PALbociclib Endocrine Therapy Followed by Talazo vs. Talazoz-Atezo Study

Study Overview
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Brief Summary
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This study is a prospective, two-arm, randomized phase II study of talazoparib versus talazoparib plus atezolizumab in ER+ premeonopausal women with metastatic breast cancer harboring HRD scar 1st line treatment: GnRH agonist + Aromatase Inhibitor(AI) + Palbociclib 28 days after the last treatment of 1st line treatment, randomization for 2nd line treatment is conducte to arm A(Talazoparib+Atezolizumab) and arm B(Talazoparib monotherapy)

Detailed Description
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st line treatment Palbociclib: A capsule will be administered once a day for 21 days and rest for 7 days (1cycle=28days) AI treatment: D1 28 days. Take once a day. Prescribed according to local prescribe guideline. GnRH agonist: At D1 for every cycle with 4 week (+3days) interval via subcutaneous injection. nd line treatment 28 days after the last treatment of 1st line treatment, randomization for 2nd line treatment is conducte to arm A(Talazoparib+Atezolizumab) and arm B(Talazoparib monotherapy) Talazoparib: Take orally once a day at the same time Atezolizumab: 1,200mg, at D1 of each cycle. Applicable for arm A only.

Official Title
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Randomized Phase II Study of Talazoparib Versus Talazoparib Plus Atezolizumab After Palbociclib Combination Endocrine Therapy for Patients With Premenopausal HR+/HER2- Metastatic Breast Cancer Harboring HRD Scar

Conditions
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Premenopausal HR+/HER2- Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Pabociclib, Endocrine, Talazoparib, Atezolizumab
* Drug: Pabociclib, Endocrine, Talazoparib,


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed metastatic breast cancer with or without measurable disease Patients who have stage IV breast cancer at diagnosis (de novo) or have progressed on distant metastatic sites after curative surgery Confirmed germline pathogenic BRCA1 and/or 2 mutation or 35 HRD-related gene alterations age > 19 years ECOG performance status 0 - 2 Patient has HER2-negative breast cancer with IHC and/or FISH (or SISH, CISH) Patient has ER positive and/or PgR positive breast cancer by local laboratory testing Patient is premenopausal Patient with treatment history as bellows A. In patients with de novo metastatic breast cancer B. In patients with recurrent metastatic breast cancer, recurrence during or after completion or discontinuation of adjuvant endocrine therapy C. One line of prior cytotoxic chemotherapy in metastatic breast cancer is permitted. No possibility of pregnancy and urine or serum beta-HCG negative Adequate bone marrow function (≥ANC 1,500/ul, ≥platelet 100,000/ul, ≥Hemoglobin 9.0 g/dl) Adequate renal function (≤ serum creatinine 1.5 mg/dl or CCr ≥ 650 ml/min) Adequate liver function (≤ serum bilirubin 2.0 mg/dl, ≤ AST/ALT x 3 upper normal limit) Patients who were already established on bisphosphonate therapy or denosumab may continue. Patient agreed to use effective contraception or not of childbearing potential. Written informed consent Patients agreed to offer tumor tissue and blood for biomarker analysis Exclusion Criteria: Postmenopausal women Serious uncontrolled intercurrent infections within 4 weeks prior to Cycle 1 Day 1 of 1st Treatment Serious intercurrent medical or psychiatric illness, including active cardiac disease Pregnancy or breast feeding within 5 months after the last dose of atezolizumab Second primary malignancy Patients has received previous endocrine treatments in the metastatic setting Patients has received previous aromatase inhibitor Patients has received previous treatment with CDK 4/6 inhibitors, PARP1 inhibitors, and immune check point inhibitors Symptomatic visceral metastases, which means lymphangitic lung metastasis and/or symptomatic hepatic metastases Known brain metastases, symptomatic or asymptomatic History of clinically significant liver disease, current alcohol abuse or known active infection History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis Prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computerised tomography (CT) scan Active tuberculosis Receipt of a live, attenuated vaccine within 4 weeks prior to Cycle 1 Day 1 of 1st Treatment or anticipation that a live, attenuated vaccine will be required during atezolizumab treatment or within 5 months after the last dose of atezolizumab Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug prior to Cycle 1 Day 1 of 1st Treatment Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1 of 1st Treatment, or anticipated requirement for systemic immunosuppressive medications during the trial

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab+Talazoparib<br>st line treatment Palbociclib 125mg po D1-21 AI : Prescribed as per local guideline GnRH agonist: Prescribed as per local guideline nd line treatment Talazoparib 1mg po Atezolizumab 1200mg IV (3week) | Drug: Pabociclib, Endocrine, Talazoparib, Atezolizumab<br>* Palbociclib 125mg AI GnRH agonist Talazoparib Atezolizumab<br>|
| Experimental: Talazoparib<br>st line treatment Palbociclib 125mg po D1-21 AI : Prescribed as per local guideline GnRH agonist: Prescribed as per local guideline nd line treatment - Talazoparib 1mg po | Drug: Pabociclib, Endocrine, Talazoparib,<br>* Palbociclib 125mg AI GnRH agonist Talazoparib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2nd Progression free survival (PFS) | To assess measures of clinical efficacy. It is a measure of the period of survival without disease progression by Kaplan-Meier method. | The time until the time of the first event(the progression of a recorded disease of breast cancer or death from all causes) in 2nd line treatment. Up to 72months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite PFS (1st PFS + 2nd PFS) | To assess measures of clinical efficacy. It is a measure of the period of survival without disease progression by Kaplan-Meier method. | The time from the day 1 of first therapy to the time of first event (documented disease progression of breast cancer or death due to any cause) in 1st and 2nd line therapy. Up to 72months | 
| Overall survival (OS) | To assess secondary measures of clinical efficacy. | Survival will be measured as the time from the randomization occurs after Progression of 1st line to the date of death. Up to 72months | 
| Toxicity assessment | Clinical and laboratory toxicity/symptomatology will be graded based on the NCIC CTG v5.0 | from the date of informed consent signature to 28 days after last drug administration | 
| Quality of Life (QoL) | The QoL will be evaluated using EQ5D | from the date of informed consent signature to 28 days after last drug administration |