Niraparib for Brain Cancer

Overseen by Priscilla K. Brastianos

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Massachusetts General Hospital

Must not be taking: PARP inhibitors

Disqualifiers: Recent chemotherapy, Major surgery, MDS, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing niraparib, a drug that may help treat cancer that has spread to the brain and spinal cord. It works by preventing cancer cells from fixing their damaged DNA, which can help kill them. The study will include about 20 participants and will last for a significant period. Niraparib is an oral drug approved for maintenance treatment in various cancers including ovarian cancer.

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 can continue taking letrozole, anastrozole, exemestane, tamoxifen, fulvestrant, trastuzumab, bisphosphonates, denosumab, or ovarian suppression therapy. If you are on other medications, it's best to discuss with the trial team.

How does the drug Niraparib differ from other treatments for brain cancer?

Niraparib is unique because it is a PARP inhibitor, which means it works by blocking a protein that helps repair DNA damage in cancer cells, potentially making it effective for brain cancer where other treatments may not target this mechanism. ^{1 2 3 4 5}

Research Team

Priscilla K. Brastianos

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults with solid tumors that have spread to the brain and are minimally symptomatic. Participants must have measurable CNS disease, be stable on medications, and not have had recent major surgery or blood transfusions. They should not have been treated with PARP inhibitors before and must not be pregnant or breastfeeding. A good performance status and normal organ function are required.

Inclusion Criteria

My cancer is triple negative or has specific genetic changes.

I have had brain surgery or a biopsy for genetic testing.

I agree not to donate blood during the study or for 90 days after the last treatment.

Exclusion Criteria

I haven't had significant radiation therapy affecting my bone marrow recently.

I haven't taken any colony stimulating factors in the last 4 weeks.

Must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive niraparib 1x daily for each 28-day cycle up to 2 years or until disease worsens or unacceptable side effects occur

Up to 2 years

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 4 months

Treatment Details

Interventions

• Niraparib (PARP Inhibitor)

Trial Overview The effectiveness of niraparib, a drug designed to combat cancer in the central nervous system (CNS), is being tested. The study focuses on patients whose cancer has metastasized to the CNS, particularly those with genetic alterations related to DNA repair pathways.

Participant Groups

Group I: Niraparib Experimental Treatment 1 Intervention

Participants will receive niraparib 1x daily for each 28 day study treatment cycle up to 2 years or until disease worsens or unacceptable side effects occur.

Niraparib is already approved in Canada for the following indications:

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+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

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 II trial involving 65 patients with recurrent glioblastoma, the pan-PI3K inhibitor buparlisib showed minimal efficacy as a single agent, with only 8% of patients achieving 6-month progression-free survival.

Despite demonstrating significant brain penetration and some reduction in PI3K pathway activity in tumor tissue, the incomplete blockade of the pathway likely contributed to the lack of clinical effectiveness, suggesting that more effective PI3K inhibitors may be needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. Wen, PY., Touat, M., Alexander, BM., et al.[2020]

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]

In a phase I study involving patients with newly diagnosed glioblastoma, the maximum tolerated dose (MTD) of buparlisib when combined with temozolomide was determined to be 80 mg/day, but the MTD for the combination with both temozolomide and radiotherapy could not be established due to significant dose-limiting toxicities.

The study reported high rates of adverse events, particularly nausea and fatigue, leading to treatment discontinuations, which contributed to Novartis's decision to halt further development of buparlisib for this indication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Wen, PY., Rodon, JA., Mason, W., et al.[2021]

In a phase I/II study involving 20 patients with glioblastoma, the combination of PTK787/ZK222584 (PTK/ZK) with standard treatments was found to be safe and well tolerated, with a recommended dose of 1000 mg once daily.

The study identified some dose-limiting toxicities at higher doses, but overall, the treatment was manageable, leading to the conclusion that prolonged administration of PTK/ZK alongside radiotherapy and temozolomide is feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma. Brandes, AA., Stupp, R., Hau, P., et al.[2022]

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]

References

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

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. [2020]

2. 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]

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

Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. [2021]

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

EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma. [2022]

5. 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]