Platinum-based Therapy + Dostarlimab + Niraparib for Ovarian Cancer

(FIRST Trial)

Recruiting at 251 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: Tesaro, Inc.

Must be taking: Platinum-based chemotherapy

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Pregnancy, CNS metastases, Cardiovascular disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 15 weeks

1402 Participants Needed

Trial Summary

What is the purpose of this trial?

Ovarian cancer is a heterogeneous disease, characterized by complex molecular and genetic changes. The high expression of vascular endothelial growth factor (VEGF) receptor, programmed death receptor ligands 1 (PD-L1) expression, and deoxyribonucleic acid (DNA) damage in ovarian tumors provide several targets for treatment and maintenance of disease response. Given the unmet medical need of participants with advanced or metastatic ovarian cancer, this study design will enable investigators to provide participants with current SOC for ovarian cancer for the duration of the study. This is a global, multicenter, randomized, double-blind, controlled Phase 3 study that will primarily compare the progression-free survival (PFS) for participants receiving dostarlimab with SOC chemotherapy +/- bevacizumab followed by niraparib and dostarlimab maintenance +/- bevacizumab versus participants receiving SOC with chemotherapy followed by niraparib maintenance. This comparison will be investigated in participants of newly diagnosed stage III or IV advanced non-mucinous epithelial ovarian cancer participants and also to compare PFS of all participants with Stage III or IV high-grade non-mucinous epithelial ovarian cancer treated with platinum-based combination therapy, dostarlimab (TSR-042), and niraparib to SOC platinum-based combination therapy. The currently recommended SOC therapy for the first line treatment of Stage III or IV ovarian cancer is the combination of paclitaxel and carboplatin, with or without concurrent and maintenance bevacizumab. Participants will receive SOC during the chemotherapy Run-In period (cycle 1) before randomization to study treatment (cycle 2). Concurrent bevacizumab use must be determined prior to randomization at cycle 2.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or have received a live vaccine recently, you may need to adjust your treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of dostarlimab and niraparib for ovarian cancer?

Research shows that niraparib, a drug used to maintain treatment response, significantly prolongs the time patients live without their cancer getting worse, regardless of genetic factors. Dostarlimab, when combined with niraparib, has shown promising results in treating recurrent ovarian cancer that resists other treatments. ^{1 2 3 4 5}

Is the combination of platinum-based therapy, dostarlimab, and niraparib safe for treating ovarian cancer?

Niraparib, a part of this combination, has been shown to have manageable side effects, including blood-related issues like low platelet counts and anemia, as well as fatigue and high blood pressure. These side effects can often be managed with dose adjustments and monitoring. There is a low risk of serious conditions like acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) associated with niraparib. ^{4 5 6 7 8}

What makes the drug combination of dostarlimab and niraparib unique for ovarian cancer?

This drug combination is unique because it combines dostarlimab, which helps the immune system attack cancer cells, with niraparib, which prevents cancer cells from repairing themselves, offering a novel approach for treating ovarian cancer, especially in patients who are resistant to platinum-based treatments. ^{1 4 5 9 10}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for women aged 18+ with advanced non-mucinous epithelial ovarian cancer (Stage III/IV). They must be postmenopausal, surgically sterilized, or use contraception. Eligible participants should have an ECOG score of 0 or 1, can take oral meds, and have normal blood pressure or controlled hypertension. They cannot join if they've had recent major surgery, uncontrolled medical issues, immunodeficiency, certain past cancers within specific time frames, active hepatitis B/C or autoimmune diseases.

Inclusion Criteria

I can provide a specific tissue sample for cancer testing.

I have Stage IV cancer and may have surgery or chemotherapy planned.

I have advanced ovarian, fallopian tube, or peritoneal cancer.

Exclusion Criteria

You have active hepatitis B or C.

My cancer is of a specific type (mucinous, germ cell, transitional cell, or undifferentiated).

My ovarian cancer is at an early stage (low-grade or Grade 1).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy Run-In

Participants receive SOC during the chemotherapy Run-In period (cycle 1) before randomization to study treatment

3 weeks

1 visit (in-person)

Treatment

Participants receive randomized treatment with SOC chemotherapy +/- bevacizumab followed by niraparib and dostarlimab maintenance +/- bevacizumab

15 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 years

Treatment Details

Interventions

• Dostarlimab (TSR-042)
• Niraparib
• Standard of care

Trial Overview The study compares the effectiveness of platinum-based therapy combined with TSR-042 (dostarlimab) and niraparib versus standard chemotherapy in treating ovarian cancer. It's a global Phase 3 trial focusing on progression-free survival rates. Participants will receive standard care initially before being randomly assigned to either the new drug combination or continued standard treatment.

Participant Groups

Group I: Participants receiving SOC+dostarlimab+niraparib Experimental Treatment 3 Interventions

Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab, and maintenance treatment of +/-bevacizumab with niraparib and dostarlimab

Group II: Participants receiving SOC+niraparib Active Control 3 Interventions

Participants in this arm will receive SOC in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/- bevacizumab with niraparib and dostarlimab placebo

Group III: Participants receiving SOC+placebo Placebo Group 3 Interventions

Participants in this arm will receive SOC (carboplatin+paclitaxel+/-bevacizumab) in cycle 1 (each cycle is of 21 days) followed by SOC with chemotherapy treatment with dostarlimab placebo from cycles 2 to 6 and maintenance treatment of +/-bevacizumab along with niraparib placebo and dostarlimab placebo

Dostarlimab (TSR-042) is already approved in European Union, United States for the following indications:

Approved in European Union as Jemperli for:

• Endometrial cancer

Approved in United States as Jemperli for:

• Mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer
• Solid tumors with dMMR

Who Is Running the Clinical Trial?

Tesaro, Inc.

Lead Sponsor

Trials

57

Recruited

10,600+

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Collaborator

Trials

41

Recruited

19,200+

Findings from Research

The combination treatment of dostarlimab and niraparib in patients with recurrent platinum-resistant ovarian cancer showed a low objective response rate of only 7.3%, leading to the early termination of the study due to insufficient efficacy.

Despite the treatment being generally safe with no new safety issues identified, 95.1% of patients experienced treatment-related adverse events, and health-related quality of life worsened over time, indicating a need for more effective therapies for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). Randall, LM., O'Malley, DM., Monk, BJ., et al.[2023]

In a study of 105 patients with newly diagnosed advanced ovarian cancer, the combination of niraparib and bevacizumab as first-line maintenance therapy resulted in a promising progression-free survival (PFS) rate of 62% at 18 months, with even higher rates in patients with homologous recombination deficiency (76%).

The safety profile of this combination therapy was consistent with the known side effects of the individual drugs, with common treatment-related adverse events including thrombocytopenia, fatigue, and anemia, indicating that the treatment is manageable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. Hardesty, MM., Krivak, TC., Wright, GS., et al.[2022]

Recent advancements in ovarian cancer treatment have introduced several new options that show improved survival rates compared to historical data, marking a significant progress after decades of stagnation.

Three new PARP inhibitors (olaparib, rucaparib, niraparib) have been approved for ovarian cancer, providing new maintenance and recurrence treatment options, alongside expanded uses for bevacizumab in combination chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Therapies for Ovarian Cancer. O'Malley, DM.[2020]

In a study of 94 patients with non-gBRCA1/2 mutated recurrent ovarian cancer, niraparib maintenance treatment demonstrated effectiveness similar to phase III trials, with a median time to first subsequent treatment of 10.7 months.

Individualized dosing based on patient weight and platelet counts led to fewer dose reductions and interruptions, highlighting the importance of personalized treatment to enhance safety and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data on niraparib maintenance treatment in patients with non-gBRCA mutated platinum-sensitive recurrent ovarian cancer. Vilming, B., Fallås Dahl, J., Bentzen, AG., et al.[2023]

Niraparib is an FDA and EMA-approved oral PARP inhibitor for maintenance treatment in women with recurrent ovarian cancer who have responded to platinum-based chemotherapy, showing efficacy in both BRCA mutated and wild-type cancers.

While niraparib is effective, it can cause significant hematologic toxicities, such as thrombocytopenia and anemia, necessitating dose adjustments for certain patients to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. Moore, KN., Mirza, MR., Matulonis, UA.[2019]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

Niraparib significantly improves progression-free survival and other key outcomes in patients with recurrent, platinum-sensitive ovarian cancer, based on the phase III NOVA trial involving a randomized, double-blind, placebo-controlled design.

The treatment has a manageable safety profile, with most serious side effects being blood-related issues, which can be effectively managed through dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. Heo, YA., Duggan, ST.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). [2023]

2. United States pubmed.ncbi.nlm.nih.gov

OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

New Therapies for Ovarian Cancer. [2020]

4. England pubmed.ncbi.nlm.nih.gov

A phase III, randomized, double blinded trial of platinum based chemotherapy with or without atezolizumab followed by niraparib maintenance with or without atezolizumab in patients with recurrent ovarian, tubal, or peritoneal cancer and platinum treatment free interval of more than 6 months: ENGOT-Ov41/GEICO 69-O/ANITA Trial. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Niraparib: First Global Approval. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Real-world data on niraparib maintenance treatment in patients with non-gBRCA mutated platinum-sensitive recurrent ovarian cancer. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. [2019]

8. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. [2022]

9. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. [2020]