| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage 3 or 4 High Grade Non-mucinous epithelial ovarian cancer (serous, endometrial, clear cell, carcinosarcoma, and mixed pathologies) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070907 |
| E.1.2 | Term | Ovarian cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070908 |
| E.1.2 | Term | Ovarian cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the progression free survival (PFS) of programmed death-ligand 1 (PD-L1) positive patients with St. III or IV high grade non-mucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab, and niraparib to standard-of-care (SOC) platinum-based combination therapy.
To compare the PFS of all patients with Stage III or IV high-grade nonmucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab, and niraparib to SOC platinum-based combination therapy.
The primary PFS analysis will be based upon the Investigator’s assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria. |
|
| E.2.2 | Secondary objectives of the trial |
For PD-L1 positive and all patients:•Blinded Independent Central Review determined PFS per RECIST v1.1
•Overall surv. (OS) •Safety and tolerab. of all treatments •Health related quality of life (HRQoL) •Time to first subseq. therapy (TFST) •Time to second subseq. therapy (TSST)
•Time from treatment random. to the earliest date of assessment of progr. on the next anticancer therapy following study treatment or death by any cause (PFS2)•Object. respons. rate (ORR) per RECIST v.1.1 for patients with measurable
disease at baseline scan •Disease control rate (DCR) per RECIST v.1.1 •Mainten. progres. free survival (MPFS) per RECIST v.1.1 •Pharmacokin. and immunogenicity of dostarlim. •PK of niraparib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients 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.
2. Patients with a histologically confirmed diagnosis of high-grade nonmucinous epithelial ovarian (serous, endometrioid, clear cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the FIGO or tumor, node and metastasis staging criteria [ie, American Joint Committee on Cancer].
3. All patients with Stage IV disease are eligible. This includes those with inoperable disease, those who undergo PDS (CC0 or macroscopic disease), or those for whom NACT is planned.
4. Patients with Stage III are eligible if they meet one or more of the following criteria:
a. Stage IIIC patients CC0 resection if they meet the following criteria: aggregate ≥ 5 cm extra-pelvic disease during PDS as assessed by the Investigator.
b. All patients with inoperable Stage III disease.
c. All Stage III patients with macroscopic residual tumor (per Investigator judgment) following PDS.
d. All Stage III patients for whom NACT is planned.
5. Patients must provide a blood sample for ctDNA HRR testing at Pre-Screening or Screening.
6. Patient must provide sufficient tumor tissue sample (a minimum of 1 FFPE block or slide at Pre-Screening or Screening) for PD-L1, homologous recombination deficiency (HRD) testing.
7. Patients of childbearing potential must have a negative serum or urine pregnancy test (beta human chorionic gonadotropin) within 3 days prior to receiving the first dose of study treatment.
8. Patients must be postmenopausal, free from menses for >1 year, surgically sterilized, or willing to use highly effective contraception to prevent pregnancy or must agree to abstain from activities that could result in pregnancy throughout the study, starting with enrollment through 180 days after the last dose of study treatment.
9. Patients must have adequate organ function, defined as follows (Note: CBC test should be obtained without transfusion or receipt of stimulating factors within 2 weeks before obtaining Screening blood sample):
a. Absolute neutrophil count (ANC) ≥1,500/µL
b. Platelet count ≥100,000 cells/µL
c. Hemoglobin ≥9 g/dL
d. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/min using the Cockcroft Gault equation
e. Total bilirubin ≤1.5 × ULN or direct bilirubin ≤1.5 × ULN
f. Aspartate aminotransferase and alanine aminotransferase (ALT) ≤2.5 × ULN unless liver metastases are present, in which case they must be ≤5 × ULN
10. Patients must have an ECOG score of 0 or 1.
11. Patients must have normal blood pressure (BP) or adequately treated and controlled hypertension (systolic BP ≤140 mmHg and/or diastolic BP ≤90 mmHg).
12. Patients must agree to complete HRQoL questionnaires throughout the study.
13. Patients must be able to take oral medication. |
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| E.4 | Principal exclusion criteria |
1. Patient has mucinous, germ cell, transitional cell, or undifferentiated tumor.
2. Patient has low grade or Grade 1 epithelial ovarian cancer.
3. Stage III patient with R0 resection after PDS (ie, no macroscopic residual disease, unless inclusion criterion #4a is met).
4. Patient has not adequately recovered from prior major surgery.
5. Patient has a known condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient’s participation for the full duration of the study treatment in the opinion of the Investigator.
6. Patient is pregnant or is expecting to conceive children while receiving study drug or for up to 180 days after the last dose of study drug. Patient is breastfeeding or is expecting to breastfeed within 30 days of receiving the final dose of study drug (women should not breastfeed or store breastmilk for use, during niraparib treatment and for 30 days after receiving the final dose of study treatment).
7. Patient has known active central nervous system metastases, carcinomatous meningitis, or both.
8. Patient has clinically significant cardiovascular disease (eg, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, uncontrolled cardiac arrhythmia or unstable angina <6 months to enrollment, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident within 6 months).
9. Patient has a bowel obstruction by clinical symptoms or CT scan, subocclusive mesenteric disease, abdominal or gastrointestinal fistula, gastrointestinal perforation, or intra abdominal abscess.
10 Patient initiating bevacizumab as SOC has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at Screening or urine dipstick for proteinuria ≥2 (patients discovered to have ≥2 proteinuria on dipstick at baseline should undergo a 24 hour urine collection and must demonstrate <2 g of protein in 24 hours to be eligible).
11. Patient has any known history or current diagnosis of MDS or AML.
12. Patient has been diagnosed and/or treated with any therapy for invasive cancer <5 years from study enrollment, completed adjuvant chemotherapy and/or targeted therapy (eg, trastuzumab) less than 3 years from enrollment, or completed adjuvant hormonal therapy less than 4 weeks from enrollment. Patients with definitively treated non invasive malignancies such as cervical carcinoma in situ, ductal carcinoma in situ, Grade 1 or 2, Stage I endometrial cancer, or non-melanomatous skin cancer are allowed.
13. Patient is at increased bleeding risk due to concurrent conditions (eg, major injuries or major surgery within the past 28 days prior to start of study treatment and/or history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
14. Patient is immunocompromised. Patients with splenectomy are allowed. Patients with known human immunodeficiency virus (HIV) are allowed if they meet all criteria as listed in the protocol.
15. Patient has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
16. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease, or active, uncontrolled infection.
17. Patient has had investigational therapy administered within 4 weeks or within a time interval less than at least 5 half lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study.
18. Patient has received a live vaccine within 14 days of planned start of study therapy. Seasonal influenza vaccines that do not contain live viruses are allowed.
19. Patient has a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, dostarlimab, or their excipients.
20.Prior treatment for high-grade nonmucinous epithelial ovarian, fallopian tube, or peritoneal cancer (immunotherapy, anticancer therapy, radiation therapy).
21.Patient has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (eg, thyroid hormone or insulin).
22.Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
This study has dual primary efficacy endpoints: PFS in PD-L1 positive patients and PFS in all patients.
PFS, defined as the time from the date of treatment randomization to the date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival
2. BICR determined PFS per RECIST v1.1
3. Health-related quality of life
4. Time to first subsequent therapy
5. Time to second subsequent therapy
6. Progression-free survival 2
7. Objective response rate
8. Duration of response
9. Disease control rate
10. Maintenance progression-free survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Date of first documentation of progression or death by any cause in
the absence of progression, whichever occurs first.
2. The earlier date of assessment of progression on the next anticancer
therapy following study treatment or death by any cause.
3. Study visits, including follow up.
4. Date of first subsequent therapy.
5. Date of second subsequent therapy.
6. The earlier date of assessment of progression on the next anticancer
therapy following study treatment or death by any cause.
7. End of study.
8. First documentation of PD or death by any cause in the absence of
progression.
9. End of study.
10. Date of first documentation of progression or death by any cause in
the absence of progression, whichever occurs first. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 114 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Ukraine |
| Belarus |
| Canada |
| Israel |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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