Clinical Trials /

Niraparib + TSR042 In BRCA Mutated Breast Cancer

NCT04584255

Description:

This research study involves pre-operative therapy that is specifically targeted for breast cancer in individuals with BRCA mutations. The names of the study drugs involved in this study are: - Niraparib (Zejula) - Dostarlimab

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Niraparib + TSR042 In BRCA Mutated Breast Cancer
  • Official Title: A Phase II Study of Niraparib With Dostarlimab Therapy as Neoadjuvant Treatment for Patients With BRCA-mutated Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20-371
  • NCT ID: NCT04584255

Conditions

  • Stage I Breast Cancer
  • Stage II Breast Cancer
  • Stage III Breast Cancer
  • Breast Cancer
  • HER2-negative Breast Cancer
  • Germline BRCA1 Gene Mutation
  • Germline BRCA2 Gene Mutation

Interventions

DrugSynonymsArms
NiraparibZejulaArm A TNBC
DostarlimabTSR042Arm A TNBC

Purpose

This research study involves pre-operative therapy that is specifically targeted for breast cancer in individuals with BRCA mutations. The names of the study drugs involved in this study are: - Niraparib (Zejula) - Dostarlimab

Detailed Description

      The research study procedures include screening for eligibility and study treatment including
      laboratory evaluations, two mandatory research biopsies, imaging assessments, and follow up
      visits.

      Participants will receive treatment for 18 weeks. After 18 weeks, participants will be
      evaluated to determine if a candidate for surgery or if additional treatment outside of the
      study.

      Participants with triple negative breast cancer will be randomized to one of two treatment
      arms.

        -  Arm A: Niraparib with Dostarlimab for 18 weeks

        -  Arm B: Niraparib alone for 3 weeks, followed by Niraparib with Dostarlimab for 15 weeks

      Participants with estrogen receptor positive breast cancer will be placed directly into Arm
      C. There is no randomization for these participants.

      - Arm C: Niraparib with dostarlimab for 18 weeks

      It is expected that about 62 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug or drug combination to learn whether the drug
      combination works in treating a specific disease. "Investigational" means that the study
      drugs, Niraparib and Dostarlimab, are being studied for use in this setting and the research
      doctors are trying to learn more about the drug combination-the side effects the combination
      may cause and if it is effective in treating this type of cancer.

      The FDA (the U.S. Food and Drug Administration) has not yet approved either of the drugs in
      this study for your type of cancer. Niraparib has been approved by the FDA for treatment of
      advanced ovarian cancer in BRCA mutation carriers.

      The use of Dostarlimab in this research study is experimental, which means that it is not
      approved by any regulatory auit is not approved by any regulatory authority, including the
      FDA, for treatment of breast cancer, or any other disease.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A TNBCExperimentalParticipants will be randomized 1:1 to treatment with the combination (Arm A) Niraparib-Daily beginning with week 1, day 1 Dostarlimab-Once every three weeks beginning with week 1, day 1
  • Niraparib
  • Dostarlimab
Arm B TNBCExperimentalParticipants will be randomized 1:1 to treatment with the combination (Arm B) 3-week lead-in of niraparib monotherapy followed by treatment with the combination Niraparib Daily beginning with week 1, day 1 Dostarlimab Once every three weeks beginning with week 4, day 1
  • Niraparib
  • Dostarlimab
Arm C ER+/HER2-Experimentalexploratory cohort of estrogen receptor (ER) positive HER2-negative participants will be enrolled to Arm C. Niraparib Daily beginning with week 1, day 1 Dostarlimab Once every three weeks beginning with week 1, day 1
  • Niraparib
  • Dostarlimab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must meet the following criteria on screening examination to be eligible
             to participate in the study. Laboratory assessments for eligibility must be completed
             within 14 days prior to the date of registration. Diagnostic imaging, such as MRIs and
             CT scans, must be performed within 28 days of the planned treatment start.

          -  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 PR testing by IHC according to local
             institutional guidelines in a 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/CEP17 ratio < 2 by 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 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.

          -  Female or male ≥ 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. SLN
             biopsy before neoadjuvant therapy is not allowed.

          -  ECOG performance status of 0 or 1

          -  Adequate organ and bone marrow function as defined below:

               -  Absolute neutrophil count (ANC) ≥ 1500/mm3

               -  Platelet count ≥ 100,000/mm3

               -  Hemoglobin ≥ 9 g/dl

               -  Total serum bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), (≤2.0 in
                  patients with documented Gilbert's Syndrome)

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 × institutional ULN

               -  Serum or plasma creatinine ≤ 1.5 × institutional ULN, OR calculated creatinine
                  clearance > 50 mL/min using the Cockcroft-Gault equation

               -  International normalized ratio (INR) OR prothrombin time (PT) ≤1.5× ULN.
                  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× ULN
                  unless patient is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants

          -  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.
                  See list of acceptable birth control methods. 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 (ie 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.

        Exclusion Criteria:

          -  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
                  nonmelanoma 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. intraarticular
             injections), inhaled, intranasal, ophthalmic, and topical corticosteroids, and
             subjects requiring corticosteroid pre-medication for hypersensitivity reactions (e.g.

        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 HIV infection are eligible provided they meet the following
             criteria:

               -  CD4+ T-cell (CD4+) counts ≥ 350 cells/uL

               -  No history of AIDS-defining opportunistic infection within 12 months prior to
                  enrollment

               -  Any medication used in an 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 described in 3.1.10 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 or acute myeloid leukemia (AML).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor-infiltrating lymphocytes (TILs)
Time Frame:baseline to 21 days
Safety Issue:
Description:The primary evaluation of change in TILs within each arm will be based on a Wilcoxon signed rank test (absolute difference) using a one-sided alpha = 0.05 for each arm

Secondary Outcome Measures

Measure:pCR rate (ER+/HER2- BC patients)
Time Frame:18 weeks
Safety Issue:
Description:the analysis of pCR will be exploratory and estimation-only, and reported with a two-sided exact 90% confidence interval
Measure:Changes in TILs
Time Frame:baseline up to 3 weeks
Safety Issue:
Description:Within each arm, the association between changes in TILs and pCR will be evaluated using a two-sample Wilcoxon rank sum test, and the log odds ratio for a fixed change in TILs will be estimated using a simple logistic regression model.
Measure:Rate of RCB 0/1 response
Time Frame:18 Weeks
Safety Issue:
Description:Rate of 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. The rate of RCB 0/1 response with preoperative combined niraparib and PD-1 blockade in patients with early stage TNBC (Arm A and B) and ER-positive HER2-negative breast cancer (Arm C) with BRCA-mutations will be estimated and the associated two-sided 90% exact confidence interval will be reported.
Measure:Number of Participants With Treatment-Related NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:baseline up to 5 years
Safety Issue:
Description:NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Invasive Breast Cancer Stage I
  • Invasive Breast Cancer Stage II
  • Invasive Breast Cancer Stage III
  • Breast Cancer
  • HER2-negative invasive tumor

Last Updated

October 8, 2020