Niraparib + Neratinib for Ovarian Cancer

(iNNOVATE Trial)

Overseen By Massey IIT Research Operations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Virginia Commonwealth University

Must not be taking: PPIs, P-gp substrates, CYP3A4 drugs

Disqualifiers: Invasive cancer, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

Trial Summary

What is the purpose of this trial?

To determine the recommended phase 2 dose (RP2D) of niraparib and neratinib in combination in patients with advanced solid tumors during Phase 1. To evaluate clinical benefit (≥4-month progression-free survival \[PFS\]) of niraparib and neratinib in patients with platinum-resistant ovarian cancer in Phase 1b.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications that might interact with the study drugs. You must stop using proton pump inhibitors 10 days before starting the trial and discontinue certain other medications at least 2 weeks prior. You can continue taking corticosteroids if your dose has been stable for at least 4 weeks before starting the trial.

What data supports the effectiveness of the drug Niraparib in treating ovarian cancer?

Niraparib has been shown to significantly extend the time patients live without their cancer getting worse when used as a maintenance treatment for ovarian cancer, especially after responding to platinum-based chemotherapy. It is effective regardless of specific genetic mutations, making it a promising option for many patients. ^{1 2 3 4 5}

Is the combination of Niraparib and Neratinib safe for treating ovarian cancer?

Niraparib is generally well tolerated in patients with ovarian cancer, with manageable side effects mainly related to blood health. However, there is no specific safety data available for the combination of Niraparib and Neratinib. ^{1 3 4 6 7}

What makes the drug combination of Niraparib and Neratinib unique for treating ovarian cancer?

The combination of Niraparib and Neratinib is unique because Niraparib is a PARP inhibitor that helps repair DNA damage in cancer cells, while Neratinib is a tyrosine kinase inhibitor that blocks signals promoting cancer cell growth. This dual approach targets different pathways in cancer cells, potentially offering a more comprehensive treatment strategy for ovarian cancer. ^{1 2 3 8 9}

Research Team

Andrew Poklepovic, MD

Principal Investigator

Massey Cancer Center

Eligibility Criteria

Adults with advanced solid tumors, including ovarian cancer patients who are platinum-resistant and have had at least two prior therapies but no BRCA mutation. Participants must have adequate organ function, not be pregnant or breastfeeding, agree to use contraception, and cannot have certain health conditions like uncontrolled infections or recent major surgeries.

Inclusion Criteria

I am 18 years old or older.

Agreement to abstain from activities that could result in pregnancy from screening through 90 days after the last dose of study treatment

Agreement to not donate blood during the study or for 90 days after the last dose of study treatment

Exclusion Criteria

My cancer has spread to my brain or its coverings.

Known hypersensitivity to study components or excipients

I cannot swallow pills.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Determine the recommended phase 2 dose (RP2D) of niraparib and neratinib using a modified 3+3 design

4 months

Regular visits for dose escalation and monitoring

Phase 1b Dose Expansion

Evaluate clinical benefit (≥4-month progression-free survival) of niraparib and neratinib in patients with platinum-resistant ovarian cancer

4 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 months

Treatment Details

Interventions

• Neratinib
• Niraparib

Trial Overview The trial is testing different doses of Niraparib and Neratinib to find the safest and most effective combination for treating advanced solid tumors. The focus is on determining the best dose during Phase 1 and assessing benefits in ovarian cancer patients during Phase 1b.

Participant Groups

Group I: Phase 1b: Platinum Resistant Expansion Cohort Experimental Treatment 2 Interventions

This portion of the study provides for cohort expansion to observe for 4 month or greater progression-free survival in patients with platinum resistant ovarian cancer treated at the recommended phase 2 dose (RP2D) determined in Phase I.

Group II: Dose Level 4 Experimental Treatment 2 Interventions

Neratinib 240 mg and Niraparib 300 mg by mouth once daily for 28 day cycles.

Group III: Dose Level 3 Experimental Treatment 2 Interventions

Neratinib 240 mg and Niraparib 200 mg by mouth once daily for 28 day cycles.

Group IV: Dose Level 2 Experimental Treatment 2 Interventions

Neratinib 200 mg and Niraparib 200 mg by mouth once daily for 28 day cycles.

Group V: Dose Level 1 Experimental Treatment 2 Interventions

Neratinib 160 mg and Niraparib 200 mg by mouth once daily for 28 day cycles.

Group VI: Dose Level -1 Experimental Treatment 2 Interventions

Neratinib 160 mg and Niraparib 100 mg by mouth once daily for 28 day cycles.

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

Approved in United States as Nerlynx for:

• Extended adjuvant treatment of women with early-stage HER2-positive breast cancer

Approved in European Union as Nerlynx for:

• Extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

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

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 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]

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]

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 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 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]

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]

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]

Niraparib significantly improves progression-free survival in patients with recurrent ovarian, fallopian tube, and primary peritoneal cancers, showing 21 months for gBRCA mutation carriers and 9.3 months for non-gBRCA patients compared to much shorter durations with placebo.

As a PARP inhibitor, niraparib works by blocking a key DNA repair mechanism in cancer cells, making it an effective maintenance therapy for patients who have responded to platinum-based treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Kerliu, L., Myruski, S., Bhatti, A., et al.[2020]

References

1. 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]

2. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Niraparib for the treatment of ovarian cancer. [2019]

4. 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]

5. France pubmed.ncbi.nlm.nih.gov

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

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

7. 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]

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

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

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

Niraparib for the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. [2020]