Ovarian Neoplasm
Conditions
Keywords
Poly-ADP-ribose polymerase (PARP) Inhibitor, Ovarian cancer, Niraparib, Bevacizumab, TSR-042, Neoadjuvant treatment
Brief summary
The primary objective of this sub study is to evaluate the efficacy of the combination of TSR-042, bevacizumab, and niraparib in participants with advanced, relapsed, high-grade ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 2 prior lines of anticancer therapy, are PARP inhibitor naïve, and have platinum-resistant but not refractory disease. This study is a sub study of the master protocol - OPAL (NCT03574779).
Interventions
DRUGDostarlimab
Dostarlimab was administered.
DRUGBevacizumab
Bevacizumab was administered.
DRUGNiraparib
Niraparib was administered.
Sponsors
Tesaro, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant 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. Participant 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 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- programmed death-1 (PD-1) or anti- programmed death-ligand 1 (PD-L1) agent * Participant has received prior treatment with anti-angiogenic therapy with the exception of bevacizumab. (Participant 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 (Participant discovered to have ≥2 proteinuria on dipstick at baseline should undergo 24-hour urine collection and must demonstrate \<2g 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: 1. Pulmonary embolism diagnosed within 3 months of enrollment 2. Lower extremity deep venous thrombosis diagnosed within 3 months of enrollment (Participant with a history of thromboembolic disease on stable therapeutic anticoagulation for more than 3 months prior to enrollment are eligible for this study.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment | Up to approximately 38 Months | ORR was defined as percentage of participants with a confirmed investigator-assessed Best Overall Response (BOR) of confirmed complete response (CR) or partial response (PR), evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 38 Months | OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. Median and 95% CI are presented. |
| Duration of Response (DOR) Per RECIST Version 1.1 by Investigator Assessment | Up to approximately 38 Months | DOR was 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. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). |
| Disease Control Rate (DCR) Per RECIST Version 1.1 by Investigator Assessment | Up to approximately 38 Months | DCR was 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. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Up to approximately 38 Months | 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. |
| Progression Free Survival (PFS) Per RECIST Version 1.1 by Investigator Assessment | Up to approximately 38 Months | PFS was defined as the time from the date of the first dose of study treatment to the earliest date of assessment of disease progression or death by any cause in the absence of progression by RECIST v1.1. Disease Progression is defined using RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Absolute Values in Urinalysis Parameter - Specific Gravity (Ratio) | Baseline (Day 1) and end of treatment (Up to approximately 32 months) | Urine samples were collected at indicated time points for the assessment of specific gravity. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug. |
| Change From Baseline in Cancer Antigen 125 (CA-125) at End of Treatment | Baseline (Day 1) and end of treatment (Up to approximately 32 months) | Blood samples were collected for the analysis of CA-125. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug. |
| Change From Baseline in Vital Signs (Weight) at End of Treatment | Baseline (Day 1) and end of treatment (Up to approximately 32 months) | Weight was measured in ordinary indoor clothing (without shoes) and was recorded at specified study visit. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug. |
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | Baseline (Day 1) and end of treatment (Up to approximately 32 months) | Performance status assessments were based on 5-grade ECOG scale (from 0 to 4), where 0=fully active, able to carry on all pre-disease performance without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work); 2=ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed or chair. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug. |
| Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters - Chemistry, Coagulation, Hematology and Thyroid | Up to approximately 38 Months | Blood samples were collected for the analysis of clinical laboratory parameters - chemistry, coagulation, hematology and thyroid. |
Countries
United States
Participant flow
Pre-assignment details
This study is a sub study of the master protocol (NCT03574779).
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 administered 500 milligrams (mg) of Dostarlimab (TSR-042) via infusion on Day 1 every 3 weeks (Q3W) for 4 cycles (each cycle is of 21 days), followed by 1000 mg every 6 weeks (Q6W) beginning from Day 1 of Cycle 5 until progressive disease (PD) or toxicity. Participants were administered 15 milligram per kilogram (mg/kg) of Bevacizumab via infusion Q3W for up to 15 months. Participants with screening actual body weight greater than or equal (≥) to 77 kg and screening platelet count ≥ 150000 cells per microliter were administered 300 mg of Niraparib orally once daily throughout each 21-day cycle until PD or toxicity. Participants with screening actual body weight less than 77 kg or screening platelet count less than 150000 cells per microliter were administered 200 mg of niraparib orally, once daily throughout each 21-day cycle until PD or toxicity. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 25 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Study Site Closed | 9 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Cohort A (Dostarlimab + Bevacizumab + Niraparib) |
|---|---|
| Age, Continuous | 63.8 years STANDARD_DEVIATION 10.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 25 / 41 |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 22 / 41 |
Outcome results
Primary
Confirmed Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment
ORR was defined as percentage of participants with a confirmed investigator-assessed Best Overall Response (BOR) of confirmed complete response (CR) or partial response (PR), evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm).
Time frame: Up to approximately 38 Months
Population: Response-evaluable population included all efficacy participants (all participants who received any amount of study treatment with measurable disease at baseline) with at least 1 evaluable post-baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Confirmed Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 by Investigator Assessment | 17.9 Percentage of participants |
Secondary
Absolute Values in Urinalysis Parameter - Specific Gravity (Ratio)
Urine samples were collected at indicated time points for the assessment of specific gravity. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug.
Time frame: Baseline (Day 1) and end of treatment (Up to approximately 32 months)
Population: Safety population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Absolute Values in Urinalysis Parameter - Specific Gravity (Ratio) | Baseline | 1.0149 Ratio | Standard Deviation 0.00794 |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Absolute Values in Urinalysis Parameter - Specific Gravity (Ratio) | End of treatment | 1.0162 Ratio | Standard Deviation 0.00786 |
Secondary
Change From Baseline in Cancer Antigen 125 (CA-125) at End of Treatment
Blood samples were collected for the analysis of CA-125. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug.
Time frame: Baseline (Day 1) and end of treatment (Up to approximately 32 months)
Population: Safety population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Change From Baseline in Cancer Antigen 125 (CA-125) at End of Treatment | 246.86 Units per milliliter (U/mL) | Standard Deviation 608.985 |
Secondary
Change From Baseline in Vital Signs (Weight) at End of Treatment
Weight was measured in ordinary indoor clothing (without shoes) and was recorded at specified study visit. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug.
Time frame: Baseline (Day 1) and end of treatment (Up to approximately 32 months)
Population: Safety population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Change From Baseline in Vital Signs (Weight) at End of Treatment | -5.07 kilogram | Standard Deviation 5.475 |
Secondary
Disease Control Rate (DCR) Per RECIST Version 1.1 by Investigator Assessment
DCR was 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. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Up to approximately 38 Months
Population: Response-evaluable population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Disease Control Rate (DCR) Per RECIST Version 1.1 by Investigator Assessment | 76.9 Percentage of participants |
Secondary
Duration of Response (DOR) Per RECIST Version 1.1 by Investigator Assessment
DOR was 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. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm).
Time frame: Up to approximately 38 Months
Population: Response-evaluable population. Only responders by investigator were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Duration of Response (DOR) Per RECIST Version 1.1 by Investigator Assessment | 11.76 Months |
Secondary
Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters - Chemistry, Coagulation, Hematology and Thyroid
Blood samples were collected for the analysis of clinical laboratory parameters - chemistry, coagulation, hematology and thyroid.
Time frame: Up to approximately 38 Months
Population: Safety population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters - Chemistry, Coagulation, Hematology and Thyroid | 0 Participants |
Secondary
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment
Performance status assessments were based on 5-grade ECOG scale (from 0 to 4), where 0=fully active, able to carry on all pre-disease performance without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work); 2=ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed or chair. Baseline is defined as the most recent non-missing measurement prior to or on the first administration of study drug.
Time frame: Baseline (Day 1) and end of treatment (Up to approximately 32 months)
Population: Safety population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | Baseline | Grade 0 | 18 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | Baseline | Grade 1 | 22 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | Baseline | Grade 2 | 0 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | Baseline | Grade 3 | 0 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | Baseline | Grade 4 | 0 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | End of Treatment | Grade 0 | 9 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | End of Treatment | Grade 1 | 20 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | End of Treatment | Grade 2 | 7 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | End of Treatment | Grade 3 | 1 Participants |
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment | End of Treatment | Grade 4 | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: Up to approximately 38 Months
Population: Safety population included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 41 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. Median and 95% CI are presented.
Time frame: Up to approximately 38 Months
Population: Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Overall Survival (OS) | 22.05 Months |
Secondary
Progression Free Survival (PFS) Per RECIST Version 1.1 by Investigator Assessment
PFS was defined as the time from the date of the first dose of study treatment to the earliest date of assessment of disease progression or death by any cause in the absence of progression by RECIST v1.1. Disease Progression is defined using RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Up to approximately 38 Months
Population: Efficacy Population included all safety participants (all participants who received any amount of study treatment) with measurable disease at baseline. Measurable disease at baseline was defined by the existence of at least 1 target lesion at baseline tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (Dostarlimab + Bevacizumab + Niraparib) | Progression Free Survival (PFS) Per RECIST Version 1.1 by Investigator Assessment | 7.92 Months |