The FIRST (First-line ovarian cancer treatment with Niraparib plus TSR-042) Study

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

27 Nov 2018 → ongoing

Decision date (initial)

2024-04-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

TESARO, Inc., a wholly owned subsidiary of GSK

External identifiers

EU CT number

2024-510605-28-00

EudraCT number

2018-000413-20

ClinicalTrials.gov

NCT03602859

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Therapy

To compare the progression free survival (PFS) of platinum-based combination therapy, dostarlimab, and niraparib treatment (Arm 3) to platinum-based combination therapy and niraparib treatment (Arm 2) in participants with Stage III or IV high grade nonmucinous epithelial ovarian cancer.

Secondary objectives 2

1. Secondary objectives comparing platinum-based combination therapy, dostarlimab, and niraparib (Arm 3) to platinum-based combination therapy and niraparib (Arm 2) will evaluate: − Overall survival (OS) − Blinded Independent Central Review (BICR) determined PFS per RECIST v1.1 criteria − Health-related quality of life (HRQoL) − Time to first subsequent therapy (TFST) − Time to second subsequent therapy (TSST) − Time from randomization to the earliest date of assessment of progression after initiation of subsequent anticancer therapy following study treatment or death by any cause (PFS2) − Objective response rate (ORR) per RECIST v.1.1 for participants with measurable disease at baseline − Duration of response (DOR) per RECIST v1.1 for participants with measurable disease at baseline − Disease control rate (DCR) per RECIST v1.1 for participants with measurable disease at baseline − Pharmacokinetics (PK) and immunogenicity of dostarlimab − PK of niraparib
2. Secondary objectives for platinum-based combination therapy (Arm 1), platinum-based combination therapy and niraparib (Arm 2) and platinum-based combination therapy, dostarlimab, and niraparib (Arm 3) for all participants will evaluate: − Safety and tolerability

Conditions and MedDRA coding

Stage 3 or 4 Non-mucinous Epithelial Ovarian Cancer

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

GSK follows ICMJE guidance with regards to data sharing. Per GSK publication Standard of Practice, for all manuscripts disclosing interventional study data, a data sharing statement is mandatory. For publications where researchers could seek anonymized subject level data (eg, clinical trials) the following data sharing statement is included in the manuscripts: Please refer to GSK weblink to access GSK’s data sharing policies and as applicable seek anonymized subject level data via the link https://www.gsk-studyregister.com/en/ In case a journal pushes back regarding the use of a general statement as above, an alternative statement will be generated based on discussion with our Publications Therapy Area Head and alignment with journals requirement. FIRST manuscripts will include a data sharing statement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Participants 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. 2. Participants 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 [i.e., American Joint Committee on Cancer].
3. 3. All participants with Stage IV disease are eligible. This includes those with inoperable disease, those who undergo PDS (R0 or macroscopic disease), or those for whom NACT is planned.
4. 4. Participants with Stage III are eligible if they meet one or more of the following criteria: a. Stage IIIC participants CC0 resection if they meet the following criteria: aggregate ≥ 5 cm extra-pelvic disease during PDS as assessed by the Investigator. b. All participants with inoperable Stage III disease. c. All Stage III participants with macroscopic residual tumor (per Investigator judgment) following PDS. d. All Stage III participants for whom NACT is planned.
5. 5. Participant must provide a blood sample for ctDNA HRR testing at PreScreening or Screening.
6. 6. Participant must provide sufficient tumor tissue sample (a minimum of 1 FFPE block or slide at Pre-Screening or Screening) for programmed death ligand 1 (PD-L1), HRD testing.
7. 7. Participants 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. 8. Participants 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. 9. Participants 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 ≥1,500/µL b. Platelet count ≥100,000/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. 10. Participants must have an ECOG score of 0 or 1.
11. 11. Participants must have normal BP or adequately treated and controlled hypertension (systolic BP ≤140 mmHg and/or diastolic BP ≤90 mmHg).
12. 12. Participants must agree to complete HRQoL questionnaires throughout the study.
13. 13. Participants must be able to take oral medication.

Exclusion criteria 22

1. 1. Participant has mucinous, germ cell, transitional cell, or undifferentiated tumor.
2. 2. Participant has low grade or Grade 1 epithelial ovarian cancer.
3. 3. Stage III participant with CC0 resection after PDS (i.e., no macroscopic residual disease, unless inclusion criterion #4a is met).
4. 4. Participant has not adequately recovered from prior major surgery.
5. 5. Participant has a known condition, therapy, or laboratory abnormality that might confound the study results or interfere with the participant's participation for the full duration of the study treatment in the opinion of the Investigator.
6. 6. Participant 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. Participant 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. 7. Participant has known active central nervous system metastases, carcinomatous meningitis, or both.
8. 8. Participant has clinically significant cardiovascular disease (e.g., 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. 9. Participant has a bowel obstruction by clinical symptoms or CT scan, subocclusive mesenteric disease, abdominal or gastrointestinal fistula, gastrointestinal perforation, or intra abdominal abscess.
10. 10. Participant initiating bevacizumab as SOC has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at Screening or urine dipstick for proteinuria ≥2 (participants 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. 11. Participant has any known history or current diagnosis of MDS or AML.
12. 12. Participant has been diagnosed and/or treated with any therapy for invasive cancer <5 years from study enrollment, completed adjuvant chemotherapy and/or targeted therapy (e.g., trastuzumab) less than 3 years from enrollment, or completed adjuvant hormonal therapy less than 4 weeks from enrollment. Participants 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 nonmelanomatous skin cancer are allowed.
13. 13. Participant is at increased bleeding risk due to concurrent conditions (e.g., 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. 14. Participant is immunocompromised. Participants with splenectomy are allowed. Participants with known HIV are allowed if they meet all criteria as listed in the protocol. a. Cluster of differentiation 4 ≥350/µL and viral load <400 copies/mL b. No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrollment c. No history of HIV associated malignancy for the past 5 years d. Concurrent antiretroviral therapy as per the most current National Institutes of Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV started >4 weeks prior to study enrollment.
15. 15. Participant has known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative] is detected).
16. 16. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non- malignant systemic disease, or uncontrolled infection.
17. 17. Participant 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. 18. Participant 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. 19. Participant has a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, dostarlimab, or their excipients.
20. 20. Prior treatment for high-grade nonmucinous epithelial ovarian, fallopian tube, or peritoneal cancer (immunotherapy, anticancer therapy, radiation therapy).
21. 21. Participant 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 (e.g., thyroid hormone or insulin).
22. 22. Participant 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint PFS is defined as the time from the date of randomization to the date of first documentation of progression or death by any cause, whichever occurs first

Secondary endpoints 10

1. 1. Overall survival (OS)
2. 2. BICR determined PFS per RECIST v1.1 criteria
3. 3. The absolute scores and change from baseline in the EQ-5D-5L Visual Analogue Score (VAS) and Health Utility Index (HUI) HRQoL assessments
4. 4. The absolute scores and change from baseline in the EORTC QLQ C30, and EORTC QLQ OV28 HRQoL assessments
5. 5. TFST, defined as the time from the date of randomization to the start date of the first subsequent anticancer therapy or death by any cause, whichever occurs first
6. 6. TSST, defined as the time from the date of randomization to the start date of the second subsequent anticancer therapy or death by any cause, whichever occurs first treatment or death by any cause (PFS2)
7. 7. PFS2, defined as the time from the date of randomization to the date of first PD per Investigator’s assessment after initiation of subsequent anticancer therapy or death by any cause, whichever occurs first
8. 8. ORR, defined as the proportion of participants with a complete response (CR) or partial response (PR) per RECIST v1.1 by Investigator assessment, for participants with measurable disease at baseline
9. 9. DOR, defined as the time from first documentation of CR or PR until the time of first documentation of PD per RECIST v1.1 criteria by Investigator assessment, or death by any cause, whichever occurs first for participants with measurable disease at baseline
10. 10. DCR, defined as the proportion of participants with a best overall response of CR, PR, or stable disease (SD), per RECIST v1.1 by Investigator assessment, for participants with measurable disease at baseline

Investigational products

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

Test 3

Placebo 1

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 17

Locations

13 EU/EEA countries · 88 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 125 files

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

Application history

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