Niraparib + Dostarlimab for Brain Cancer

Overseen By Timothy Yap, MBBS,PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: PARP inhibitors, PD-1/L1 inhibitors

Disqualifiers: Prostate cancer, Active hepatitis, HIV, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

To learn if the combination of niraparib and dostarlimab can help to control advanced cancer that has spread to the brain.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be receiving other interventional anticancer treatments at the same time. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Niraparib and Dostarlimab for brain cancer?

Dostarlimab has been approved for treating certain types of endometrial cancer, showing it can be effective against some cancers. Niraparib has been studied for advanced breast cancer with specific genetic mutations, indicating it may help in treating cancers with similar characteristics. ^{1 2 3 4 5}

How is the drug combination of Niraparib and Dostarlimab unique for brain cancer treatment?

The combination of Niraparib and Dostarlimab is unique because it targets cancer cells by exploiting their DNA repair weaknesses and enhancing the immune system's ability to fight cancer. Niraparib, a PARP inhibitor, increases DNA damage in cancer cells, while Dostarlimab, an immune checkpoint inhibitor, helps the immune system recognize and attack these damaged cells, offering a novel approach compared to traditional treatments. ^{2 4 5 6 7}

Research Team

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults (18+) with advanced cancers that have spread to the brain, including specific types such as BRCA1/2m cancer and various lung and breast cancers. Participants must have had previous treatment, possess measurable brain metastasis not requiring immediate intervention or steroids, and adequate organ function. They cannot be pregnant or breastfeeding and must agree to contraception.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My organs are functioning well.

I am 18 years old or older.

Exclusion Criteria

I cannot swallow pills or have a gut condition affecting medication absorption.

Participants with an inactive, known or suspected autoimmune disease

Participants unable to undergo contrast enhanced brain MRI

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive niraparib and dostarlimab to assess intracranial objective response rate and systemic antitumor activity

12 weeks

Follow-up

Participants are monitored for safety, tolerability, and effectiveness after treatment

8 weeks

Treatment Details

Interventions

• Dostarlimab
• Niraparib

Trial Overview The trial is testing a combination of two drugs: Niraparib, a PARP inhibitor, and Dostarlimab, a PD-1 inhibitor. The goal is to see if these drugs can control advanced cancer in patients whose disease has progressed into the brain.

Participant Groups

Group I: Monotherapy Experimental Treatment 2 Interventions

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

Approved in European Union as Jemperli for:

• Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer
• dMMR/MSI-H recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen

Approved in United States as Jemperli for:

• Adults with dMMR recurrent or advanced solid tumors who have progressed on or following prior treatment and lack satisfactory alternative treatment options
• Primary advanced or recurrent dMMR endometrial cancer in combination with carboplatin and paclitaxel

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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]

Dostarlimab-gxly (Jemperli) has received accelerated approval from the FDA for treating adults with mismatch repair deficient recurrent or advanced endometrial cancer and solid tumors, indicating its potential effectiveness in these specific cancer types.

This approval highlights the importance of targeted therapies in oncology, particularly for patients with specific genetic markers that may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Drug for Mismatch Repair Deficient Endometrial Cancer and Solid Tumors. Aschenbrenner, DS.[2023]

In a phase II trial involving 17 patients with melanoma brain metastasis (MBM) who had previously undergone multiple treatments, buparlisib, a PI3K inhibitor, was well tolerated but did not result in any intracranial responses, with only three patients achieving stable disease.

The median progression-free survival was 42 days and median overall survival was 5 months, suggesting limited efficacy in this heavily pretreated population, highlighting the need for further exploration of combination therapies targeting the PI3K-AKT pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study. Amaral, T., Niessner, H., Sinnberg, T., et al.[2022]

Dostarlimab is a monoclonal antibody that targets the PD-1 receptor and has been approved for treating adult patients with mismatch repair deficient recurrent or advanced endometrial cancer based on promising results from the GARNET trial.

The approval of dostarlimab in the EU and USA marks a significant milestone in cancer treatment, highlighting its potential efficacy in targeting specific cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab: First Approval. Markham, A.[2021]

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 clinical trial involving 55 patients with advanced solid tumors, the PD-1 inhibitor dostarlimab was found to be well tolerated in both doublet and triplet combination therapies, with no new safety concerns arising.

The triplet combinations showed higher disease control rates compared to doublets, with preliminary antitumor activity observed in various combinations, indicating potential for improved efficacy in treating advanced cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. Yap, TA., Bessudo, A., Hamilton, E., et al.[2022]

The study investigates the safety and effectiveness of combining niraparib, a PARP inhibitor, with dostarlimab, an immune checkpoint inhibitor, in treating advanced non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) in patients with homologous recombination deficiency (HRD) and PD-L1 expression of 1% or higher.

A total of 700 to 1000 patients will be screened to find 70 eligible participants, with the primary goal of assessing progression-free survival, while also evaluating overall survival and safety, highlighting the potential for this combination therapy to enhance cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design. Passiglia, F., Bironzo, P., Righi, L., et al.[2021]

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

New Drug for Mismatch Repair Deficient Endometrial Cancer and Solid Tumors. [2023]

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

An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Dostarlimab: First Approval. [2021]

5. 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]

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

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. [2022]

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

A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design. [2021]