Recurrent or primary advanced (Stage III or IV) endometrial cancer MedDRA version: 21.0 Level: PT Classification code 10014740 Term: Endometrial cancer stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10014741 Term: Endometrial cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
TESARO, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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. Sub
Exclusion criteria
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: Lowdose 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 nonendometrial 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 [GMCSF], 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 ris
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1: To compare the 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.;Secondary Objective: 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 immunogenocity. Part 2 Key Secondary Objective: •To compare OS of subjects treated with dostarlimab plus carboplatinpaclitaxel 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.;P | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. OS in Part 2, 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.;Timepoint(s) of evaluation of this end point: 1. Date of death. 2. Date of first documentation | — |
Countries
Belarus, Belgium, Canada, Czechia, Denmark, Finland, Germany, Greece, Hungary, Israel, Italy, Netherlands, Norway, Poland, Spain, Sweden, Türkiye, Ukraine, United Kingdom, United States
Contacts
Public ContactRUBY Study Team
TESARO, Inc.
Outcome results
None listed