Niraparib + Radiation for Brain Tumor

Recruiting at 1 trial location

Overseen By Phase 0 Navigator

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nader Sanai

Must not be taking: Coumarin anticoagulants

Disqualifiers: Pregnancy, Active infection, Heart failure, others

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

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: 1

42 Participants Needed

Trial Summary

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

The protocol does not specify if you need to stop all current medications. However, if you are using coumarin-derived anticoagulants, you must discontinue them before surgery. Also, if you've had chemotherapy, a 21-day washout period is required before starting the trial.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of at least 21 days between the last chemotherapy and the start of the study. If you are taking coumarin-derived anticoagulants, you must stop them before surgery, but other anticoagulants like heparin are allowed.

What data supports the idea that Niraparib + Radiation for Brain Tumor is an effective treatment?

The available research shows that Niraparib, when combined with radiation, can make cancer cells more sensitive to the treatment. For example, studies have shown that Niraparib helps enhance the effects of radiation on lung, breast, and prostate cancer cells, making them more likely to be destroyed. Additionally, a case report highlighted the successful use of Niraparib in treating brain metastases from endometrial cancer, where the patient remained free of disease progression for 6 months. This suggests that Niraparib can effectively reach the brain and improve treatment outcomes. However, there is no direct data on its use specifically for brain tumors, so more research is needed to confirm its effectiveness for this condition. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Niraparib combined with radiation therapy for treating brain tumors?

Research shows that Niraparib, a drug that helps prevent cancer cells from repairing themselves, can make cancer cells more sensitive to radiation. This combination has been effective in treating various cancers, including lung, breast, and prostate cancers, and has shown promise in treating brain metastases from endometrial cancer. ^{1 2 3 4 5}

What safety data exists for the combination of Niraparib and radiation therapy?

The safety data for Niraparib primarily comes from its use in ovarian cancer trials, where it has shown significant adverse events, including hematologic issues like thrombocytopenia, anemia, and neutropenia, as well as gastrointestinal events. These adverse events led to dose interruptions and reductions in a significant number of patients. While there is research on Niraparib's radiosensitization effects in various cancer cell lines, including head and neck, lung, breast, prostate, and melanoma, specific safety data for its combination with radiation therapy in brain tumors is not directly available from the provided studies. The existing studies suggest that Niraparib can enhance the effects of radiation on cancer cells, but the impact on healthy tissues and overall safety in a clinical setting requires further investigation. ^{2 3 4 6 7}

Is the combination of Niraparib and radiation therapy safe for humans?

Niraparib has been studied in combination with radiation therapy for various cancers, and while it shows promise in enhancing the effects of radiation on cancer cells, it can cause side effects. In trials for ovarian cancer, nearly all patients experienced some side effects, with serious ones like low blood cell counts being common. The combination with radiation may increase sensitivity in cancer cells, but healthy cells can also be affected, so careful monitoring is needed. ^{2 3 4 6 7}

Is the drug Niraparib a promising treatment for brain tumors?

Yes, Niraparib is a promising drug for brain tumors. It has been shown to improve survival in cancer patients and can enter the brain to effectively target tumors. It also works well with radiation therapy, making cancer cells more sensitive to treatment. ^{3 4 5 6 8}

How is the drug Niraparib unique in treating brain tumors?

Niraparib is unique because it is a PARP inhibitor that can cross the blood-brain barrier, allowing it to reach higher concentrations in brain tissues, which may enhance its tumor-suppressing effects when combined with radiation therapy. ^{3 4 5 6 8}

What is the purpose of this trial?

This is an open-label, multi-center Phase 0 study with an expansion phase that will enroll up to 24 participants with newly-diagnosed glioblastoma and up to 18 recurrent glioma participants with IDH mutation and ATRX loss. The trial will be composed of a Phase 0 component (subdivided into Arm A and B) and a therapeutic expansion phase. Patients with tumors demonstrating a positive PK Response (in Arm A) or a positive PD Response (in Arm B) of the Phase 0 component of the study will graduate to a therapeutic expansion phase that combines therapeutic dosing of niraparib plus standard-of-care fractionated radiotherapy (in Arm A) or niraparib monotherapy (in Arm B) until progression of disease.

Research Team

Nader Sanai, MD

Principal Investigator

Chief Scientific Officer/Director of the Ivy Brain Tumor Center

Eligibility Criteria

Adults over 18 with newly-diagnosed glioblastoma or recurrent glioma with specific genetic mutations can join. They must have recovered from any previous chemotherapy, have normal blood pressure, adequate organ function, and not be pregnant or breastfeeding. Participants need to agree to use effective contraception and adhere to lifestyle considerations for the study duration.

Inclusion Criteria

I am not pregnant or cannot become pregnant due to surgery, menopause, or other reasons.

For females of reproductive potential: use of highly effective contraception for at least 1 month prior to treatment and agreement to use such a method during study participation and for an additional 6 months after the end of treatment administration

I am having surgery for a suspected new glioblastoma diagnosis.

Exclusion Criteria

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

I haven't needed antibiotics or antivirals for an infection or high fever in the last 4 weeks.

I do not have an active infection needing IV antibiotics or a known virus like HIV or hepatitis B/C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 0

Participants receive niraparib for 4 days prior to surgical resection

1 week

1 visit (in-person)

Therapeutic Expansion

Participants receive niraparib plus standard-of-care fractionated radiotherapy or niraparib monotherapy until disease progression

6-7 weeks for radiotherapy, followed by maintenance

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Niraparib
• Radiation therapy

Trial Overview The trial is testing Niraparib in combination with standard radiotherapy for some patients (Arm A), and as a single therapy for others (Arm B). It's an open-label Phase 0 study followed by an expansion phase based on initial responses, aiming to enroll up to 42 participants across multiple centers.

Participant Groups

Group I: Arm B: Recurrent Glioma (Grades II-IV) Experimental Treatment 1 Intervention

Participants undergoing resection of a recurrent WHO Grade II, III, or IV glioma with IDH1 or IDH2 mutation and ATRX loss will be treated with niraparib for 4 days prior to a planned surgical resection. Participants who proceed to the Expansion cohort will receive niraparib in 28d cycles after surgery.

Group II: Arm A: Presumed Newly-Diagnosed glioblastoma Experimental Treatment 2 Interventions

Participants undergoing resection for a presumed newly-diagnosed glioblastoma (WHO grade 4) will be treated with niraparib for 4 days prior to surgical resection. Participants who proceed to the therapeutic expansion phase of this study will receive niraparib in combination with radiation (60 Gy over 6-7 weeks, as per standard of care). Following radiotherapy, eligible study participants may receive niraparib maintenance treatment.

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?

Nader Sanai

Lead Sponsor

Trials

11

Recruited

440+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

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

Barrow Neurological Institute

Collaborator

Trials

27

Recruited

7,100+

Ivy Brain Tumor Center

Collaborator

Trials

12

Recruited

910+

Findings from Research

In a phase 2 study involving 36 patients with radiation-induced brain injury, 61.1% achieved a significant reduction in brain edema after 4 weeks of treatment with oral apatinib, indicating its efficacy.

Apatinib was well-tolerated, with only mild to moderate side effects reported, such as hand-foot syndrome and fatigue, and no severe treatment-related toxic effects were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Apatinib for Radiation-induced Brain Injury Among Patients With Head and Neck Cancer: An Open-Label, Single-Arm, Phase 2 Study. He, L., Pi, Y., Li, Y., et al.[2022]

Niraparib, a PARP inhibitor, effectively radiosensitizes human tumor cells from lung, breast, and prostate cancers, enhancing their sensitivity to radiation regardless of their p53 status, as shown in clonogenic survival assays.

The mechanism behind this radiosensitization involves niraparib converting single strand breaks (SSBs) into lethal double strand breaks (DSBs) during DNA replication, suggesting its potential for clinical use in combination with radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Bridges, KA., Toniatti, C., Buser, CA., et al.[2021]

Niraparib, a DNA damage repair inhibitor, significantly increased the sensitivity of four head and neck cancer cell lines to both photon and proton radiotherapy, suggesting it could enhance treatment effectiveness.

The study found that niraparib not only reduced colony formation in some cell lines but also increased the relative biological effectiveness (RBE) of protons compared to photons, indicating a potential advantage of proton therapy when combined with niraparib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells. Wang, L., Cao, J., Wang, X., et al.[2021]

Niraparib and Talazoparib, when combined with ionizing radiation, significantly sensitize melanoma cells to treatment, leading to increased cell death compared to radiation alone.

Healthy fibroblasts are less affected by the combination therapy than melanoma cells, indicating a potential for targeted treatment that spares normal tissue while effectively targeting cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation. Jonuscheit, S., Jost, T., Gajdošová, F., et al.[2021]

Niraparib, a PARP inhibitor, was successfully used to treat a 62-year-old woman with endometrial cancer and brain metastases, leading to 6 months of disease-free progression, highlighting its potential efficacy in this rare condition.

The drug's ability to cross the blood-brain barrier allows for higher concentrations in brain tissues, which may enhance its tumor-suppressing effects, suggesting a promising mechanism of action for treating brain metastases from endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of a patient with brain metastases from endometrial cancer using Niraparib: a case report. Wang, Q., Zhang, F., Gao, H., et al.[2021]

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, a PARP inhibitor, significantly improves progression-free survival in patients with advanced epithelial ovarian cancer, but nearly all patients (≥99%) experience treatment-emergent adverse events, with 51-74% experiencing severe (grade ≥3) events.

An individualized starting dose of niraparib based on body weight and platelet count leads to fewer severe adverse events and dose modifications, suggesting a tailored approach can enhance safety while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and management of niraparib monotherapy in ovarian cancer clinical trials. Monk, BJ., González-Martin, A., Buckley, L., et al.[2023]

In a phase III trial involving patients with advanced breast cancer and germline BRCA1/2 mutations, niraparib showed a median progression-free survival (PFS) of 4.1 months compared to 3.1 months for physician's choice chemotherapy, although the difference was not statistically significant (P = 0.86).

Despite the trial being halted due to issues with data assessment, niraparib demonstrated a 35% objective response rate, indicating its potential effectiveness in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. Turner, NC., Balmaña, J., Poncet, C., et al.[2023]

References

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

Efficacy and Safety of Apatinib for Radiation-induced Brain Injury Among Patients With Head and Neck Cancer: An Open-Label, Single-Arm, Phase 2 Study. [2022]

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

Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. [2021]

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

Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation. [2021]

5. China pubmed.ncbi.nlm.nih.gov

Successful treatment of a patient with brain metastases from endometrial cancer using Niraparib: a case report. [2021]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Safety and management of niraparib monotherapy in ovarian cancer clinical trials. [2023]

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

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. [2023]