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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two drugs, niraparib and dostarlimab (an immunotherapy drug), can control advanced cancers that have spread to the brain. It targets patients with specific types of cancer, such as certain breast or lung cancers, who have experienced brain metastasis. Suitable participants should have undergone previous cancer treatment, have a brain tumor that shows no symptoms, and not require immediate surgery or other urgent treatments. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that niraparib was generally well-tolerated over 6.2 years, with no new safety concerns. Common side effects included nausea in 70% of patients and fatigue in 58%. However, some cases showed serious side effects like bone marrow problems and a type of blood cancer.

Research has shown that dostarlimab has a safety profile similar to other drugs that help the immune system fight cancer, with common issues resembling those seen with similar treatments.

Both treatments have FDA approval for other uses, indicating a basic level of safety. However, their combined use is still under study, so potential participants should stay informed and consult their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the potential of combining Niraparib and Dostarlimab for brain cancer because these drugs bring a fresh approach to treatment. Most current options focus on chemotherapy and radiation, which target rapidly dividing cells. Niraparib, however, is a PARP inhibitor that targets cancer cell DNA repair mechanisms, while Dostarlimab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. This combination leverages both direct DNA damage and immune system enhancement, offering a two-pronged attack that could provide more effective outcomes than existing treatments alone.

What evidence suggests that the combination of niraparib and dostarlimab could be effective for brain cancer?

Previous studies have shown promising results for niraparib in treating brain cancers like glioblastoma. It effectively reached tumors and slowed their growth, with patients experiencing an average of 11.7 months without disease progression, suggesting it can delay cancer's progress. Dostarlimab, another drug in this trial, has proven effective for certain cancers, particularly those with specific genetic traits, by enhancing the immune system's ability to attack cancer cells. In this trial, participants will receive either niraparib or dostarlimab as monotherapy, aiming to control brain cancer that has spread by leveraging the strengths of each drug. ^{6 7 8 9 10}

Who Is on the Research Team?

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 have a brain tumor that can be measured.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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]

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]

Citations

1. webmd.com webmd.com/cancer/brain-cancer/ss/brain-cancer-treatment-advances

Brain Cancer Treatment Advances Learn about recent advances in brain cancer treatment, from targeted therapies and new drugs to precision surgery and the role of AI.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37004983/

Promise of dostarlimab in cancer therapy Recent clinical trials have shown that dostarlimab is effective in treating mismatch repair deficiency (dMMR) in endometrial cancer patients.

3. cancerresearch.org cancerresearch.org/immunotherapy-by-cancer-type/brain-cancer

What Makes Immunotherapy for Brain Cancer ... Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced brain or nervous system ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2216334

Dostarlimab for Primary Advanced or Recurrent ... Dostarlimab plus carboplatin–paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer.

5. withpower.com withpower.com/trial/phase-2-neoplasm-metastasis-5-2023-fc7e9

Niraparib + Dostarlimab for Brain Cancer 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% ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02715284

NCT02715284 | Study of TSR-042, an Anti-programmed ... Part 2B of the study will examine the safety and clinical activity of dostarlimab in cohorts of participants with specific types of advanced solid tumors.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8739161/

Safety, antitumor activity, and pharmacokinetics of ... Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2021/761223Orig1s000MultidisciplineR.pdf

JEMPERLI (dostarlimab-gxly) Review - accessdata.fda.gov The safety review focused on safety from 267 patients with dMMR recurrent or advanced solid tumors from cohorts A1 and F in Part 2B of the ...

9. ema.europa.eu ema.europa.eu/en/documents/product-information/jemperli-epar-product-information_en.pdf

Jemperli, INN-dostarlimab - EMA The safety and efficacy of JEMPERLI in children and adolescents aged under 18 years have not been established. No data are available. Method of administration.

10. jemperlihcp.com jemperlihcp.com/

Primary Advanced or Recurrent Endometrial Cancer ... Discover JEMPERLI (dostarlimab-gxly) + CP, an IO-based treatment for primary advanced or recurrent endometrial cancer. See full Indication, Safety, & PI.