Phase 3 Randomized Study of Dostarlimab Plus Carboplatin-Paclitaxel Versus Placebo in Recurrent or Primary Advanced Endometrial Cancer
- Trial ID
- 2023-506551-23-00
- Protocol
- 4010-03-001
- Sponsor
- Tesaro Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival (PFS)** of patients with recurrent or primary advanced endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab, against those treated with placebo plus carboplatin-paclitaxel followed by placebo. This comparison is assessed by the Investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). The study also aims to compare the overall survival (OS) of these treatment groups. The clinical relevance of this objective lies in determining the efficacy of dostarlimab in delaying disease progression and improving survival outcomes in this patient population.
Secondary objectives include:
- Evaluating various measures of clinical benefit such as PFS based on blinded independent central review (BICR), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and patient-reported outcomes (PROs) using the European Quality of Life scale and EORTC Quality of Life Questionnaires.
- Assessing the safety and tolerability of dostarlimab in combination with carboplatin-paclitaxel, followed by dostarlimab, compared to placebo.
- Evaluating the pharmacokinetics (PK) and immunogenicity of dostarlimab when administered with carboplatin and paclitaxel.
- Comparing OS in subjects treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib, against those treated with placebo.
- Assessing the PK of niraparib when given in combination with dostarlimab.
Participants
The clinical trial involves a total of **560 participants** who are exclusively female, as the study focuses on individuals with **recurrent or primary advanced (Stage III or IV) endometrial cancer**. Participants are required to be at least 18 years of age, ensuring they are adults capable of providing informed consent. The trial population was selected based on specific inclusion criteria, including a confirmed diagnosis of endometrial cancer with recurrent or advanced disease, and the ability to provide adequate tumor tissue samples for MMR/MSI status testing. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The study does not include male subjects, and it is noted that the population includes vulnerable individuals. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate organ function and, for Part 2 of the study, controlled blood pressure. The selection process ensures that participants meet the necessary health criteria to safely participate in the trial.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, multicenter study designed to evaluate the efficacy of **dostarlimab** in combination with carboplatin-paclitaxel compared to a placebo in patients with recurrent or primary advanced endometrial cancer. The trial is structured into two parts, with the primary objective of comparing progression-free survival (PFS) and overall survival (OS) between the treatment and control groups. The study is expected to conclude by November 26, 2026, with recruitment having commenced on July 18, 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically proven endometrial cancer, adequate organ function, and an **ECOG performance status** of 0 or 1. Following randomization, participants will receive either the investigational treatment or placebo, with follow-up visits scheduled to monitor treatment response and safety. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.
The expected duration of participant involvement is up to 138 days for those receiving **niraparib** and up to 36 days for those receiving **dostarlimab**. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial's endpoints include PFS and OS, with secondary endpoints assessing overall response rate (ORR), duration of response (DOR), and disease control rate (DCR) based on **RECIST v.1.1** criteria. The study also evaluates the pharmacokinetics and immunogenicity of dostarlimab and niraparib when administered in combination.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Niraparib Tosilate Monohydrate** is an experimental medication used in this study. It is available in two pharmaceutical forms: hard capsules and tablets. The active substance, **Niraparib Tosilate Monohydrate**, is a chemical compound provided by GlaxoSmithKline. The maximum daily dose is 300 mg, with a total maximum dose of 290,400 mg over a treatment period of 138 days. The medication is administered orally, and participant compliance is monitored throughout the trial.
Another experimental treatment in the study is **Dostarlimab**, marketed under the name JEMPERLI. It is provided as a 500 mg concentrate for solution for infusion. The active substance, **Dostarlimab**, is a protein-based monoclonal antibody targeting the Programmed Cell Death Protein 1 (PD-1). The maximum daily dose is 1000 mg, with a total maximum dose of 26,000 mg over a treatment period of 36 weeks. The administration route is intravenous, and the drug is supplied by GlaxoSmithKline (Ireland) Limited. Compatibility with additional materials is ensured, and a closed system transfer device is permitted for clinical use.
Non-experimental treatments include **Niraparib Placebo Capsules** and **Niraparib Placebo Tablets**, which serve as control treatments in the study. These placebos are used to maintain the double-blind nature of the trial. Additionally, **G5W (5% glucose in water)** is utilized as a placebo or comparator treatment. These non-experimental treatments do not contain active substances and are used to assess the efficacy and safety of the experimental medications.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary efficacy endpoints for Part 1 include **progression-free survival (PFS)** and overall survival (OS). PFS is defined as the time from randomization to the earliest date of radiographic assessment of progressive disease (PD) or death by any cause in the absence of PD, as evaluated by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). OS is defined as the time from randomization to the date of death by any cause. For Part 2, the primary efficacy endpoint is PFS, similarly defined and assessed.
Secondary endpoints include OS for Part 2, PFS based on blinded independent central review (BICR), overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and PFS2. ORR is defined as the proportion of subjects with a best overall response of complete response or partial response. DOR is the time from the first documentation of complete or partial response until the first documentation of subsequent PD or death. DCR is the proportion of subjects achieving complete response, partial response, or stable disease. PFS2 is the time from treatment randomization to progression on the first subsequent anticancer therapy or death. Patient-reported outcomes (PRO) will be assessed using EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ EN24 instruments. Pharmacokinetics (PK) and immunogenicity of dostarlimab, and PK of niraparib when combined with dostarlimab, will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- (Part 1 and 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.
- (Part 1 and Part 2): 2. Subject has histologically or cytologically proven endometrial cancer with recurrent or advanced disease.
- (Part 1 and Part 2): 3. Subject must provide adequate tumor tissue sample at Screening for MMR/MSI status testing. Note: The quality of the tumor tissue sample must be confirmed by the central laboratory during screening. Subjects should not be randomized without central laboratory confirmation.
- (Part 1 and Part 2): 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 anticancer therapy and had a recurrence or PD ≥ 6 months after completing treatment (first recurrence). Note: Subjects with uterine sarcoma are not allowed.
- (Part 1 and Part 2): 5. Subject has an ECOG performance status of 0 or 1.
- (Part 1 and Part 2): 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 creatinine clearance ≥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) Aspartate aminotransferase and alanine aminotransferase ≤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 the intended use of anticoagulants.
- (Part 1 and Part 2): 7. Contraceptive use by subjects should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a) A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: • The participant is a woman of nonchildbearing potential. OR • The participant is a 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. (Note: Duration of contraceptive use may be longer than 180 days in order to comply with local requirements and local approved product labels). Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. The Investigator should evaluate the potential for contraceptive method failure (eg, noncompliance and recently initiated) in relationship to the first dose of study treatment. 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. Note: The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Note: Additional requirements for pregnancy testing during and after study treatment are located in (Section 12.2.6.7).
- Part 2 only: 8. Subjects must have normal BP or adequately treated and controlled hypertension (systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg).
- Part 2 only: 9. Subjects must be able to take medication PO.
Exclusion Criteria
- (Part 1 and 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 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.
- (Part 1 and Part 2) 2. Subject has had >1 recurrence of endometrial cancer.
- (Part 1 and Part 2) 3. Subject has received prior therapy with an anti-PD-1, anti PD-L1, or anti programmed cell death-ligand 2 agent.
- (Part 1 and Part 2) 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. Note: Palliative radiation therapy to a small field ≥1 week prior to Day 1 of study treatment may be allowed.
- (Part 1 and Part 2) 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.
- (Part 1 and Part 2) 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.
- (Part 1 and Part 2) 7. Subject has a known history of HIV (HIV 1/2 antibodies).
- (Part 1 and Part 2) 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).
- (Part 1 and Part 2) 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 (eg, thyroid hormone or insulin)
- (Part 1 and Part 2) 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.
- (Part 1 and Part 2) 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.
- (Part 1 and Part 2) 12. Subject has not recovered adequately from AEs or complications from any major surgery prior to starting therapy.
- (Part 1 and Part 2) 13. Subject has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients.
- (Part 1 and Part 2) 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.
- (Part 1 and Part 2) 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).
- (Part 1 and Part 2) 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.
- (Part 1 and Part 2) 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.
- Part 2 only: 19. Subject 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 congestive heart failure, serious cardiac arrhythmia requiring medication, Grade ≥2 peripheral vascular disease, and history of cerebrovascular accident within 6 months).
- Part 2 only: 20. Subject has any known history or current diagnosis of myelodysplastic syndrome or acute myeloid leukemia.
- Part 2 only: 21. Subject 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, history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
- Part 2 only: 22. Subject has a known hypersensitivity to niraparib components or excipients.
- Part 2 only: 23. Subject has participated in Part 1 of this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Jul 2019 | 7 |
 Czechia | Not Recruiting | 18 Jul 2019 | 9 |
 Denmark | Not Recruiting | 18 Jul 2019 | 28 |
 Finland | Not Recruiting | 18 Jul 2019 | 14 |
 Germany | Not Recruiting | 18 Jul 2019 | 44 |
 Greece | Not Recruiting | 18 Jul 2019 | 1 |
 Hungary | Not Recruiting | 18 Jul 2019 | 12 |
 Italy | Not Recruiting | 18 Jul 2019 | 36 |
 The Netherlands | Not Recruiting | 18 Jul 2019 | — |
 Norway | Not Recruiting | 18 Jul 2019 | 14 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Niraparib Placebo Capsules | Placebo | N/A | — | — | — | N/A |
Niraparib Placebo Tablets | Placebo | N/A | — | — | — | N/A |
G5W5% glucose in water | Placebo | N/A | — | — | — | N/A |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 36 | PRD8877508 |