Niraparib for Recurrent Brain Cancer

Overseen By Isabel Arrillaga-Romany, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Massachusetts General Hospital

Must not be taking: Lomustine, Investigational agents

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, 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

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, two-arm, open-label, phase 0 trial to assess intratumoral pharmacokinetics and pharmacodynamics of niraparib in subjects with progressive IDH1 or IDH2 mutant glioma. - This research study involves an experimental treatment called Niraparib.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have received systemic anticancer therapy or certain investigational agents within 28 days before starting the study drug. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Niraparib for treating recurrent brain cancer?

Niraparib has been shown to improve progression-free survival in patients with ovarian cancer, including those with brain metastases, suggesting potential effectiveness in similar conditions. ^{1 2 3 4 5}

What safety data exists for Niraparib in humans?

Niraparib, also known as Zejula, has been studied for safety in patients with ovarian cancer. Common side effects include blood-related issues like low platelet counts (thrombocytopenia), low red blood cell counts (anemia), and low white blood cell counts (neutropenia), as well as digestive problems. These side effects often lead to changes in dosage or temporary pauses in treatment. ^{1 2 4 6 7}

How is the drug Niraparib unique for treating recurrent brain cancer?

Niraparib is unique because it is a PARP inhibitor, which works by preventing cancer cells from repairing their DNA, leading to cell death. This mechanism is different from other treatments like chemotherapy or anti-angiogenesis drugs, which target blood vessels or cell growth pathways. ^{8 9 10 11 12}

Research Team

Isabel Arrillaga-Romany, MD, Ph.D

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults with confirmed IDH1/2 mutant glioma, evidence of tumor progression, and a Karnofsky Performance Score (KPS) ≥ 70. Must be at least 12 weeks post-CNS radiation, not pregnant or breastfeeding, agree to contraception use, have adequate organ function and no major surgery within the last 4 weeks. Cannot be on other clinical trials or have had certain treatments recently.

Inclusion Criteria

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

It has been over 12 weeks since I completed radiation therapy to my brain.

- Hemoglobin ≥ 9 g/dL

Exclusion Criteria

Participants who are pregnant or breast-feeding.

Participants with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate, or participate in the study.

Participants with known hypersensitivity to any of the components of niraparib.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment - Arm A

Participants receive 1 cycle of Niraparib followed by surgery, then up to 12 cycles of Niraparib

13 cycles (1 cycle is 28 days)

Monthly visits for each cycle

Treatment - Arm B

Participants undergo surgery followed by up to 12 cycles of Niraparib

12 cycles (1 cycle is 28 days)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Regular follow-up visits

Treatment Details

Interventions

• Niraparib
• Resection/Treatment with Niraparib

Trial Overview The trial is testing Niraparib's effects directly in the brain tumors of patients with progressive IDH1/2 mutant gliomas. It's an open-label phase 0 study where participants will undergo resection/treatment to assess how well Niraparib works inside these tumors.

Participant Groups

Group I: Arm A Treatment with Niraparib Experimental Treatment 2 Interventions

Patients randomized to arm A will receive niraparib daily and undergo tumor resection after 28 days (+/- 7 days) of treatment. The participants in both arms will resume/start on treatment with niraparib 2 -4 weeks after surgery . Participants will continue treatment for up to 12 total cycles of treatment or until tumor progression, unacceptable toxicity or withdrawal of consent

Group II: Arm B No Treatment with Niraparib Active Control 1 Intervention

Subjects in arm B will not receive niraparib prior to surgery. The participants in both arms will resume/start on treatment with niraparib 2 -4 weeks after surgery . Participants will continue treatment for up to 12 total cycles of treatment or until tumor progression, unacceptable toxicity or withdrawal of consent.

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

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

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 has been approved by the FDA for patients with complete or partial response to first-line platinum-based chemotherapy, regardless of their BRCAm or HRD status, expanding treatment options for more patients.

Olaparib, in combination with bevacizumab, has also received FDA approval for patients with epithelial ovarian cancer, indicating that PARP inhibitors are now beneficial not only for BRCAm and HRD-deficient patients but also for those with HRD-proficient tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. Washington, CR., Moore, KN.[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]

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, a PARP inhibitor, is recommended as a maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer, leveraging the concept of synthetic lethality in BRCA mutation carriers.

A case study of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer showed that she remained free of disease progression for over 17 months while on niraparib after second-line chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. Gray, S., Khor, XY., Yiannakis, D.[2021]

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]

Niraparib, a treatment for recurrent ovarian cancer, has a high dose reduction rate of 68.9% due to treatment-emergent adverse events, with thrombocytopenia being a notable cause for 3.3% of patients.

Baseline body weight and platelet count are significant predictors for the risk of severe thrombocytopenia, suggesting that patients with a body weight under 77 kg or platelet count below 150,000/µl may benefit from starting at a lower dose of 200 mg/day without compromising progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and dose modification for patients receiving niraparib. Berek, JS., Matulonis, UA., Peen, U., et al.[2021]

In a phase III clinical trial involving 325 patients with recurrent glioblastoma, cediranib did not significantly improve progression-free survival compared to lomustine alone, whether used as a monotherapy or in combination.

Despite not meeting the primary endpoint, cediranib demonstrated some clinical benefits in secondary outcomes, such as delaying neurological deterioration and reducing the need for corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. Batchelor, TT., Mulholland, P., Neyns, B., et al.[2022]

In a study involving seven nude rats with gliomas, the combination of the anti-angiogenesis agent cediranib with the chemotherapy drug temozolomide (TMZ) resulted in a slight increase in the intratumoral concentration of TMZ, suggesting improved drug delivery to the tumor.

The MRI results indicated that cediranib treatment led to a normalization of the blood-brain barrier, which may enhance the effectiveness of chemotherapy in treating malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. Grossman, R., Tyler, B., Rudek, MA., et al.[2021]

Pazopanib significantly reduced the size of brain metastases in breast cancer models, showing a 73% decline in large metastases and a 39% decline in micrometastases, indicating its efficacy in preventing brain metastasis formation.

The drug acts directly on tumor cells by inhibiting B-Raf activation, which is crucial for cancer cell proliferation, suggesting a new mechanism of action for pazopanib beyond its known antiangiogenic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis. Gril, B., Palmieri, D., Qian, Y., et al.[2022]

In a phase Ib/II study involving 35 patients with recurrent glioblastoma, the maximum tolerable dose (MTD) of the pan-PI3K inhibitor buparlisib was established at 100 mg per day when combined with carboplatin, showing a consistent safety profile without new safety concerns.

However, the combination of buparlisib with either carboplatin or lomustine did not demonstrate sufficient antitumor activity compared to historical data for these single-agent treatments, indicating limited efficacy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study. Rosenthal, M., Clement, PM., Campone, M., et al.[2021]

Gefitinib, a medication used for non-small-cell lung cancer (NSCLC), has shown clinical activity in some patients with brain metastases, leading to improvements in neurological and systemic symptoms.

Case studies indicate that gefitinib can result in partial and even complete responses in brain metastases, suggesting the need for larger trials to better understand its efficacy and potential role in treatment, especially in combination with radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-of-life benefits and evidence of antitumour activity for patients with brain metastases treated with gefitinib. Katz, A., Zalewski, P.[2018]

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. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. [2023]

3. 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]

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. England pubmed.ncbi.nlm.nih.gov

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. [2021]

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

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

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

Safety and dose modification for patients receiving niraparib. [2021]

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

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. [2021]

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

Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Quality-of-life benefits and evidence of antitumour activity for patients with brain metastases treated with gefitinib. [2018]