scientific rationale for synergistic activity in participants with recurrent ovarian cancer. This study will consist of screening, treatment and end of treatment periods.

Condition or disease Intervention/treatment Phase
Ovarian Neoplasms Drug: Niraparib Drug: TSR-042 Drug: Bevacizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: This is an open-label study
Primary Purpose: Treatment
Official Title: Phase 2 Multicohort Study to Evaluate the Safety and Efficacy of Novel Treatment Combinations in Patients With Recurrent Ovarian Cancer
Actual Study Start Date : November 15, 2018
Estimated Primary Completion Date : April 28, 2022
Estimated Study Completion Date : June 12, 2025

Arm Intervention/treatment
Experimental: Cohort A: 1-2 prior lines of therapy
PARP Inhibitor-Naive Platinum-Resistant Ovarian Cancer Treatment Cohort with TSR-042, Bevacizumab, and Niraparib. TSR-042 administered every 3 weeks for 4 cycles (each cycle is 21 days), followed by every 6 weeks beginning on cycle 5 day 1 until progressive disease (PD) or toxicity. Bevacizumab administered 15 milligram per kilogram (mg/kg) every 3 weeks for up to 15 months. Niraparib 200 or 300 mg per day until PD or toxicity.
Drug: Niraparib
Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment for participants with tumors that harbor defects in the homologous recombination deoxyribonucleic acid (DNA) repair pathway or that are driven by PARP-mediated transcription factors.
Other Name: ZEJULA

Drug: TSR-042
TSR-042 is a humanized monoclonal antibody that binds with high affinity to Programmed cell death protein 1 (PD-1) resulting in inhibition of binding to programmed death receptor ligands 1 and 2 (PD-L1 and PD-L2).

Drug: Bevacizumab
Bevacizumab is an Food Drug and Administration (FDA) approved antiangiogenic recombinant humanized monoclonal Immunoglobulin (Ig) G1 antibody against the vascular endothelial growth factor protein, which has been shown to be efficacious against a variety of different cancer types, including colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma.
Other Name: Avastin

Primary Outcome Measures :
  1. Objective response rate [ Time Frame: Up to 6 years ]
    Objective Response Rate is defined as proportion of participants who have achieved confirmed complete response (CR) or partial response (PR), evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on investigator assessment.

Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Up to 6 years ]
    PFS is defined as the time from the date of the first dose of study treatment to the earlier date of assessment of progression or death by any cause in the absence of progression by RECIST version 1.1.

  2. Overall survival (OS) [ Time Frame: Up to 6 years ]
    OS is defined as the time from the date of the first dose of study treatment to the date of death by any cause.

  3. Duration of Response (DOR) [ Time Frame: Up to 6 years ]
    DOR is defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression by RECIST version 1.1 based on Investigator's assessment or death by any cause.

  4. Disease Control Rate (DCR) [ Time Frame: Up to 6 years ]
    DCR is defined as the percentage of participants who have achieved best overall response of CR, PR, or stable disease (SD) per RECIST version 1.1 based on Investigator's assessment.

  5. Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 6 years ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Participant must be female >=18 years of age, able to understand the study procedures, and agree to participate in the study by providing written informed consent.
  • Participant has histologically diagnosed high-grade recurrent epithelial (ie, serous, endometrioid, mucinous, clear cell) ovarian, fallopian tube, or primary peritoneal cancer or recurrent carcinosarcoma of the ovary. Participants with high-grade mixed histology are also eligible.
  • The allowed number of prior lines of anticancer therapy for ovarian cancer will be specified in each cohort-specific supplement. Treatment with hormonal agents alone are not counted in the number of lines of therapy. Treatment with single-agent bevacizumab or PARP inhibitors given as maintenance is not counted as a separate line of therapy. If a therapeutic regimen is modified or changed for a reason other than lack of response or PD (such as allergic reaction, toxicity, or drug availability), this is not counted as a separate line of therapy.
  • Participant has measurable disease according to RECIST version 1.1.
  • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Participant has adequate organ function, defined as follows: a. Absolute neutrophil count >=1,500 per microliter (/mcL), without growth factor support (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administration is not permitted within 2 weeks of screening). b. Platelets >=100,000/mcL without platelet transfusion support within 2 weeks of screening. c. Hemoglobin >=9 gram/deciliter (g/dL) without transfusion or growth factor (recombinant erythropoietin) within 2 weeks of screening. d. Serum creatinine <=1.5* upper limit of normal (ULN) or calculated creatinine clearance >=50 milliliter per minute (mL/min) using Cockcroft-Gault equation. e. Total bilirubin <=1.5* ULN, except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin is <=1.5* ULN for the direct bilirubin. f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5* ULN, unless liver metastases are present, in which case they must be <=5* ULN. g. International normalized ratio or prothrombin time (PT) <=1.5* ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants. h. Activated partial thromboplastin time (aPTT) <=1.5* ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Participants with known lupus anticoagulant and elevated PTT may be eligible on a case-by-case basis after discussion with the Sponsor's Medical Monitor.
  • Female participant (of childbearing potential) is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study treatment, and agrees to abstain from activities that could result in pregnancy from enrollment through 180 days after the last dose of study treatment;
  • Female participant is of non-childbearing potential, other than medical reasons, defined as follows: >=45 years of age and has not had menses for >1 year; amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon screening evaluation; and has undergone hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure; otherwise, the participant must be willing to use highly effective contraception throughout the study, starting with the screening visit through 180 days after the last dose of study therapy.
  • Participant is willing to undergo a pre-treatment tumor biopsy, unless an appropriate archival tumor tissue is available. Additionally, participant must be willing to undergo 1 on-treatment biopsy, provided it is deemed safe and feasible by the Investigator.

Cohort A-specific Inclusion Criteria: In addition to the general inclusion criteria, participants must also meet the following additional criterion to be considered eligible to participate in this study.

  • Participants must be resistant to the most recent platinum-based therapy, defined for the purpose of this protocol as progression within 6 months from completion of a minimum of 4 cycles of platinum-containing therapy. This should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing disease progression. Participants with primary platinum-refractory disease as defined by those who progressed during or within 4 weeks of completion of first platinum-based chemotherapy are not eligible.
  • Participant must not have received any prior therapy for ovarian cancer with a PARP inhibitor.
  • Participant has had 1 to 2 prior lines of anticancer therapy for ovarian cancer.
  • Participant is able to take oral medications.

Exclusion Criteria:

  • Participant has not recovered (ie, to Grade <=1 or to Baseline) from prior chemotherapy-induced AEs.
  • Participant has a known diagnosis of immunodeficiency or is receiving systemic steroid therapy exceeding an equivalent of prednisone 10 mg daily or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
  • Participant is currently participating in a treatment study or has participated in a study of an investigational agent within 4 weeks of the first dose of treatment.
  • Participant has received prior systemic anticancer therapy including cytotoxic chemotherapy, PARP inhibitor, immune checkpoint inhibitors, hormonal therapy given with the intention to treat ovarian cancer, or biological therapy within 3 weeks of the first dose of study treatment.
  • Participant has received live vaccine within 30 days of planned start of study therapy.
  • Participant has symptomatic uncontrolled brain or leptomeningeal metastases. Participants who have untreated brain metastases and who are not symptomatic may enroll if the Investigator feels that treatment of these metastases is not indicated. A scan to confirm the absence of brain metastases is not required. Participants with spinal cord compression may be considered if they have received definitive treatment for this and evidence of clinically SD for 28 days prior to the first dose of study treatment.
  • Participant had major surgery within 4 weeks of starting the study or participant has not recovered from any effects of any major surgery.
  • Participant has a known additional malignancy that progressed or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer that is considered to be low risk for progression by the investigator.
  • Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. These include, but are not limited to, significant cardiovascular disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, and any psychiatric disorder that prohibits obtaining informed consent.
  • Participant has a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, might interfere with the participant's participation for the full duration of the study treatment, or is not in the best interest of the participant to participate.
  • Participant has known active hepatitis B or hepatitis C.

Cohort A-specific Exclusion Criteria:

  • Participant has known hypersensitivity to TSR-042, bevacizumab, niraparib, their components, or their excipients.
  • Participant has a known history of myelodysplastic syndrome or acute myeloid leukemia.
  • Participant has active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
  • Participant received prior treatment with an anti-PD-1 or anti-PD-L1 agent.
  • Participant has received prior treatment with anti-angiogenic therapy with the exception of bevacizumab. (Participants who received prior bevacizumab are eligible only if they did not discontinue bevacizumab due to toxicity, as established by the Investigator).
  • Participant has bowel obstruction, had bowel obstruction within the past 3 months, or is otherwise judged by the Investigator to be at high risk for bowel obstruction related to the underlying disease. Participant has any history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesses. Evidence of recto-sigmoid involvement by pelvic examination or significant bowel involvement on computed tomography scan.
  • Participant has proteinuria as demonstrated by urine protein:creatinine ratio >=1.0 at screening or urine dipstick for proteinuria >=2 (Participants discovered to have >=2 proteinuria on dipstick at baseline should undergo 24-hour urine collection and must demonstrate <2 gram of protein in 24 hours to be eligible).
  • Participant is at increased bleeding risk due to concurrent conditions (eg, major injuries or surgery within the past 28 days prior to start of study treatment, history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
  • Participant has a history of recent major thromboembolic event defined as follows: Pulmonary embolism diagnosed within 3 months of enrollment; and Lower extremity deep venous thrombosis diagnosed within 3 months of enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03574779

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United States, Alabama
GSK Investigational Site
Birmingham, Alabama, United States, 35249
United States, California
GSK Investigational Site
Los Angeles, California, United States, 90095
GSK Investigational Site
Palo Alto, California, United States, 94304
GSK Investigational Site
Ventura, California, United States, 93003
United States, Connecticut
GSK Investigational Site
New Haven, Connecticut, United States, 06511
United States, Illinois
GSK Investigational Site
Chicago, Illinois, United States, 60637
GSK Investigational Site
Orland Park, Illinois, United States, 60462
United States, Maryland
GSK Investigational Site
Baltimore, Maryland, United States, 21287
United States, Massachusetts
GSK Investigational Site
Boston, Massachusetts, United States, 02114
GSK Investigational Site
Boston, Massachusetts, United States, 02215
United States, Minnesota
GSK Investigational Site
Rochester, Minnesota, United States, 55905
United States, Oklahoma
GSK Investigational Site
Oklahoma City, Oklahoma, United States, 73104
Sponsors and Collaborators
Tesaro, Inc.
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Study Director: GSK Clinical Trials GlaxoSmithKline
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Responsible Party: Tesaro, Inc. Identifier: NCT03574779    
Other Study ID Numbers: 213357
3000-02-005 ( Other Identifier: Tesaro )
First Posted: July 2, 2018    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Tesaro, Inc.:
PARP Inhibitor
Ovarian cancer
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action