A Study to Evaluate TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 Negative Patients With PD-L1+ Metastatic Triple Negative Breast Cancer
Condition: Breast Cancer; Triple Negative Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Talazoparib; Atezolizumab; Radiation
Intervention description: Talazoparib 1 mg Orally Day 1 to Day 28; Atezolizumab 840 mg IV over 60 minutes Day 15 of Cycle 1 then Day 1 and Day 15 of subsequent Cycles; Radiation 8 Gy will be given in 3 fractions QOD beginning Day 12, 13 or 14 of Cycle 1 but 24-72 hours prior to 1st dose of Atezolizumab
Intervention MeSH terms: Atezolizumab; Talazoparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase II study designed to assess efficacy and safety of talazoparib, high dose
      radiation, and atezolizumab in patients with metastatic TNBC that is PD-L1 positive. A total
      of 23 gBRCA pathogenic variant negative patients will be enrolled. All patients will be
      treated with induction talazoparib of 1mg PO daily starting Day 1. Patients will then receive
      8 Gy x 3 fractions to 2-4 metastatic lesions beginning Day 12,13, or 14 and given QOD. 840 mg
      of atezolizumab will be given intravenously (IV) on Day 15 of the 1st cycle and then on Day 1
      and Day 15 of the remaining cycles. The sequence of administration is not specified on the
      days in which talazoparib and atezolizumab are given on the same day. Each cycle equals 28
      days. Treatment will continue until progression or severe toxicity.

      A safety lead in of up to 6 patients will be performed. Immune-related and non-immune related
      adverse events will be tracked up to 12 weeks post initiation of atezolizumab, as the
      majority of treatment-related toxicities from talazoparib, radiation, and atezolizumab occur
      within this time period.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent/assent and HIPPA for the
             trial.

          2. Ages 18-75 years old at time of consent. Female or male patients allowed.

          3. ECOG PS of 0-2, KPS >/= 60%.

          4. Biopsy proven metastatic triple negative breast cancer (estrogen receptor (</=10%),
             progesterone receptor (</=10%) and no overexpression of HER2 as evaluated by local
             institutions with at least 2 exracranial lesions of metastatic disease on imaging.

          5. PD-L1 positive tumor infiltrate as defined as >/= 1% on IHC using the SP142 Ventana
             Assay.

          6. Known gBRCA 1/2 status (gBRCA 1/2 negative [e.g. gBRCA wild-type, gBRCA variants of
             uncertain significance] are eligible).

          7. Patients must have at least 1 extracranial metastatic lesion (may be measurable or
             non-measurable disease by RECIST v 1.1) that is amenable to high dose radiotherapy and
             at least one additional extracranial lesion of measurable disease by Response
             Evaluation Criteria in Solid Tumors (RECIST v1.1) that will not receive radiotherapy
             on this study. Of note, lesions maybe in the same organ but must be 2 cm apart and
             breast lesions may be treated.

          8. Patients must have received at least one and no more than three previous lines of
             systemic treatment in the advanced setting with or without immune therapy. Patients
             with disease recurrence or progression following neoadjuvant or adjuvant cytotoxic
             chemotherapy are not eligible unless they have received at least one line of
             chemotherapy with or without immune therapy in the advanced setting. NOTE: Targeted
             small molecules (e.g. tyrosine kinase inhibitors), hormonal agents and monoclonal
             antibodies that inhibit angiogenesis (e.g. bevacizumab, afilbercept) are not counted
             in the number of lines of therapy. Cytotoxic chemotherapy with or without immune
             therapy for advanced disease prior to protocol treatment is not permitted within 2
             weeks of the protocol treatment. Patients may or may not have received radiotherapy or
             neoadjuvant or adjuvant chemotherapy in the treatment of their initial, non-metastatic
             breast cancer, but must be entered on study 2 weeks after their last dose of
             radiotherapy, last cycle of chemotherapy and biologic therapy (if applicable) for
             mTNBC and have sufficient resolution of side effects per physician assessment at time
             of talazoparib.

          9. Demonstrate adequate organ function as defined in the table below. All screening labs
             to be obtained within 14 days prior to registration.

               -  Absolute neutrophil count > 1500/mcL

               -  Platelets >/= 100,000 mm

               -  Anemia >/= 9.0 g/dL (NOTE: The use of transfusion or other intervention to
                  achieve Hgb >/= 9.0g/dl is acceptable)

               -  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine
                  clearance ≥ 60 mL/min using Cockcroft-Gault equation for patients with creatinine
                  levels > 1.5× institutional ULN

               -  Total bilirubin ≤ 1.5× ULN OR direct bilirubin ≤ 1× ULN

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN
                  unless liver metastases are present, in which case they must be ≤ 5×ULN

               -  International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless
                  patient is receiving anticoagulant therapy as long as PT or partial
                  thromboplastin time (PTT) is within therapeutic range of intended use of
                  anticoagulants

               -  Activated partial thromboplastin time (aPTT) ≤ 1.5× ULN unless patient is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants

         10. Patients must be eligible for radiotherapy, talazoparib, and atezolizumab.

         11. Females of childbearing potential must have a negative serum or urine pregnancy test
             within 14 days prior to Cycle 1 Day 1. If a urine test is done and it is positive or
             cannot be confirmed as negative, a serum pregnancy test will be required. NOTE:
             Females are considered of child bearing potential unless they are surgically sterile
             (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
             or they are naturally postmenopausal for at least 12 consecutive months.

         12. Women of childbearing potential and males must agree to use two effective methods of
             contraception or complete abstinence, from the time of signing the informed consent
             (females) or first day of study treatment (males), during the course of the study and
             for 7 months (females) and for 4 months (males) after the last dose of study drug.

         13. Patients must not have active wound healing issues from surgery and sufficient
             resolution of surgical side effects, per physician assessment, at time of
             radiotherapy.

         14. During participation on this study, no other investigation or commercial agents or
             therapy for cancer other than bisphosphonate, rank ligand inhibitors, atezolizumab,
             radiotherapy and talazoparib should be administered. NOTE: Patients may have received
             bisphosphonates or rank ligand inhibitors prior to and while on enrollment on study.

         15. Patients must have the psychological ability and general health that permits
             completion of the study requirements and required follow up.

        Exclusion Criteria

          1. gBRCA1/2 pathogenic variant positive

          2. Four or more lines of cytotoxic chemotherapy for mTNBC.

          3. Previous radiation to the metastases to be treated with radiation on this protocol.

          4. Previous PARPi treatment (e.g. talazoparib, niraparib, olazaparib).

          5. Progression of breast cancer within the first 3 months of prior immune therapy for
             non-metastatic or metastatic breast cancer.

          6. Untreated CNS disease (patients with stable CNS disease for at least 28 days and
             asymptomatic treated CNS metastases are permitted).

          7. History of leptomeningeal disease.

          8. History of autoimmune disease that has required systemic treatment (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.

          9. Use of systemic glucocorticoid or immunosuppressive medications at time of enrollment.

         10. Severe, active co-morbidity such as CHF or unstable angina within last 6 months,
             transmural MI within the last 6 months.

         11. Acute bacterial or fungal infection requiring IV antibiotics at time of registration.

         12. COPD or other respiratory illness requiring hospitalization at time of registration.

         13. HIV positive with CD4 count <200 cells/ microliter.

         14. Current hormone replacement therapy use.

         15. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy. Indolent cancers (such as low
             risk prostate or in-situ cancers) that are not being treated, are acceptable.

         16. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         17. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         18. Receipt of the last dose or treatment of anti-cancer chemotherapy, radiotherapy,
             surgery, endocrine therapy, targeted therapy, biologic therapy, or tumor embolization
             ≤ 2 weeks (4 weeks for any monoclonal Antibody (mAb), 6 weeks for nitrosoureas or
             mitomycin C) prior to first dose of study treatment, or has not recovered (i.e., to
             ≤Grade 1 or Baseline) from clinically significant adverse events (AEs) due to these
             previously administered agents.