| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or primary advanced (Stage III or IV) endometrial cancer |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014740 |
| E.1.2 | Term | Endometrial cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014741 |
| E.1.2 | Term | Endometrial cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: To compare PFS of subjects treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab to subjects treated with placebo plus carboplatin-paclitaxel followed by placebo, as assessed by the Investigator per RECIST v.1.1, in the following:
- All subjects with recurrent or primary advanced endometrial cancer
- Subjects with dMMR/ MSI-H recurrent or primary advanced endometrial cancer
To compare the OS of subjects treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab to subjects treated with placebo plus carboplatin-paclitaxel followed by placebo, in subjects with recurrent or primary advanced endometrial cancer.
Part 2: To compare the PFS of subjects treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib to subjects treated with placebo plus carboplatin-paclitaxel followed by placebo, as assessed by the Investigator per RECIST v.1.1, in subjects with recurrent or primary advanced endometrial cancer. |
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| E.2.2 | Secondary objectives of the trial |
Part 1 Secondary Objective:
•To evaluate the following measures of clinical benefit of treatment with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab compared to treatment with placebo plus carboplatin-paclitaxel followed by placebo in subjects with recurrent or primary advanced endometrial cancer (all comers):
-PFS based on BICR assessment;
-ORR based on BICR and Investigator assessment;
-DOR based on BICR and Investigator assessment;
-DCR based on BICR and Investigator assessment;
-PROs: EQ-5D-5L, EORTC QLQ-C30 and QLQ EN24;
-PFS2.
•To evaluate the safety and tolerability.
•To assess the pharmacokinetics (PK) and immunogenicity.
Part 2 Key Secondary Objective:
•To compare OS of subjects treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib to subjects treated with placebo plus carboplatin-paclitaxel followed by placebo in subjects with recurrent or primary advanced endometrial cancer. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1 & Part 2
1. Female subject at least 18 years of age, who is able to understand the study procedures and agrees to participate in the study by providing written informed consent.
2. Subject has histologically or cytologically proven endometrial cancer with recurrent or advanced disease.
3. Subject must provide adequate tumor tissue sample at Screening for MMR/MSI status testing.
4. Subject must have primary Stage III or Stage IV disease or first recurrent endometrial cancer with a low potential for cure by radiation therapy or surgery alone or in combination, and meet at least 1 of the following criteria:
a. Subject has primary Stage IIIA to IIIC1 disease with presence of evaluable or measurable disease per RECIST v.1.1 based on Investigator’s assessment. Lesions that are equivocal or can be representative of post-operative change should be biopsied and confirmed for the presence of tumor.
b. Subject has primary Stage IIIC1 disease with carcinosarcoma, clear cell, serous, or mixed histology (containing ≥10% carcinosarcoma, clear cell, or serous histology) regardless of presence of evaluable or measurable disease on imaging.
c. Subject has primary Stage IIIC2 or Stage IV disease regardless of presence of evaluable or measurable disease.
d. Subject has first recurrent disease and is naïve to systemic anticancer therapy.
e. Subject has received prior neo-adjuvant/adjuvant systemic systemic anticancer therapy and had a recurrence or PD ≥6 months after completing treatment (first recurrence).
5. Subject has an ECOG performance status of 0 or 1.
6. Subject has adequate organ function, defined as follows:
a. Absolute neutrophil count ≥1,500 cells/μL
b. Platelets ≥100,000 cells/μL
c. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
d. Serum creatinine ≤1.5× upper limit of normal (ULN) or calculated CrCl ≥50 mL/min using the Cockcroft-Gault equation for subjects with creatinine levels >1.5× institutional ULN
e. Total bilirubin ≤1.5× ULN and direct bilirubin ≤1× ULN
f. AST and 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 and activated partial thromboplastin time ≤1.5× ULN. Subjects receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of intended use of anticoagulants.
7. Contraceptive use by subjects should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
The subject is a woman of nonchildbearing potential (WONCBP) OR
The subject is a woman of childbearing potential (WOCBP), using a contraceptive method that is highly effective (with a failure rate of <1% per year and, preferably, 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 or oocytes) for the purpose of reproduction during this period.
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local guidelines) within 72 hours before the first dose of study treatment. If a urine test cannot be confirmed as negative (eg, 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.
Part 2 only:
8. Subjects must have normal BP or adequately treated and controlled hypertension (systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg).
9. Subjects must be able to take medication PO.
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| E.4 | Principal exclusion criteria |
Part 1 & Part 2
1. Subject has received neo-adjuvant/adjuvant systemic anticancer therapy for primary Stage III or IV disease and:
a. has not had a recurrence or PD prior to first dose on the study OR
b. has had a recurrence or PD within 6 months of completing systemic anticancer therapy treatment prior to first dose on the study Note: Low-dose cisplatin given as a radiation sensitizer or hormonal therapies do not exclude subjects from study participation.
2. Subject has had >1 recurrence of endometrial cancer.
3. Subject has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed cell death-ligand 2 agent.
4. Subject has received prior anticancer therapy (chemotherapy, targeted therapies, hormonal therapy, radiotherapy, or immunotherapy) within 21 days or < 5 times the half-life of the most recent therapy prior to Study Day 1, whichever is shorter.
5. Subject has a concomitant malignancy, or subject has a prior non-endometrial invasive malignancy who has been disease-free for <3 years or who received any active treatment in the last 3 years for that malignancy. Non-melanoma skin cancer is allowed.
6. Subject has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of PD by imaging [using the identical imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and have not been using steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a subject from study participation regardless of clinical stability.
7. Subject has a known history of HIV (HIV 1/2 antibodies).
8. Subject has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
9. Subject 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.
10. Subject 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.
11. Subject has not recovered (ie, to Grade ≤ 1 or to baseline) from cytotoxic therapy-induced AEs or has received transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 21 days prior to the first dose of study drug. Note: Subjects with Grade ≤ 2 neuropathy, Grade ≤ 2 alopecia, or Grade ≤ 2 fatigue are an exception to this criterion and may qualify for the study.
12. Subject has not recovered adequately from AEs or complications from any major surgery prior to starting therapy.
13. Subject has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients.
14. Subject is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment.
15. Subject is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, noninfectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
16. Subject is pregnant or breastfeeding or is expecting to conceive children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.
17. Subject has received, or is scheduled to receive, a live vaccine within 30 days before first dose of study treatment, during study treatment, and for up to 180 days after receiving the last dose of study treatment.
Part 2 only:
18. Subject has received prior therapy with a PARP inhibitor.
19. Subject has clinically significant cardiovascular disease.
20. Subject has any known history or current diagnosis of myelodysplastic syndrome or acute myeloid leukemia.
21. Subject is at increased bleeding risk due to concurrent conditions.
22. Subject has a known hypersensitivity to niraparib components or excipients.
23.Subject has participated in Part 1 of this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) based on the Investigator assessment, which is defined as the time from the date of randomization to the earliest date of radiographic assessment of PD or death by any cause in the absence of PD, whichever occurs first.
Overall Survival (OS) is a primary endpoint for Part 1, and is defined as the time from randomization to the date of death by any cause. |
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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 for PFS.
Date of death for OS. |
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| E.5.2 | Secondary end point(s) |
1. OS, defined as the time from randomization to the date of death by any cause (Part 2 only).
2. PFS based on BICR assessment, defined as the time from randomization to the earliest date of assessment of PD per RECIST v.1.1 based or death by any cause in the absence of PD per RECIST v.1.1, whichever occurs first.
3. Objective Response Rate (ORR), based on BICR and Investigator assessment, defined as the proportion of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR).
4. Duration of Response (DOR), based on BICR and Investigator assessment, defined as the time from first documentation of CR or PR until the time of the first documentation of subsequent PD per RECIST v.1.1 or death by any cause in the absence of PD per RECIST v.1.1, whichever occurs first.
5. Disease Control Rate (DCR), based on BICR and Investigator assessment, is defined as the proportion of subjects who have achieved a BOR of CR, PR, or SD per RECIST v.1.1.
6. Progression-free Survival 2 (PFS2), defined as the time from treatment randomization to the date of assessment of progression on the first subsequent anticancer therapy following study treatment or death by any cause, whichever is earlier.
7. Patient-reported Outcome. EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-EN24 will be used to determine PRO assessment of treatment throughout study participation.
8. Pharmacokinetics and Immunogenicity. Blood samples for the determination of dostarlimab serum concentrations and antidrug antibody (ADA) formation will be collected from all subjects.
Blood samples for the determination of niraparib plasma concentrations will be collected from subjects in Part 2 who received at least 1 dose of niraparib or placebo.
Blood samples for the determination of dostarlimab ADAs will be part of the same blood collections as those for the PK assessments. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Date of death.
2. Date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first.
3. End of study.
4. First documentation of PD or death by any cause in the absence of progression from the first documentation of CR or PR.
5. End of study.
6. Date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first.Study visits, including follow up.
7. End of study.
8. End of study. |
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| 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 | No |
| 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 | Yes |
| 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 | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
| Türkiye |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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