Clinical Trials /

Radiation, Immunotherapy and PARP Inhibitor in Triple Negative Breast Cancer

NCT04837209

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Radiation, Immunotherapy and PARP Inhibitor in Triple Negative Breast Cancer
  • Official Title: A Phase II Study of NirAparib, Dostarlimab and Radiotherapy in Metastatic, PD-L1 Negative or Immunotherapy-Refractory Triple-Negative Breast Cancer (NADiR)

Clinical Trial IDs

  • ORG STUDY ID: 20-649
  • NCT ID: NCT04837209

Conditions

  • Breast Cancer
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
NiraparibZejulaNiraparib + Dostarlimab + Radiation therapy
DostarlimabTSR-042, WBP-285Niraparib + Dostarlimab + Radiation therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Niraparib + Dostarlimab + Radiation therapyExperimentalStudy 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.
  • Niraparib
  • Dostarlimab

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-amplified63. 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.

          -  At least one radiographically-confirmed metastases index lesion that will not undergo
             RT and is measurable based on RECIST v1.1.

          -  Prior therapy with targeted agents or other forms of immunotherapy is allowed

          -  Prior RT is permitted, provided the treating radiation oncologist deems that study RT
             treatment planning guidelines can be achieved.

          -  Available archived tumor tissue of a metastatic tumor collected up to 28 days prior to
             registration. If archival tissue is unavailable, participant willingness to provide
             tissue from a newly obtained core or excisional biopsy of a tumor lesion.
             Newly-obtained is defined as a specimen obtained up to 28 days prior to study
             registration.

          -  Adequate organ function (assessed within 8 days prior to initiation of protocol
             treatment, unless otherwise indicated) as follows:

               -  Hematology

                    -  Absolute Neutrophil Count (ANC) ≥1500/mm3

                    -  Platelet Count ≥100,000/mm3

                    -  Hemoglobin ≥9.0 g/dL

               -  Renal Function

                    -  Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) or

                    -  Measured or calculated a creatinine clearance ≥ 60 mL/min for participant
                       with (GFR can also be used in place of creatinine creatinine levels > 1.5 X
                       ULN or CrCl

               -  Hepatic Function

                    -  Total Bilirubin ≤ 1.5 mg/dL (Direct bilirubin ≤ ULN for participants with
                       total bilirubin levels > 1.5 ULN)

                    -  INR, PT, aPTT ≤ 1.5 x ULN (participants receiving anticoagulant therapy must
                       have PT or PTT within therapeutic range)

                    -  Albumin ≥ 2.5 mg/dL

                    -  Aspartate Aminotransferase (AST) ≤ 2.5 x ULNb

                    -  Alanine Aminotransferase (ALT) ≤ 2.5 x ULNb ULN = upper normal limit of
                       institution's normal range

                         1. Creatinine clearance should be calculated per institutional standard.

                         2. Participants with liver metastases may have AST and/or ALT ≤ 5 x ULN

          -  Female participant has a negative urine or serum pregnancy test within 7 days prior to
             study treatment if a woman has child-bearing potential and agrees to abstain from
             activities that could result in pregnancy from screening through 180 days after the
             last dose of study treatment or is of non-childbearing potential.

        Non-childbearing potential is defined as follows (by other than medical reasons):

          -  ≥45 years of age and has not had menses for >1 year

          -  Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and
             oophorectomy must have a follicle stimulating hormone value in the postmenopausal
             range upon screening evaluation

          -  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.

               -  Women of childbearing potential should be willing to use 2 methods of birth
                  control or be surgically sterile, or abstain from heterosexual activity for the
                  course of the study through 180 days after the last dose of study medication.
                  Participants of childbearing potential are those who have not been surgically
                  sterilized or have not been free from menses for > 1 year.

        Note: Abstinence is acceptable if this is the established and preferred contraception for
        the patient.

          -  Male participant agrees to use an adequate method of contraception starting with the
             first dose of study treatment through 90 days after the last dose of study treatment.
             Note: Abstinence is acceptable if this is the established and preferred contraception
             for the patient.

          -  Male subjects must not donate sperm starting with the first dose of study drug through
             90 days after the last dose of study drug.

          -  Participant must agree not to breastfeed during the study or for 30 days after the
             last dose of study treatment.

          -  Participant must agree to not donate blood during the study or for 90 days after the
             last dose of study treatment.

          -  Ability to swallow (whole) and retain oral medications.

          -  Ability to understand and the willingness to sign a written informed consent document.

        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.

          -  Patients who have undergone any major surgery within 3 weeks prior to study entry:
             patients must have recovered adequately from the toxicity and/or complications from
             the intervention prior to starting therapy.

          -  Active autoimmune disease that has required systemic treatment in 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.

          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to the first dose of trial
             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. CT scan
             pre-medication) are allowed.

          -  Known history of/active, non-infectious pneumonitis requiring treatment with steroids
             or has history of/active interstitial lung disease.

          -  Active infection requiring systemic therapy.

          -  History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the patient's participation
             for the full duration of the trial, or is not in the best interest of the patient to
             participate, in the opinion of the treating investigator.

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial.

          -  Participant has a serious, uncontrolled medical disorder, nonmalignant systemic
             disease, or active, uncontrolled infection. Examples include, but are not limited to,
             uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction,
             uncontrolled major seizure disorder, unstable spinal cord compression.

        Pregnant or breastfeeding or expecting to conceive or father children within the projected
        duration of the trial, starting with the pre-screening or screening visit through 180 days
        after the last dose of trial treatment.

          -  Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

          -  Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Known active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Known history of active TB (Bacillus Tuberculosis)

          -  Receipt of a live vaccine within 14 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.

          -  Participant must not have received a transfusion (platelets or red blood cells) ≤ 4
             weeks prior to initiating protocol therapy.

          -  Participant must not have received colony stimulating factors (eg, granulocyte
             colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
             recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.

          -  Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due
             to prior chemotherapy that persisted > 4 weeks and was related to the most recent
             treatment.

          -  Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy, with the
             exception of non-clinically significant lab abnormalities.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)-RECIST
Time Frame:Enrollment to end of treatment up to 5 years
Safety Issue:
Description: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 Outcome Measures

Measure:Overall response rate (ORR) by irRECIST criteria
Time Frame:Enrollment to end of treatment up to 5 years
Safety Issue:
Description:Assessed by irRECIST (Immune-related Response Evaluation Criteria in Solid Tumors)
Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0
Time Frame:Enrollment to end of treatment up to 5 years
Safety Issue:
Description:NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting
Measure:Overall survival (OS)
Time Frame:First day of study treatment to the date of death due to any cause, assessed up to 5 years
Safety Issue:
Description:The OS rate will be estimated by the Kaplan-Meier method with 95% confidence intervals based on the complementary log-log transformation
Measure:Progression-free survival (PFS)
Time Frame: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
Safety Issue:
Description:The PFS rate will be estimated by the Kaplan-Meier method with 95% confidence intervals based on the complementary log-log transformation
Measure:Change in Quality of Life
Time Frame:First day of study treatment to 10 weeks
Safety Issue:
Description:To evaluate the change from baseline to 10-weeks in quality of life as assessed by the PROMIS Global Health measure
Measure:Change in PRO-CTCAE
Time Frame:First day of study treatment to 10 weeks
Safety Issue:
Description:To assess the change from baseline to 10 weeks in patient reported symptoms, as assessed by PRO-CTCAE measure
Measure:Change in Social Activity Level
Time Frame:First day of study treatment to 10 weeks
Safety Issue:
Description:To assess the change from baseline to 10 weeks in social activity level, as assessed by PROMIS Ability to Participate in Social Roles and Activities measure
Measure:Trial Satisfaction
Time Frame:First day of study treatment to end of treatment, assessed up to 2 years
Safety Issue:
Description:To assess trial satisfaction at the end of study treatment, as assessed by Was It Worth It (WIWI) measure.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Breast Cancer
  • Triple Negative Breast Cancer

Last Updated

June 9, 2021