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Talazoparib, Radiation Therapy, and Atezolizumab for the Treatment of gBRCA 1 / 2 Negative, PD-L1 Positive, Metastatic Triple-Negative Breast Cancer, TARA Study

Trial Status: Active

This phase II trial investigates how well the combination of talazoparib, radiation therapy, and atezolizumab work in treating patients with germline (g) BRCA 1 / 2 negative, PD-L1 positive, triple-negative breast cancer that has spread to other places in the body (metastatic). Genes are like an instruction manual for the body. Germline mutation is a gene change in a body's reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. BRCA 1 and 2 are genes that normally help to suppress cell growth. Breast cancers in women with a harmful BRCA1 mutation tend to be "triple-negative cancers" (that is, the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2 / neu protein), which generally have poorer prognosis than other breast cancers. Talazoparib is a targeted therapy. Talazoparib blocks an enzyme called PARP. PARP enzymes are involved in cellular growth regulation. Talazoparib causes cancer cells to die by damaging the genetic structure of tumor and then stopping the tumor cells from repairing the damage. PD-L1 is a protein that acts as a kind of “brake” to keep the body’s immune responses under control. Radiation therapy increases PD-L1 expression on cells making them more sensitive to atezolizumab. Atezolizumab is an immunotherapy drug that blocks the activity of PD-L1. By blocking PD-L1, a specific type of immune cells called T-cells function better and the immune system can better find and kill cancer cells. Talazoparib may enhance the effect of radiation therapy and atezolizumab in treating gBRCA 1 / 2 negative, PD-L1 positive, metastatic triple-negative breast cancer patients.

Inclusion Criteria

  • Be willing and able to provide written informed consent/assent and Health Insurance Portability and Accountability Act (HIPAA) for the trial
  • Eastern Cooperative Oncology Group ECOG performance status (PS) of 0-2, Karnofsky performance status (KPS) >= 60%
  • Biopsy proven metastatic triple negative breast cancer (estrogen receptor [< 1%], progesterone receptor [< 1%] and no overexpression of HER2, according to American Society of Clinical Oncology – 2020 College of American Pathologists Guideline Criteria updated, as evaluated by local institutions with at least 3 extracranial lesions of metastatic disease on imaging)
  • PD-L1 positive tumor infiltrate as defined as >= 1% on immunohistochemistry (IHC) using the SP142 Ventana Assay
  • Known gBRCA1/2 status (gBRCA 1/2 negative [e.g. gBRCA wild-type, gBRCA variants of uncertain significance] and gBRCA 1/2 pathogenic variant positive carriers are eligible)
  • Patients must have at least 2 extracranial metastatic lesions 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 be treated with radiotherapy on this study. Of note, lesions maybe in the same organ but must be 2 cm apart
  • Patients must have received at least one and no more than two 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, aflibercept) 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
  • Absolute neutrophil count >= 1500/mcL (obtained within 14 days prior to registration)
  • Platelets >= 100,000 mm (obtained within 14 days prior to registration)
  • Anemia >= 9.0 g/dL (obtained within 14 days prior to registration) (NOTE: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance >= 60 mL/min using Cockcroft-Gault equation for patients with creatinine levels >= 1.5 x institutional ULN (obtained within 14 days prior to registration)
  • Total bilirubin =< 1.5 x ULN OR direct bilirubin =< 1 x ULN (obtained within 14 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN unless liver metastases are present, in which case they must be =< 5 x ULN (obtained within 14 days prior to registration)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x 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 (obtained within 14 days prior to registration)
  • Activated partial thromboplastin time (aPTT) =< 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 (obtained within 14 days prior to registration)
  • Patients must be eligible for radiotherapy, talazoparib, and atezolizumab
  • Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to cycle 1 day 1. 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
  • Women of childbearing potential and males must agree to use two effective methods of contraception, 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 after the last dose of study drug
  • Patients must not have active wound healing issues from surgery and sufficient resolution of surgical side effects, per physician assessment, at time of radiotherapy
  • 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
  • Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up

Exclusion Criteria

  • Three or more lines of cytotoxic chemotherapy for mTNBC
  • Previous radiation to the metastases to be treated with radiation on this protocol
  • Previous PARP inhibitor (i) treatment (e.g. talazoparib, niraparib, olaparib)
  • Progression of breast cancer within the first 3 months of prior immune therapy for non-metastatic or metastatic breast cancer
  • Untreated central nervous system (CNS) disease (patients with stable CNS disease for at least 28 days and asymptomatic treated CNS metastases are permitted)
  • History of leptomeningeal disease
  • 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
  • Use of systemic glucocorticoid or immunosuppressive medications at time of enrollment
  • Severe, active co-morbidity such as congestive heart failure (CHF) or unstable angina within last 6 months, transmural myocardial infarction (MI) within the last 6 months
  • Acute bacterial or fungal infection requiring IV antibiotics at time of registration
  • Chronic obstructive pulmonary disease (COPD) or other respiratory illness requiring hospitalization at time of registration
  • Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/ microliter
  • Current hormone replacement therapy use
  • 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
  • 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
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • 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

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE
Contact: Mylin Ann Torres

PRIMARY OBJECTIVE:

I. Estimate objective response rate (ORR) of talazoparib, high dose radiotherapy and atezolizumab, eight weeks after the first dose of atezolizumab in non-irradiated lesions of gBRCA1/2 pathogenic variant negative metastatic triple negative breast cancer (mTNBC) patients whose tumors are immune cell (IC)-positive.

SECONDARY OBJECTIVES:

I. Determine the frequency and severity of adverse events using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 after induction talazoparib followed by concurrent talazoparib, high dose radiation, and atezolizumab given as second or third-line treatment for PD-L1 positive metastatic triple negative breast cancer (mTNBC) (>= 3 lesions).

II. Obtain progression free survival (PFS) data in gBRCA 1/2 negative mTNBC patients with PD-L1 positive infiltrate treated with talazoparib, radiation, and atezolizumab.

III. Obtain overall survival (OS) data in gBRCA 1/2 negative mTNBC patients with PD-L1 positive infiltrate treated with talazoparib, radiation, and atezolizumab.

IV. ORR by immune-related Response Evaluation Criteria in Solid Tumors (RECIST) (irRECIST).

V. Determine duration of overall response (DOR) to talazoparib, high dose radiation, and atezolizumab given in the second or third-line setting to gBRCA1/2 negative mTNBC patients with PD-L1 positive infiltrate.

VI. Determine disease control rate (DCR) in gBRCA1/2 negative patients with PD-L1 positive infiltrate treated with talazoparib, high dose radiation, and atezolizumab given in the second or third-line setting.

VII. Determine time to progression (TTP) in gBRCA1/2 negative mTNBC patients with PD-L1 positive infiltrate treated with talazoparib, high dose radiation, and atezolizumab given in the second or third-line setting.

VIII. Determine adherence to prescribed talazoparib, high dose radiation, and atezolizumab in the second or third-line setting among PD-L1 positive mTNBC patients.

IX. Determine best overall tumor response in each patient to talazoparib, high dose radiation, and atezolizumab in the second or third-line setting among PD-L1 positive mTNBC patients.

CORRELATIVE/EXPLORATORY OBJECTIVES:

I. Assess patient reported outcomes (PRO) measures of quality of life and fatigue before talazoparib, during and after radiation and atezolizumab in mTNBC patients with PD-L1 positive infiltrate treated with talazoparib, radiation, and atezolizumab.

II. Collect and store peripheral blood and plasma collected from gBRCA1/2 negative mTNBC patients with PD-L1 positive infiltrate before, during, and after treatment with talazoparib, radiation, and atezolizumab.

III. Collect and store formalin-fixed paraffin-embedded (FFPE) of tumor tissue from any metastatic lesion and fresh tumor tissue from one non-irradiated metastatic breast cancer site before and after radiotherapy in a subset of patients from gBRCA1/2 negative mTNBC patients (n~10 patients) for future analyses.

OUTLINE:

Patients receive talazoparib orally (PO) once daily (QD) on days 1-28 and atezolizumab intravenously (IV) over 30-60 minutes on day 15 of cycle 1 and days 1-15 of subsequent cycles. Beginning 12-14 days after initiation of talazoparib, patients undergo 3 fractions of radiation therapy every other day (QOD) in the absence of disease progression or unacceptable toxicity. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months until disease progression, and then every 4 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Emory University Hospital / Winship Cancer Institute

Principal Investigator
Mylin Ann Torres

  • Primary ID HCRNBRE19-433
  • Secondary IDs NCI-2020-05880, STUDY00001245, WINSHIP5099-20
  • Clinicaltrials.gov ID NCT04690855