Premenopausal HR+/HER2- Metastatic Breast Cancer
Conditions
Brief summary
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
1. 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. (or ET + CDK4/6 inhibitors + GnRH agonist) 2. 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.
Interventions
DRUGPabociclib, Endocrine(or ET + CDK4/6 inhibitors), Talazoparib, Atezolizumab
* Palbociclib 125mg * AI * GnRH agonist (or ET + CDK4/6 inhibitors + GnRH agonist) * Talazoparib * Atezolizumab
DRUGPabociclib, Endocrine(or ET + CDK4/6 inhibitors), Talazoparib,
* Palbociclib 125mg * AI * GnRH agonist (or ET + CDK4/6 inhibitors + GnRH agonist) * Talazoparib
Sponsors
Samsung Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eligibility criteria prior to 1L treatment: 1. Histologically confirmed metastatic breast cancer with or without measurable disease 2. Patients who have stage IV breast cancer at diagnosis (de novo) or have progressed on distant metastatic sites after curative surgery: locally advanced disease not amenable to distant metastasis are eligible as well as disease with distant metastasis 3. Confirmed germline pathogenic BRCA1 and/or 2 mutation or 35 HRD-related gene alterations (see Appendix 16.5) 4. age \> 19 years 5. ECOG performance status 0 - 2 6. Patient has HER2 IHC0, IHC1+, or ICH2+/ISH-, as determined according to ASCO/CAP guidelines breast cancer 7. Patient has ER positive and/or PgR positive according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, defined as 1% of tumor cells stained positive based on the most recent tumor biopsy and assessed locally 8. Female patients should be premenopausal. Premenopausal status is defined as either: A. Patient had last menstrual period within the last 12 months B. If on tamoxifen within the past 3 months, with a plasma estradiol ≥10 pg/mL and FSH ≤40 IU/l or in the premenopausal range, according to local laboratory definition C. in case of chemotherapy induced amenorrhea, with a plasma estradiol ≥10 pg/mL) and/or FSH ≤40IU/l or in the premenopausal range according to local laboratory definition. 9. Patient with treatment history as bellows: A. In patients with de novo metastatic breast cancer(who had stage IV disease at first diagnosis of breast cancer), B. In patients with recurrent metastatic breast cancer, recurrence during or after completion or discontinuation of adjuvant endocrine therapy (regardless of the treatment free interval) are eligible. C. One line of prior cytotoxic chemotherapy(except platinum based chemotherapy) in metastatic breast cancer is permitted. 10. No possibility of pregnancy and/or urine or serum beta-HCG negative 11. Adequate bone marrow function (≥ ANC 1,500/ul, ≥ platelet 100,000/ul, ≥ Hemoglobin 9.0 g/dl) 12. Adequate renal function (≤ serum creatinine 1.5 mg/dl or CCr ≥ 60 ml/min) 13. Adequate liver function (≤ serum bilirubin 2.0 mg/dl, ≤ AST/ALT x 3 upper normal limit). If the subject has liver metastasis, AST/ALT x 5 upper normal limit is acceptable. 14. Patients who were already established on bisphosphonate therapy or denosumab may continue. 15. Patients agreed to use effective contraception or not of childbearing potential 16. Written informed consent 17. Patients agreed to offer tumor tissue and blood for biomarker analysis *
Exclusion criteria
prior to 1L treatment 1. Postmenopausal women except women who had BSO (Bilateral Salpingo Oophorectomy) 2. Serious uncontrolled intercurrent infections within 4 weeks prior to Cycle 1 Day 1 of 1st Treatment 3. Serious intercurrent medical or psychiatric illness, including active cardiac disease 4. Participants who are pregnant or breast feeding or intending to become pregnant during the study or within 5 months after the final dose of study treatments. 5. Second primary malignancy(except in situ carcinoma of the cervix or adequately treated nonmelanomatous carcinoma of the skin or favorable thyroid papillary carcinoma(follicular thyroid cancer, including PTC) or other malignancy treated at least 5 years previously with no evidence of recurrence) 6. Patients has received previous endocrine treatments in the metastatic setting (Except tamoxifen only ± GnRH agonist) 7. Patients has received previous aromatase inhibitor (less than 1 year after the last dose) 8. Patients has received previous treatment with CDK 4/6 inhibitors, OR PARP1 inhibitors, OR immune check point inhibitors (less than 1 year after the last dose) 9. Known brain metastases, symptomatic or asymptomatic 10. History of clinically significant liver disease, current alcohol abuse or known active infection 11. 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 12. Prior allogeneic stem cell or solid organ transplantation 13. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computerised tomography (CT) scan 14. Active tuberculosis 15. 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 16. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interlukin \[IL\]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to Cycle 1 Day 1 of 1st Treatment 17. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, mycophenolate, and anti-tumour necrosis factor \[TNF\] agents) within 2 weeks prior to Cycle 1 Day 1 of 1st Treatment, or anticipated requirement for systemic immunosuppressive medications during the trial * Inclusion criteria prior to 2L treatment * For subjects who were enrolled in the 1L treatment part of the study, inclusion criteria 1)-4) should be met. * For subjects who were not enrolled in the 1L treatment part of the study, all of the following inclusion criteria should be met prior to the study enrollment. 1. ECOG performance status 0 - 2 2. Adequate bone marrow function (≥ANC 1,500/ul, ≥platelet 100,000/ul, ≥Hemoglobin 9.0 g/dl) 3. Adequate renal function (≤ serum creatinine 1.5 mg/dl or CCr ≥ 60 ml/min) 4. Adequate liver function (≤ serum bilirubin 2.0 mg/dl, ≤ AST/ALT x 3 upper normal limit) If the subject has liver metastasis, AST/ALT x 5 upper normal limit is acceptable 5. Histologically confirmed metastatic or locally advanced breast cancer that is not amenable to curative surgery, 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 are eligible. 6. Prior treatment with endocrine-based therapy + CDK4/6 inhibitor for metastatic or inoperable locally advanced breast cancer. Allowed endocrine-based therapy is as below: A. Aromatase Inhibitor B. For subjects who had disease progression during or after the adjuvant aromatase inhibitor therapy, fulvestrant C. Up to one line of chemotherapy for metastatic or inoperable locally advanced breast cancer is allowed except for platinum based chemotherapy. 7. Confirmed germline pathogenic BRCA1 and/or BRCA2 mutation or 35 HRD-related gene alterations (see Appendix 16.5) 8. age \> 19 years 9. Patient has HER2 IHC0, IHC1+, or ICH2+/ISH-, as determined according to ASCO/CAP guidelines breast cancer 10. Patient has ER positive and/or PgR positive according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, defined as 1% of tumor cells stained positive based on the most recent tumor biopsy and assessed locally 11. Female patients should be premenopausal. Premenopausal status is defined as either: A. Patient had last menstrual period within the last 12 months B. If on tamoxifen within the past 3 months, with a plasma estradiol ≥10 pg/mL and FSH ≤40 IU/l or in the premenopausal range, according to local laboratory definition C. in case of chemotherapy induced amenorrhea, with a plasma estradiol ≥10 pg/mL) and/or FSH ≤40IU/l or in the premenopausal range according to local laboratory definition. D. If the subject started ovarian function suppression, above A-C criteria should be met prior to starting ovarian function suppression. 12. No possibility of pregnancy and/or urine or serum beta-HCG negative 13. Patients may continue an ongoing bisphosphonate or denosumab therapy. 14. Patients who agreed to use an effective contraception method or have no childbearing potential 15. Written informed consent 16. Patients who agreed to offer tumor tissue and blood for biomarker analysis *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2nd Progression free survival (PFS) | 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 | To assess measures of clinical efficacy. It is a measure of the period of survival without disease progression by Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite PFS (1st PFS + 2nd PFS) | 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 | To assess measures of clinical efficacy. It is a measure of the period of survival without disease progression by Kaplan-Meier method. |
| Overall survival (OS) | Survival will be measured as the time from the randomization occurs after Progression of 1st line to the date of death. Up to 72months | To assess secondary measures of clinical efficacy. |
| Toxicity assessment | from the date of informed consent signature to 28 days after last drug administration | Clinical and laboratory toxicity/symptomatology will be graded based on the NCIC CTG v5.0 |
| Quality of Life (QoL) | from the date of informed consent signature to 28 days after last drug administration | The QoL will be evaluated using EQ5D |
Countries
South Korea
Contacts
Primary ContactYeon Hee Park, phD
Backup Contactmieun Kim, CRA
Outcome results
None listed