A Phase II Study of NirAparib, Dostarlimab and Radiotherapy in Metastatic, PD-L1 Negative or Immunotherapy-Refractory Triple-Negative Breast Cancer (NADiR)
Overview
- Phase
- Phase 2
- Intervention
- Niraparib
- Conditions
- Breast Cancer
- Sponsor
- Massachusetts General Hospital
- Enrollment
- 32
- Locations
- 4
- Primary Endpoint
- Overall response rate (ORR)-RECIST
- Status
- Active, not recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
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.
Detailed Description
This is an open-label, phase II study that will evaluate how safe and well the combination of niraparib, dostarlimab, and Radiation Therapy (RT) works in metastatic triple negative breast cancer. Niraparib is a type of drug called a "PARP inhibitor", which blocks DNA (the genetic material of cells) damage from being repaired or may prevent damage from occurring in the first place. In cancer treatment, inhibiting PARP may help kill cancer cells by not allowing the cancer cells to repair its DNA damage or prevent DNA damage associated with metastatic triple negative breast cancer from occurring. Dostarlimab is a type of immunotherapy. It is believed to work by inhibiting (stopping) a protein called PD-1 from working. The PD-1 protein controls parts of the immune system (the system in a person's body that fights against diseases) by shutting down certain immune responses that are responsible for recognizing and destroying cancer cells. The investigators believe that dostarlimab may inhibit the PD-1 protein on triple negative breast cancer cells, thus allowing the immune cells to recognize and destroy cancer cells.Radiation therapy is a standard-of-care treatment that is given to stop the growth of tumors. Radiation therapy can also stimulate the immune system, which leads to the destruction of tumor cells in the treated areas. Combining radiation therapy with anti-cancer drugs like dostarlimab and niraparib may increase the ability of the immune system to control or destroy cancer cells throughout the body. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants will receive the study drugs for up to 2 years or until their triple negative breast cancer worsens Participants will then be followed for up to 5 years. It is expected that about 32 people will take part in this research study. The FDA has not approved niraparib for metastatic triple negative breast cancer, but it has been approved for other uses. The U.S. Food and Drug Administration (FDA) has not approved dostarlimab as treatment for any disease.
Investigators
Steven J Isakoff, MD, PhD
Principal Investigator
Massachusetts General Hospital
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years.
- •ECOG performance status ≤ 1
- •Histologically or cytologically-confirmed TNBC (ER \<1%, PR \<1%, HER-2-neu 0-1+ by IHC or non-FISH-amplified
- •ER-low, PR-low (defined as ER and/or PR 1-10%) and HER2-negative patients may also be eligible, as per treating MD discretion).
- •Metastatic or recurrent TNBC.
- •Prior progression on immune-checkpoint inhibitor and/or PDL1-negative. Note: PDL1-status may be determined on tissues from either primary or mTNBC. PD-L1 status must be determined by an FDA-approved assay approved for breast cancer, such as PharmDx IHC (22C3) for pembrolizumab, Ventana (SP142) for atezolizumab
- •No more than 2 prior lines of systemic therapy for inoperable/recurrent or metastatic disease.
- •Note: Prior line of systemic therapy includes targeted or biologic agents in combination or the absence of chemotherapy
- •Radiation is clinically indicated for local control or palliation.
- •At least one tumor for which RT is considered clinically appropriate.
Exclusion Criteria
- •Participants who meet any of the following criteria will be excluded:
- •Known germline or somatic BRCA mutation-positive status
- •Known active brain metastases or LMD (leptomeningeal disease). Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging \[using the identical imaging modality for each assessment, either MRI or CT scan\] for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and have not been using steroids for at least 7 days prior to study treatment.
- •Known additional malignancy that progressed or required treatment in the last 2 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- •Prior treatment with either a PARP inhibitor or ICI is permitted, however, prior receipt of both therapies is excluded
- •Receipt of \>2 lines of chemo in the metastatic setting (including targeted or biologic agents in combination or the absence of chemotherapy)
- •Hypersensitivity to niraparib or dostarlimab components or its excipients.
- •Participation in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks (or at least 5 half-lives from previous therapy) of the first dose of study treatment.
- •Receipt of prior cytotoxic therapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., \> Grade 1 or at baseline) from adverse events due to a previously administered agent, including grade 2 alopecia.
- •Note: Participants with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
Arms & Interventions
Niraparib + Dostarlimab + Radiation therapy
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.
Intervention: Niraparib
Niraparib + Dostarlimab + Radiation therapy
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.
Intervention: Dostarlimab
Niraparib + Dostarlimab + Radiation therapy
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.
Intervention: Radiation therapy
Outcomes
Primary Outcomes
Overall response rate (ORR)-RECIST
Time Frame: Enrollment to end of treatment up to 5 years
Primary endpoint of the study is ORR as measured by RECIST v1.1. ORR will be estimated with the 95% confidence interval, based on the exact binomial distribution
Secondary Outcomes
- Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0(Enrollment to end of treatment up to 5 years)
- Progression-free survival (PFS)(First day of study treatment to the date of disease progression or death due to any cause, whichever came first, assessed up to 5 years)
- Overall response rate (ORR) by irRECIST criteria(Enrollment to end of treatment up to 5 years)
- Overall survival (OS)(First day of study treatment to the date of death due to any cause, assessed up to 5 years)