Radiation + Immunotherapy + PARP Inhibitor for Breast Cancer

(NADiR Trial)

Recruiting at 6 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

32 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment combining radiation, immunotherapy, and PARP inhibitors for breast cancer?

Research shows that combining PARP inhibitors like niraparib with radiotherapy can enhance the treatment's effectiveness by targeting DNA damage repair, as seen in head and neck cancer studies. Additionally, combining PARP inhibitors with immunotherapy has shown antitumor activity in breast cancer, suggesting potential benefits for this combination treatment. ^{1 2 3 4 5}

Is the combination of radiation, immunotherapy, and PARP inhibitor safe for breast cancer treatment?

The combination of niraparib (a PARP inhibitor) and dostarlimab (an immunotherapy drug) is being studied for safety in patients with certain types of lung cancer and mesothelioma, but specific safety data for breast cancer is not available. However, these drugs have been used in other cancers, suggesting they are generally safe for human use, though more research is needed for breast cancer specifically. ^{2 6 7 8 9}

How is the treatment with Dostarlimab, Niraparib, and Radiation unique for breast cancer?

This treatment is unique because it combines radiation therapy with immunotherapy (Dostarlimab) and a PARP inhibitor (Niraparib), which may enhance the effectiveness of radiation by making cancer cells more sensitive to it, potentially leading to better outcomes compared to using these therapies separately. ^{1 2 10 11 12}

What is the purpose of this trial?

This research study is looking to see whether the combination of Dostarlimab and Niraparib plus Radiation Therapy (RT) is safe and effective in participants with metastatic triple negative breast cancer. The names of the study treatment involved in this study are: * Dostarlimab * Niraparib * Radiation Therapy (RT), which is given per standard of care.

Research Team

Steven Isakoff, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation. [2022]

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

Olaparib shows promise in multiple tumor types. [2014]

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

Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells. [2021]

4. England 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. [2021]

5. United States 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. [2021]

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

Dostarlimab: First Approval. [2021]

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

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

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Dostarlimab: A Review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts. [2021]

11. United States 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. [2022]

12. Ireland pubmed.ncbi.nlm.nih.gov

Phase I study of the PARP inhibitor talazoparib with radiation therapy for locally recurrent gynecologic cancers. [2021]