Niraparib and Dostarlimab as Neoadjuvant Treatment for Patients with BRCA-Mutated Stage I-III Breast Cancer
- Participants must have histologically or cytologically confirmed invasive breast cancer stage I to III with primary tumor size at least 1.5 cm defined by physical exam or imaging (whichever is larger). In the case of a multifocal, multicentric, or bilateral disease, the largest lesion must be >= 1.5 cm and designated as the “index” lesion for tumor evaluations. Patients with inflammatory breast carcinoma are not eligible
- Participants must have documentation of ER and progesterone receptor (PR) testing by immunohistochemistry (IHC) according to local institutional guidelines in a Clinical Laboratory Improvement Act (CLIA)-approved setting. Central confirmation of ER/PR status is not required. All tumors must be HER2 negative. * Arms A and B: Target lesion must be ER and PR negative (< 10% staining) by local review * Arm C: Target lesion must be ER and/or PR positive (> 10% staining) by local review
- Participants must have documented HER2-negative invasive tumor according to local institutional guidelines in a CLIA-approved setting. Central confirmation of HER2 status is not required. HER2 negative is defined as: * 0 or 1+ by IHC, OR * Lack of gene amplification with HER2/chromosome 17 centromere (CEP17) ratio < 2 by in situ hybridization (ISH), OR * Copy number < 6 by ISH
- Participants must have documented germline mutation in BRCA1 or BRCA2 that is deleterious or suspected to be deleterious (known or predicted to be detrimental/lead to loss of function). Mutation must be identified through a CLIA-approved laboratory. Final determination of eligibility for any discordant results in pathogenicity will be made by the sponsor-investigator. A formal eligibility exception will not be required in these cases as long as approval by overall study principal investigator (PI) is granted and documented
- Participants with multifocal, multicentric or bilateral disease are eligible if at least one lesion meets criteria for the study. In this circumstance, the investigator must determine which will represent the target lesion to be assessed for response. This should remain consistent throughout the study. The target lesion should be selected on the basis of its size (lesion with the longest diameter) and suitability for accurate repetitive measurements
- Participants with an eligible target lesion, and another small HER2+ tumor (for example, < 6 mm), may be eligible for enrollment following discussion and agreement with the overall principal investigator. A formal eligibility exception will not be required in these cases as long as approval by the sponsor-investigator is granted and documented
- >= 18 years of age
- Breast imaging should include imaging of the ipsilateral axilla. For subjects with a clinically positive axilla by physical examination or imaging, axillary tissue acquisition is not required. For patients with a clinically negative axilla by examination and imaging, tissue acquisition is not required. For equivocal imaging findings, tissue acquisition (a needle aspiration, core biopsy) is required. Sentinel lymph node (SLN) biopsy before neoadjuvant therapy is not allowed
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days prior to the date of registration)
- Platelet count >= 100,000/mm^3 (within 14 days prior to the date of registration)
- Hemoglobin >= 9 g/dl (within 14 days prior to the date of registration)
- Total serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to the date of registration), (=< 2.0 in patients with documented Gilbert’s Syndrome)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN (within 14 days prior to the date of registration)
- Serum or plasma creatinine =< 1.5 x institutional ULN, OR calculated creatinine clearance > 50 mL/min using the Cockcroft-Gault equation (within 14 days prior to the date of registration)
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN (within 14 days prior to the date of registration). Participants who are receiving anticoagulant therapy are eligible as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) must be =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to the date of registration)
- Premenopausal women must have a negative urine or serum pregnancy test within 7 days of treatment start. Women are considered non-childbearing (by other than medical reasons) if they: * Are >= 45 years of age and without menses for > 1 year * Have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy with a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Are post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate barrier method throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. Information must be captured appropriately within the site’s source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
- Male and female participants of childbearing potential must agree to adhere to adequate contraception as defined in the protocol for the duration of study participation and for 150 days after the last dose of study treatment
- Female participants must agree to not breastfeed during the study or for 150 days after the last dose of study treatment
- Participants must agree to not donate blood during the study or for 90 days after the last dose of study treatment
- Ability to understand and willingness to sign an informed consent document
- Ability to swallow and retain oral medication
- Patients undergoing breast conserving therapy (i.e. lumpectomy) should not have any contraindications to radiation therapy
- Participants must be willing to undergo the mandatory research biopsy at baseline and after 3 weeks on study treatment. Participants who undergo an attempted research biopsy procedure for the purpose of this protocol and in whom inadequate tissue is obtained are not required to undergo a repeat biopsy in order to continue on the protocol
- Stage IV breast cancer
- Concurrent therapy with any other investigational product
- Prior treatment for the current breast cancer, including prior chemotherapy, immune therapy, hormonal therapy, radiation, or investigational therapy for this diagnosis
- Excisional biopsy of the primary tumor and/or excision of axillary lymph nodes, including sentinel lymph node biopsy (SLNB), prior to study treatment
- Participants with a history of malignancy are ineligible except in the following circumstances: * Individuals with a history of invasive breast cancer are not eligible unless they have been disease-free for a minimum of three years * Individuals with a malignancy history other than invasive breast cancer are eligible if they have no active malignancy and are deemed by the investigator to be at low risk for recurrence of that malignancy * Individuals with the following cancer history are eligible: adequately treated non-melanoma skin cancers, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma * Other exceptions may exist following agreement with the sponsor-investigator
- Patients with a diagnosis of immunodeficiency, or currently receiving systemic steroid therapy or any other form of immunosuppressive within 7 days prior to the first dose of study treatment. Use of local corticosteroid injections (e.g. intra-articular injections), inhaled, intranasal, ophthalmic, and topical corticosteroids, and subjects requiring corticosteroid pre-medication for hypersensitivity reactions (e.g. computed tomography [CT] scan pre-medication) are allowed
- Patients with autoimmune disease that has required systemic treatment within the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Patients with a history of interstitial lung disease or pneumonitis
- Patients who have received a live vaccine within 2 weeks prior to the start of study treatment
- Patients who have undergone any major surgery within 3 weeks prior to study entry: patients must have recovered to baseline from any effects of any major surgery
- Patients with concurrent human immunodeficiency virus (HIV) infection are eligible provided they meet the following criteria: * CD4+ T-cell (CD4+) counts >= 350 cells/uL * No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 12 months prior to enrollment * Any medication used in an antiretroviral therapy (ART) regimen must have no known interaction with the study agents
- Patients with active or chronic hepatitis B or C are eligible provided they meet the liver function laboratory criteria and cannot be on any medication with a known interaction with the study agents
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome or psychiatric illness/social situations that would limit compliance with study requirements
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to niraparib, dostarlimab, or their excipients
- Transfusion (platelets or red blood cells) =< 4 weeks prior to initiating protocol therapy
- Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
I. To evaluate the pathologic complete response (pCR) rate of preoperative combined niraparib and PD-1 blockade in patients with early stage triple-negative breast carcinoma (TNBC) with BRCA-mutations.
II. To assess the change in tumor-infiltrating lymphocytes (TILs) pre- and post-treatment with niraparib alone and with preoperative combined niraparib and PD-1 blockade in patients with early stage BRCA-mutated TNBC (via multiplex immunofluorescence).
I. To explore the pCR rate and changes in TILs (via multiplex immunofluorescence) in participants with estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)-negative BRCA-mutated breast cancer.
II. To explore the rate of residual cancer burden (RCB) 0/1 response with preoperative combined niraparib and PD-1 blockade in patients with early stage TNBC and ER-positive HER2-negative breast cancer with BRCA-mutations.
I. To assess changes in immune checkpoint protein expression after niraparib alone and after combined niraparib and PD-1 blockade (via multiplex immunofluorescence).
II. To assess activation of the STING pathway after niraparib alone and after combined niraparib and PD-1 blockade (via immunohistochemistry).
III. To assess changes in expression of kynurenine and indoleamine 2,3 dioxygenase (IDO) post-niraparib and post-combined niraparib and PD-1 blockade (via mass spectrometry).
IV. To assess changes in mutational load and neoantigen expression post-niraparib alone and post-combined niraparib and immune checkpoint blockade (via whole-exome sequencing).
V. To assess changes in immune signatures post-niraparib alone and post-combined niraparib and PD-1 blockade (via ribonucleic acid [RNA]-sequencing).
VI. To assess changes in blood-based biomarkers post-niraparib alone and post-combined niraparib and PD-1 blockade.
OUTLINE: Patients with triple negative breast cancer are randomized to arms A or B. Patients with hormone-receptor positive breast cancer are assigned to Arm C
ARM A: Patients receive niraparib orally (PO) once daily (QD) beginning day 1 of week 1 and dostarlimab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks for 18 weeks in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive niraparib PO QD beginning day 1 of week 1. Beginning week 4, patients also receive dostarlimab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for 18 weeks in the absence of disease progression or unacceptable toxicity.
ARM C: Patients with hormone receptor positive breast cancer receive niraparib and dostarlimab as in arm A.
After completion of treatment, patients followed up until definitive surgery and then annually for 5 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Erica L. Mayer
- Primary ID 20-371
- Secondary IDs NCI-2020-13969
- Clinicaltrials.gov ID NCT04584255