A study to determine whether the addition of Dostarlimab (TSR-042) delays recurrence of advanced endometrial cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Tesaro Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

21 Nov 2019 → ongoing

Decision date (initial)

2024-07-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

TESARO, Inc.

External identifiers

EU CT number

2023-506551-23-00

EudraCT number

2019-001576-11

ClinicalTrials.gov

NCT03981796

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

• Part 1:
To compare the progression-free survival (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 Response Evaluation Criteria in Solid Tumors version 1.1 (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 overall survival (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 the following:
- All subjects with recurrent or primary advanced endometrial cancer.
- Subjects with MMRp/MSS recurrent or primary advanced endometrial cancer. MMRp/MSS status will be determined by the MMR/MSI status entered at randomization.

Secondary objectives 8

1. Part 1: Secondary Objectives: • 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 blinded independent central review (BICR) assessment -Objective response rate (ORR) based on BICR and Investigator assessment -Duration of response (DOR) based on BICR and Investigator assessment -Disease control rate (DCR) based on BICR and Investigator assessment -Patient-reported outcomes (PROs): European Quality of Life scale, 5-Dimensions, 5 Levels (EQ-5D-5L) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 [Core] and QLQ EN24 [Endometrial Cancer Module]) -Progression-free survival 2 (PFS2). PFS2 is 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.
2. Part 1: Secondary Objectives: • To evaluate the safety and tolerability of dostarlimab plus carboplatin-paclitaxel followed by dostarlimab compared to placebo plus carboplatin-paclitaxel followed by placebo (all comers).
3. Part 1: Secondary Objectives: • To assess the pharmacokinetics (PK) and immunogenicity of dostarlimab when given in combination with carboplatin and paclitaxel (all comers).
4. Part 2: Key Secondary Objective: To compare OS of subjects treated with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib compared to subjects treated with placebo plus carboplatin paclitaxel followed by placebo, in subjects with recurrent or primary advanced endometrial cancer.
5. Part 2: Other Secondary Objectives: • To evaluate the following measures of clinical benefit of treatment with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib 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 EORTC QLQ EN24 -PFS2
6. Part 2: Other Secondary Objectives: • To evaluate the safety and tolerability of treatment with dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib compared to treatment with placebo plus carboplatin-paclitaxel followed by placebo (all comers).
7. Part 2: Other Secondary Objectives: • To assess the PK and immunogenicity of dostarlimab when given in combination with carboplatin and paclitaxel or with niraparib (all comers).
8. Part 2: Other Secondary Objectives: • To assess the PK of niraparib when given in combination with dostarlimab (all comers).

Conditions and MedDRA coding

Recurrent or primary advanced (Stage III or IV) endometrial cancer

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. (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.
2. (Part 1 and Part 2): 2. Subject has histologically or cytologically proven endometrial cancer with recurrent or advanced disease.
3. (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.
4. (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.
5. (Part 1 and Part 2): 5. Subject has an ECOG performance status of 0 or 1.
6. (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.
7. (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).
8. 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. Part 2 only: 9. Subjects must be able to take medication PO.

Exclusion criteria 23

1. (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.
2. (Part 1 and Part 2) 2. Subject has had >1 recurrence of endometrial cancer.
3. (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.
4. (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.
5. (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.
6. (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.
7. (Part 1 and Part 2) 7. Subject has a known history of HIV (HIV 1/2 antibodies).
8. (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).
9. (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)
10. (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.
11. (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.
12. (Part 1 and Part 2) 12. Subject has not recovered adequately from AEs or complications from any major surgery prior to starting therapy.
13. (Part 1 and Part 2) 13. Subject has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients.
14. (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.
15. (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).
16. (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.
17. (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.
18. Part 2 only: 18. Subject has received prior therapy with a PARP inhibitor.
19. 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).
20. Part 2 only: 20. Subject has any known history or current diagnosis of myelodysplastic syndrome or acute myeloid leukemia.
21. 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).
22. Part 2 only: 22. Subject has a known hypersensitivity to niraparib components or excipients.
23. Part 2 only: 23. Subject has participated in Part 1 of this study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Primary Endpoints for Part 1: The primary efficacy endpoint of PFS is 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. Tumor response will be evaluated using RECIST v.1.1.
2. Primary Endpoints for Part 1: The primary efficacy endpoint of overall survival is defined as the time from randomization to the date of death by any cause.
3. Primary Endpoint for Part 2: The primary efficacy endpoint of PFS is 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. Tumor response will be evaluated using RECIST v.1.1.

Secondary endpoints 8

1. 1. OS, defined as the time from randomization to the date of death by any cause (Part 2 only).
2. 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 or death by any cause in the absence of PD per RECIST v.1.1, whichever occurs first
3. 3. 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. 4. DOR based on BICR and Investigator assessment, defined as the time from the 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. 5. DCR based on BICR and Investigator assessment, defined as the proportion of subjects who have achieved a BOR of CR, PR, or stable disease per RECIST v.1.1
6. 6. 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. 7. PRO assessment of treatment using EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ EN24
8. 8. PK and immunogenicity of dostarlimab (Part 1 and Part 2) and PK of niraparib when administered in combination with dostarlimab (Part 2 only)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Tesaro Inc.

Sponsor organisation

Tesaro Inc.

Address

1000 Winter Street Suite 3300

City

Waltham

Postcode

02451-1230

Country

United States

Scientific contact point

Organisation

Tesaro Inc.

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Tesaro Inc.

Contact name

EU GSK Clinical Trials Call Center

Third parties 11

Locations

13 EU/EEA countries · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 116 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications