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

Active:	No
Cancer Type:	Breast Cancer	NCT ID:	NCT04690855
Trial Phases:	Phase II	Protocol IDs:	HCRNBRE19-433 (primary) NCI-2020-05880 STUDY00001245 WINSHIP5099-20
Eligibility:	18 - 75 Years, Male and Female	Study Type:	Treatment
Study Sponsor:	Emory University Hospital/Winship Cancer Institute
NCI Full Details:	http://clinicaltrials.gov/show/NCT04690855

Summary

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.

Objectives

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 and 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.

Patients also undergo bone, computed tomography (CT), and positron emission tomography (PET) scan, or magnetic resonance imaging (MRI) at screening, then every odd-numbered cycle starting day 15 of cycle 3, and then every 4 months for up to 2 years, collection of blood samples on days 1, 8, and 15 of cycle 1, day 1 of cycle 2, and day 15 of cycle 3, and collection of archival or fresh tumor samples at screening.

After completion of study treatment, patients are followed up at 30 days, every 4 months up to 2 years after treatment discontinuation.

Treatment Sites in Georgia

Winship Cancer Institute of Emory University
1365 Clifton Road NE
Building C
Atlanta, GA 30322
404-778-5180
winshipcancer.emory.edu

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