Radiation + Immunotherapy + PARP Inhibitor for Breast Cancer

(NADiR Trial)

Not currently recruiting at 7 trial locations

Overseen By Steven Isakoff, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: BRCA mutation, Brain metastases, Autoimmune, 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: 4

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for treating metastatic triple-negative breast cancer, a challenging form that has spread to other parts of the body. Researchers aim to determine if a combination of two drugs, Dostarlimab (an immunotherapy) and Niraparib (a PARP inhibitor), along with radiation therapy, can be both safe and effective. This study targets individuals who have tried up to two other treatments without success and have a type of breast cancer lacking certain common receptors (triple-negative). Participants should be prepared for regular treatment cycles involving these medications and radiation. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer treatment.

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

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you should not have received certain treatments like cytotoxic therapy or targeted small molecule therapy within 2 weeks before starting the trial. It's best to discuss your current medications with the trial team to get specific guidance.

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

Research has shown that Dostarlimab and Niraparib, combined with Radiation Therapy, have been studied for safety in various contexts. For instance, a study with breast cancer patients found some responded well to Dostarlimab and Niraparib, though specific safety details from this trial are not provided. Another study found that this combination improved outcomes for endometrial cancer patients, suggesting it might be safe and effective.

Dostarlimab and Niraparib have received FDA approval for treating other cancer types, indicating they have passed safety checks for those uses. This approval suggests some confidence in their safety, though side effects can still occur.

As this is a Phase 2 trial, the safety of Dostarlimab and Niraparib with Radiation Therapy is under careful observation. This phase typically includes more participants than earlier stages, allowing for more detailed safety information. Participants in the trial will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining dostarlimab, niraparib, and radiation therapy for breast cancer because it introduces a novel approach to treatment. Unlike standard options like chemotherapy and hormone therapy, this combination leverages immunotherapy and a PARP inhibitor. Dostarlimab is an immune checkpoint inhibitor, which helps the immune system better recognize and attack cancer cells. Niraparib, a PARP inhibitor, disrupts cancer cell DNA repair, making them more vulnerable. Together with radiation, which directly targets tumor cells, this combination aims to provide a more potent and targeted attack on breast cancer.

What evidence suggests that this trial's treatments could be effective for metastatic triple negative breast cancer?

Research has shown that combining radiation therapy with anti-cancer drugs like dostarlimab and niraparib may enhance the immune system's ability to fight cancer. In studies involving patients with BRCA-mutated breast cancer, some achieved a complete response when treated with niraparib and dostarlimab. This indicates that this drug combination can be effective against certain types of breast cancer. In this trial, participants will receive a combination of niraparib, dostarlimab, and radiation therapy to assess its safety and effectiveness in treating triple-negative breast cancer, a particularly challenging type to treat. Although more research is needed, early results for this combination therapy are promising. ^{1 3 6 7 8}

Who Is on the Research Team?

Steven Isakoff, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults with metastatic triple negative breast cancer who need radiation therapy and haven't had a positive response to immune-checkpoint inhibitors or are PDL1-negative. Participants must have good organ function, not be pregnant, agree to use contraception, and can't have certain conditions like active hepatitis, known BRCA mutations, brain metastases, recent major surgery or immunosuppressive treatments.

Inclusion Criteria

You have a sample of tumor tissue collected within the last 28 days.

My cancer progressed after treatment with immune-checkpoint inhibitors or is PDL1-negative.

I am fully active and can carry on all my pre-disease activities without restriction.

Exclusion Criteria

I have received more than 2 chemotherapy treatments for my cancer after it spread.

I have an active tuberculosis infection.

I have had another cancer that got worse or needed treatment in the past 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Niraparib daily, Dostarlimab every 3 weeks for 4 cycles, then every 6 weeks, and Radiation Therapy on Days 1, 2, and 3 of Cycle 1

Up to 2 years

Regular visits every 3 weeks initially, then every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Periodic follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Dostarlimab
• Niraparib
• Radiation therapy

Trial Overview The study tests the safety and effectiveness of combining Dostarlimab (an immunotherapy drug) with Niraparib (a PARP inhibitor) alongside standard Radiation Therapy in treating metastatic triple negative breast cancer. The goal is to see if this combination works better than current treatments.

How Is the Trial Designed?

Group I: Niraparib + Dostarlimab + Radiation therapy Experimental Treatment 3 Interventions

Study cycle length is 3 weeks. Participants will receive: * Niraparib 1x daily during each study cycle * Dostarlimab 1x every 3 weeks for 4 study cycles, then 1x every 6 weeks beginning on Cycle 5 * Radiation therapy will be given on Days 1, 2, and 3 of Cycle 1.

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

University of North Carolina

Collaborator

Trials

174

Recruited

1,457,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Sibley Memorial Hospital

Collaborator

Trials

2

Recruited

50+

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

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]

NanoOlaparib, a lipid-based formulation of the PARP inhibitor olaparib, significantly enhances the sensitivity of radiation-resistant prostate cancer cells and tumors, leading to improved tumor growth inhibition compared to traditional oral olaparib.

In a mouse model, combining NanoOlaparib with radiation not only tripled median survival time but also resulted in a complete response in half of the treated mice, indicating its potential as a powerful strategy for treating tumors with PTEN and TP53 deletions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation. van de Ven, AL., Tangutoori, S., Baldwin, P., et al.[2022]

This phase I study investigates the safety and tolerability of talazoparib, a PARP inhibitor, when used alongside radiotherapy in women with recurrent gynecologic cancers.

PARP inhibitors like talazoparib have been shown to enhance the effectiveness of radiation therapy, potentially improving treatment outcomes for patients with these types of cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the PARP inhibitor talazoparib with radiation therapy for locally recurrent gynecologic cancers. Lakomy, DS., Urbauer, DL., Westin, SN., et al.[2021]

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[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]

Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody that has received rapid FDA approval for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, showing promising tumor response rates.

A clinical trial (NCT04165772) reported a remarkable 100% remission rate for rectal cancer patients treated with Dostarlimab, highlighting the potential of matching tumor genetics with targeted therapies, and the trial is ongoing for other cancer types like gastric, prostate, and pancreatic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab: A Review. Costa, B., Vale, N.[2022]

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]

The RADIOPARP trial, involving 24 patients with triple-negative breast cancer (TNBC), showed that the combination of Olaparib and radiotherapy can be safely escalated to 200 mg twice a day without causing severe side effects, indicating a favorable safety profile.

At the 1-year follow-up, the treatment demonstrated minimal low-grade adverse events, with no significant toxicities related to the heart, lungs, or digestive system, suggesting that this combination therapy could be a promising option for TNBC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Olaparib with radiotherapy for triple-negative breast cancers: One-year toxicity report of the RADIOPARP Phase I trial. Loap, P., Loirat, D., Berger, F., et al.[2021]

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]

A phase II study of the PARP inhibitor olaparib confirmed its clinical benefits for cancer patients with inherited BRCA1 and BRCA2 mutations, particularly in advanced breast and ovarian cancers.

The study also provided evidence that olaparib is effective against pancreatic and prostate cancers, expanding its potential use in treating various cancer types associated with these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib shows promise in multiple tumor types. [2014]

The maximum tolerated dose (MTD) of olaparib, a PARP inhibitor, in combination with radiotherapy for non-small cell lung cancer was determined to be 25 mg once daily, but the combination with cisplatin resulted in unacceptable toxicity levels.

Severe pulmonary adverse events occurred in 18% of patients, highlighting the need for more precise radiotherapy techniques to minimize damage to the lungs and esophagus during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and Pharmacologic Study of Olaparib in Combination with High-dose Radiotherapy with and without Concurrent Cisplatin for Non-Small Cell Lung Cancer. de Haan, R., van den Heuvel, MM., van Diessen, J., et al.[2022]

In this study of melanoma cells and healthy fibroblasts, the PARP inhibitors talazoparib and niraparib, when combined with ionizing radiation, significantly increased cell death and caused G2/M cell cycle arrest, particularly in melanoma cells, which are homologous recombination deficient.

While the combination treatment shows potential, the effects vary between different melanoma cell lines, indicating that individual responses should be evaluated before recommending this therapy for broader use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts. Weigert, V., Jost, T., Hecht, M., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04837209

Radiation, Immunotherapy and PARP Inhibitor in Triple ... Combining radiation therapy with anti-cancer drugs like dostarlimab and niraparib may increase the ability of the immune system to control or destroy cancer ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12146980/

Phase II Study Evaluating the Efficacy of Niraparib and ... In this study, we combine niraparib (PARPi) with dostarlimab (anti–PD-L1) to evaluate clinical benefit in patients with R/M HNSCC. Introduction.

3. cancernetwork.com cancernetwork.com/view/niraparib-dostarlimab-shows-promise-in-brca-er-her2-breast-cancer

Niraparib/Dostarlimab Shows Promise in BRCA+ ER+/HER2 Of 18 patients with BRCA-mutated ER+/HER2– breast cancer, 3 had a pathological complete response when treated with niraparib plus dostarlimab.

4. dana-farber.org dana-farber.org/clinical-trials/20-371

A phase II study of niraparib with dostarlimab therapy as ... This research study involves pre-operative therapy that is specifically targeted for breast cancer in individuals with BRCA and PALB2 mutations.

5. cancertherapyadvisor.com cancertherapyadvisor.com/news/niraparib-dostarlimab-radiotherapy-triple-negative-breast-cancer/

Niraparib Plus Dostarlimab and Radiotherapy in TNBC Researchers are conducting a phase 2 trial to investigate the safety and efficacy of niraparib in combination with dostarlimab and radiotherapy in patients ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-08759

Niraparib, Dostarlimab, and Radiation Therapy for the ... This phase II trial studies of the effect of niraparib, dostarlimab, and radiation therapy in treating patients with PD-L1 negative triple negative breast ...

7. gsk.com gsk.com/en-gb/media/press-releases/jemperli-plus-zejula-combination-significantly-improved-progression-free-survival-in-endometrial-cancer-phase-iii-trial/

Jemperli (dostarlimab) plus Zejula (niraparib) combination ... Jemperli (dostarlimab) plus Zejula (niraparib) combination significantly improved progression-free survival in primary advanced or recurrent endometrial cancer.

8. aacrjournals.org aacrjournals.org/cancerrescommun/article/5/6/939/762896/Phase-II-Study-Evaluating-the-Efficacy-of

Phase II Study Evaluating the Efficacy of Niraparib and ... We designed a single-arm, open-label, phase II clinical trial to evaluate the combination of niraparib and dostarlimab in patients with R/M HNSCC.