A Study to Evaluate TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 Negative Patients With PD-L1+ Metastatic Triple Negative Breast Cancer (TARA)

NCT04690855

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Breast Cancer, Triple Negative Breast Cancer
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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 (<1%), progesterone receptor (<1%) and no overexpression of HER2, according to American Society of Clinical Oncology - 2020 College of American Pathologists Guideline Criteria updated,1,2 as evaluated by local institutions with at least 3 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 gBRCA1/2 status (gBRCA 1/2 negative [e.g. gBRCA wild-type, gBRCA variants of uncertain significance] are eligible).

7. 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 and breast lesions may be treated.

8. 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, 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. gBRCA1/2 pathogenic variant positive


2. Three 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.

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Advanced Information
Descriptive Information
Brief Title  ICMJE A Study to Evaluate TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 Negative Patients With PD-L1+ Metastatic Triple Negative Breast Cancer (TARA)
Official Title  ICMJE A Multi-institutional Phase II Study to Evaluate Efficacy and Safety of TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 Negative Patients With PD-L1+ Metastatic Triple Negative Breast Cancer (TARA)
Brief 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer
  • Triple Negative Breast Cancer
Intervention  ICMJE
  • Drug: Talazoparib
    Talazoparib 1 mg Orally Day 1 to Day 28
    Other Name: Talzenna
  • Drug: Atezolizumab
    Atezolizumab 840 mg IV over 60 minutes Day 15 of Cycle 1 then Day 1 and Day 15 of subsequent Cycles
    Other Name: Tecentriq
  • Radiation: Radiation
    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
Study Arms  ICMJE Experimental: Study Treatment Arm

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.

Interventions:
  • Drug: Talazoparib
  • Drug: Atezolizumab
  • Radiation: Radiation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: December 28, 2020)
23
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2023
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 (<1%), progesterone receptor (<1%) and no overexpression of HER2, according to American Society of Clinical Oncology - 2020 College of American Pathologists Guideline Criteria updated,1,2 as evaluated by local institutions with at least 3 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 gBRCA1/2 status (gBRCA 1/2 negative [e.g. gBRCA wild-type, gBRCA variants of uncertain significance] are eligible).
  7. 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 and breast lesions may be treated.
  8. 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, 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. Three 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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mylin Torres, MD404-778-5047[email protected]
Contact: Ahran Lee317-634-5842 ext 14[email protected]
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04690855
Other Study ID Numbers  ICMJE HCRN BRE19-433
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Mylin A. Torres, MD, Hoosier Cancer Research Network
Study Sponsor  ICMJE Mylin A. Torres, MD
Collaborators  ICMJE
  • Genentech, Inc.
  • Pfizer
  • Emory University
Investigators  ICMJE
Principal Investigator:Mylin Torres, MDWinship Cancer Institute, Emory University
PRS Account Hoosier Cancer Research Network
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP