Genetic Profile-Guided Therapy for Ovarian Cancer

Overseen By Stephanie Lheureux

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Investigational drugs

Disqualifiers: Hypertension, Brain metastases, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

40 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have taken an investigational drug (other than a PARP inhibitor) within 30 days or a PARP inhibitor within 14 days before starting the study treatment.

What data supports the effectiveness of the drug combination including Niraparib for ovarian cancer?

Research shows that Niraparib, a drug in the treatment plan, helps extend the time patients with ovarian cancer live without the disease getting worse, especially after initial chemotherapy. It is effective for patients with or without specific genetic mutations. ^{1 2 3 4 5}

Is niraparib safe for use in humans?

Niraparib is generally well tolerated in humans, with the main safety concern being myelosuppression (a decrease in bone marrow activity leading to fewer blood cells). This side effect is manageable with monitoring and dose adjustments based on weight and platelet count. ^{6 7 8 9 10}

How is the drug Niraparib unique in treating ovarian cancer?

Niraparib is unique because it is a PARP inhibitor that can be used as maintenance therapy for ovarian cancer patients who have responded to platinum-based chemotherapy, regardless of their BRCA mutation or homologous recombination deficiency status. This makes it a versatile option for patients with limited maintenance treatment choices. ^{4 5 7 8 11}

What is the purpose of this trial?

The purpose of this research study is to see how useful it is to look at biomarkers in the blood and tumor tissue of participants with ovarian, fallopian tube or primary peritoneal cancer who have previously received treatment with a drug called a PARP inhibitor, and using the results to determine the best treatment for these participants. Biomarkers are molecules such as genes (molecules that contain instructions for the development and function of cells in the body) and proteins that may be used to see how well a body responds to certain treatments.

Research Team

Stephanie Lheureux

Principal Investigator

Princess Margaret Cancer Centre

Eligibility Criteria

This trial is for patients with ovarian, fallopian tube, or primary peritoneal cancer who have relapsed after PARP inhibitor therapy. They must have a good heart function, measurable disease by RECIST 1.1 criteria, and proper organ function. Women of childbearing potential need to use effective contraception and not breastfeed during the study.

Inclusion Criteria

I agree not to donate blood during and for 3 months after the study.

Patient must agree to not breastfeed during the study or for 30 days after the last dose of study treatment

My cancer has returned after treatment, regardless of how many treatments I've had.

Exclusion Criteria

I have been diagnosed with myelodysplastic syndrome or acute myeloid leukemia.

I have not had major chest or belly surgery in the last 2 weeks or any unhealed surgical cuts.

I don't have lasting side effects from cancer treatment worse than mild.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Biomarker Testing

Blood and tumor tissue samples are collected for biomarker testing to determine the participant's molecular profile

3 weeks

1 visit (in-person)

Initial Treatment

Participants receive bevacizumab and niraparib for 3 cycles, each cycle being 21 days

9 weeks

3 visits (in-person)

Cohort-Specific Treatment

Participants are assigned to a cohort based on genetic testing results and receive a combination of study drugs until disease progression or discontinuation criteria are met

Up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Bevacizumab
• Dostarlimab
• Niraparib
• Paclitaxel

Trial Overview The trial tests if using genetic markers from blood and tumor tissue can guide treatment choices post-PARP inhibitors in cancers like ovarian cancer. It involves drugs Niraparib, Dostarlimab, Bevacizumab, Paclitaxel to see which works best based on these biomarkers.

Participant Groups

Group I: Initial/Cohort C Experimental Treatment 2 Interventions

Niraparib by mouth (orally), once a day, every day. Bevacizumab, by vein (intravenously), once every 3 weeks for up to 1 year, then every 6 weeks.

Group II: Cohort B Experimental Treatment 3 Interventions

Paclitaxel, by vein (intravenously), once a week. Bevacizumab, by vein (intravenously), once every 3 weeks for up to 1 year, then every 6 weeks. Dostarlimab, by vein (intravenously), once every 3 weeks for 4 doses, then every 6 weeks afterwards.

Group III: Cohort A Experimental Treatment 3 Interventions

Niraparib by mouth (orally), once a day, every day. Bevacizumab, by vein (intravenously), once every 3 weeks for up to 1 year, then every 6 weeks. Dostarlimab, by vein (intravenously), once every 3 weeks for 4 doses, then every 6 weeks afterwards.

Niraparib is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Zejula for:

• Maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy
• Maintenance treatment of adults with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy

Approved in United States as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy
• Treatment of adults with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status

Approved in Canada as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

In a phase 3 trial involving 733 patients with newly diagnosed advanced ovarian cancer, niraparib significantly improved progression-free survival compared to placebo, with a median of 21.9 months versus 10.4 months for patients with homologous-recombination deficiency.

Niraparib also demonstrated a notable overall survival rate of 84% at 24 months, with manageable side effects, including anemia and thrombocytopenia, but no treatment-related deaths, indicating its safety and efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. González-Martín, A., Pothuri, B., Vergote, I., et al.[2019]

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]

In a real-world study of 22 ovarian cancer patients treated with niraparib at a dose of 200 mg/day, the objective response rate was 33.3%, indicating promising efficacy, especially in patients with homologous recombination deficiency (HRD).

The most common adverse events included nausea, thrombocytopenia, and anemia, with severe thrombocytopenia managed through dose adjustments, suggesting that niraparib can be tolerated with appropriate monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of niraparib for ovarian cancer: a single-center observational study from China. Ni, J., Cheng, X., Zhao, Q., et al.[2021]

In a phase 3 trial involving 553 patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly improved progression-free survival compared to placebo, with median durations of 21.0 months versus 5.5 months for patients with gBRCA mutations, and 12.9 months versus 3.8 months for those with homologous recombination deficiency.

While niraparib was effective, it was associated with moderate bone marrow toxicity, with common grade 3 or 4 adverse events including thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%), which were managed through dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. Mirza, MR., Monk, BJ., Herrstedt, J., et al.[2022]

In a study of 331 patients with recurrent ovarian cancer, niraparib maintenance therapy significantly improved progression-free survival (PFS) in patients with somatic BRCA mutations and those with BRCA wild-type tumors, indicating its efficacy across different genetic backgrounds.

Patients with BRCA wild-type tumors that had other homologous recombination repair (HRR) mutations, as well as those without any HRR mutations, also experienced PFS benefits from niraparib, suggesting its potential as a treatment option regardless of specific mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects. Mirza, MR., Lindahl, G., Mahner, S., et al.[2023]

Niraparib is the first PARP inhibitor approved for ovarian cancer treatment in patients without BRCA mutations, showing good tolerability and manageable hematologic side effects, especially with new dose modification guidelines.

Current research is exploring niraparib's effectiveness as a maintenance therapy after platinum-based chemotherapy and in recurrent high-grade serous ovarian cancer, highlighting the need for better biomarkers to identify which patients will benefit most from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for the treatment of ovarian cancer. Essel, KG., Moore, KN.[2019]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[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]

In a Phase 2 study involving 20 Japanese women with heavily pretreated ovarian cancer, niraparib demonstrated an objective response rate of 35%, indicating that it can effectively reduce tumor size in some patients.

The treatment was generally well-tolerated, with a high disease control rate of 90%, although common side effects included anemia and nausea, and 70% of patients experienced dose reductions or interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer. Okamoto, A., Kondo, E., Nakamura, T., et al.[2021]

Niraparib is the first FDA- and EMA-approved PARP inhibitor for maintenance therapy in platinum-sensitive ovarian cancer, effective regardless of BRCA status in first-line treatment.

The review highlights niraparib's pharmacological properties and summarizes efficacy and safety data from key trials, indicating its significant role in improving treatment outcomes for ovarian cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting. Maiorano, MFP., Maiorano, BA., Biancofiore, A., et al.[2023]

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 in Patients with Newly Diagnosed Advanced Ovarian Cancer. [2019]

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. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of niraparib for ovarian cancer: a single-center observational study from China. [2021]

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

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. [2022]

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

Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects. [2023]

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

Niraparib for the treatment of ovarian cancer. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. [2019]

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

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

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting. [2023]

11. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. [2019]