Ovarian Neoplasms
Conditions
Keywords
Poly-ADP-ribose polymerase (PARP) Inhibitor, Ovarian cancer, Niraparib, Bevacizumab, TSR-042, Neoadjuvant treatment
Brief summary
This study will evaluate the efficacy and safety of niraparib and novel treatment combinations of niraparib as described within each cohort-specific supplement in participants with ovarian, fallopian tube, or primary peritoneal cancer. Cohort A (single arm) includes participants with recurrent ovarian cancer. Cohort B will not be initiated. Cohort C (randomized-2 arms) includes participants with newly diagnosed ovarian cancer.
Interventions
DRUGNiraparib
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.
BIOLOGICALTSR-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).
BIOLOGICALBevacizumab
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.
DRUGCarboplatin
Carboplatin will be infused intravenously over 60 minutes at the prescribed dose of area under the concentration versus time curve of 5 to 6 mg/milliliters (mL) per minute on Day 1 of every 21-day cycle
DRUGPaclitaxel
Paclitaxel will be administered intravenously over 180 minutes at the prescribed dose of 175 mg/meter square (m\^2) on Day 1 of every 21-day cycle
Sponsors
Tesaro, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Participant must be female greater than or equal to (\>=)18 years of age, able to understand the study procedures, and agree to participate in the study by providing written informed consent. * Participants must have the following histologic diagnosis unless otherwise specified in a cohort-specific supplement: 1. Phase 2 cohorts: Participant has histologically diagnosed high-grade recurrent epithelial (that is \[i.e.\], serous, endometrioid, mucinous, clear cell) ovarian, fallopian tube, or primary peritoneal cancer or carcinosarcoma of the ovary. Participant with high-grade mixed histology is also eligible. 2. For the Phase 1B components: Participant has histologically diagnosed gynecologic malignancy (i.e., any cancer that started in a woman's reproductive system). Gynecologic malignancies include cervical cancer; endometrial cancer; vaginal cancer; vulvar cancer; high-grade recurrent epithelial (i.e., serous, endometrioid, mucinous, clear cell) ovarian, fallopian tube, or primary peritoneal cancer; or advanced carcinosarcoma of the ovary. Participant with high-grade mixed histology is also eligible. * The allowed number of prior lines of anticancer therapy for primary 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. * Phase 2 cohorts: Participant must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. * Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. * Participant has adequate organ function, defined as follows: 1. Absolute neutrophil count \>=1500 per microliter (/mcL), without growth factor support (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administration is not permitted within 2 weeks prior to screening). 2. Platelets \>=100,000/mcL without platelet transfusion support within 2 weeks prior to screening. 3. Hemoglobin \>=9 grams/deciliter (g/dL) without transfusion or growth factor (recombinant erythropoietin) within 2 weeks of screening. 4. Serum creatinine less than or equal to (\<=)1.5 times (\*) upper limit of normal (ULN) or calculated creatinine clearance \>=50 milliliter per minute (mL/min) using Cockcroft-Gault equation. 5. 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. 6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5\* ULN, unless liver metastases are present, in which case they must be \<=5\* ULN. 7. 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. 8. 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. Participant with known lupus anticoagulant and elevated PTT may be eligible on a case-by-case basis after discussion with the Sponsor's Medical Monitor. * Participant is not pregnant or breastfeeding, and at least 1 of the following conditions apply: 1. Is not a woman of childbearing potential (WOCBP), or 2. Is a WOCBP using a contraceptive method that is highly effective (with a failure rate of less than \[\<\]1 percent \[%\] per year), with low user dependency, during the treatment period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relation to the first dose of study treatment. * A WOCBP must have a negative pregnancy test (highly sensitive urine test or serum test as required by local regulations) within 72 hours before the first dose of study treatment. If a urine test cannot be confirmed as negative (for example \[e.g.\], an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. * Additional requirements for pregnancy testing during and after study treatment as per protocol. * Participant must provide sufficient tumor tissue samples based on requirements defined in each cohort-specific supplement. Inclusion criteria specific to Cohort A: * 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. Inclusion criteria specific to Cohort C: * Participant has newly diagnosed Stage III or IV ovarian, fallopian tube, or primary peritoneal cancer according to the International Federation of Gynecology and Obstetrics staging criteria. * Participant must provide sufficient tumor tissue at Prescreening and agree to undergo a central HRD tumor testing using a fully validated assay. The tumor must be HRd as per central HRD tumor testing. If central testing does not confirm tumor HRd, the participant will not be eligible for the study. 1. Participants with documented germline breast cancer gene (BRCA)1/2 deleterious or suspected deleterious mutations by approved test (e.g., BRAC Analysis companion diagnostic \[CDx\]) will be eligible but will require central HRD testing. Participants with local, academic, or university-based germline BRCA1/2 testing will not be allowed to enroll without results of central HRD test. 2. All participants must agree to provide tumor tissue collected from IDS. 3. Participant must provide 2 formalin-fixed paraffin-embedded tissue blocks (or slides if blocks are not available) with sufficient tumor content (as confirmed by the sponsor's designated central and/or testing laboratory) for central HRD testing at Prescreening and for exploratory biomarker testing at Prescreening or Screening. If sufficient tumor tissue is provided at Prescreening, participants do not need to provide additional tissue at Screening. * Participant must have completed 1 run-in cycle of carboplatin-paclitaxel and not experienced disease progression after this treatment. Completion is defined as receiving \>=50% of the prescribed dose of therapy within 5 weeks. * Participant must not have known contraindication or uncontrolled hypersensitivity to carboplatin and paclitaxel and their excipients and no known pre-existing conditions that would preclude treatment with these agents. * Participant must not have known contraindication or uncontrolled hypersensitivity to niraparib and its excipients. * Participant must not have symptomatic ascites or pleural effusions as defined by the following criterion: presence of fluid in the abdominal or pleural cavities requiring removal within 1 week prior to signing the informed consent. * Participant must agree to complete patient-reported outcomes (PRO) and work productivity questionnaires throughout the study.
Exclusion criteria
* Participant has not recovered (i.e., to Grade \<=1 or to Baseline) from prior chemotherapy-induced adverse events (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 cancer, or biological therapy within 3 weeks of the first dose of study treatment. This washout period is required to ensure prior therapy is not confounding the toxicity profile of the investigational study drug or study drug combinations in cohorts. * Participant has received live vaccine within 14 days of planned start of study therapy. * Participant has symptomatic uncontrolled brain or leptomeningeal metastases. Participant who has untreated brain metastases and who is 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. Participant with spinal cord compression may be considered if she has received definitive treatment for this and evidence of clinically stable disease (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 because reoccurrence of another malignancy would confound interpretation of ORR by RECIST v1.1 criteria. 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, Coronavirus disease 2019 (COVID-19), 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 (hepatitis B surface antigen reactive) or hepatitis C (hepatitis C virus ribonucleic acid \[qualitative\] is detected). Cohort A-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Enrolled Across Cohorts | Day 1 | Number of Participants enrolled across cohorts are presented. |
Countries
Canada, Spain, United States
Participant flow
Recruitment details
This master record includes screening phase data for participants of the sub-studies 213357-COHORT-A (NCT05751629) and 213357-COHORT-C (NCT06964165). Results are presented separately for each sub study.
Pre-assignment details
A total of 173 participants started the overall study, which included all the screened participants who signed an ICF prior to enrollment. However, only 77 met the eligibility criteria and were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) Participants with platinum-resistant advanced, relapsed, high-grade ovarian, fallopian tube, or primary peritoneal cancer, and poly (adenosine diphosphate \[ADP\] ribose) polymerase \[PARP\] inhibitor naive were screened and enrolled in Cohort A sub-study to receive Dostarlimab + Bevacizumab + Niraparib. | 54 |
| Cohort C (Niraparib OR Platinum-taxane) Participants with ovarian cancer were screened and enrolled in Cohort C sub-study to receive either Niraparib OR Platinum-taxane. | 119 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Screening failure | 13 | 83 |
Baseline characteristics
| Characteristic | Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Cohort C (Niraparib OR Platinum-taxane) | Total |
|---|---|---|---|
| Age, Customized 18-64 years | 25 Participants | 59 Participants | 84 Participants |
| Age, Customized Over 64 years | 29 Participants | 60 Participants | 89 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 9 Participants | 14 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 49 Participants | 107 Participants | 156 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 54 Participants | 119 Participants | 173 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 119 |
| other Total, other adverse events | 8 / 54 | 37 / 119 |
| serious Total, serious adverse events | 3 / 54 | 5 / 119 |
Outcome results
Primary
Number of Participants Enrolled Across Cohorts
Number of Participants enrolled across cohorts are presented.
Time frame: Day 1
Population: The screened population includes all the screened participants who signed an ICF to determine their eligibility for the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants Enrolled Across Cohorts | 41 Participants |
| Cohort C (Niraparib OR Platinum-taxane) | Number of Participants Enrolled Across Cohorts | 36 Participants |