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Talazoparib Maintenance Therapy in Triple-negative Breast Cancer

Primary Purpose

TNBC - Triple-Negative Breast Cancer

Status
Not yet recruiting
Phase
Phase 2
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Talazoparib
Placebo
Sponsored by
Yonsei University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for TNBC - Triple-Negative Breast Cancer focused on measuring BRCA +, Breast cancer

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Histologically or cytologically confirmed TNBC patients receiving first- or second-line chemotherapy for recurrent, metastatic, or unresectable disease. The triple-negative breast cancer is defined as ER negative, PR negative, and HER2 negative receptor status

    • ER and PR negative defined as IHC nuclear staining < 1% AND
    • HER2 negative defined as:

      1. IHC 0, 1+ without ISH OR
      2. IHC 2+ and ISH non-amplified (average HER2 gene copy number < 4 signals/cell using single-probe ISH or HER2/CEP17 ratio < 2.0 and average HER2 gene copy number < 4 signals/cell in dual-probe ISH) OR
      3. ISH non-amplified without IHC
  2. Female patients with ≥19 years of age
  3. Patients on first- or second-line platinum-based (cisplatin or carboplatin) chemotherapy regimen for recurrent, metastatic, or unresectable TNBC showing platinum-sensitivity during chemotherapy

    • The platinum-based chemotherapy can be either monotherapy or combination doublet chemotherapy of carboplatin or cisplatin with following combination partners: Paclitaxel, Docetaxel, Gemcitabine, Eribulin, Vinorelbine, Capecitabine, and Nab-paclitaxel.
    • For the patient who recurred within 12 months after the last dose of (neo)adjuvant chemotherapy for operable stage breast cancer, the (neo)adjuvant chemotherapy will be considered as one line of chemotherapy.
    • The combined targeted therapy agents including bevacizumab will be allowed but should be discontinued before randomization.

    The platinum sensitivity is determined as follows,

    • Remaining stable disease after 6 tri-weekly doses or 18 weekly doses of platinum-based therapy (stable disease after 6 cycles)
    • Remaining complete or partial response status after 4-6 tri-weekly doses or 12-18 weekly doses of platinum-based chemotherapy (partial or complete response after 4-6 cycles)
  4. Patients who can receive germline BRCA1/2 mutation test or patients with previously known germline BRCA1/2 mutation status.
  5. Provision of informed consent prior to any study specific procedures
  6. Measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT as defined by RECIST 1.1
  7. Patients who have received platinum as potentially curative treatment for a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for breast cancer are eligible with at least 12 months elapsed between the last dose of curative platinum-based treatment and initiation of the platinum-based chemotherapy for recurrent, metastatic, or unresectable breast cancer.
  8. ECOG performance status 0 or 1
  9. Adequate organ function within 14 days before enrollment for treatment A. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 B. Platelets ≥ 100,000 cells/mm3 C. Hemoglobin ≥ 9.0g/dL with no blood transfusions (packed red blood cells) in the past 7 days D. Bilirubin ≤ 2.0 x ULN E. AST (SGOT) ≤ 3 x ULN (5.0 x ULN if hepatic metastases) F. ALT (SGPT) ≤ 3 x ULN (5.0 x ULN if hepatic metastases) G. Creatinine clearance ≥ 30mL/min as calculated using the Cockcroft-Gault equation or serum creatinine ≤ 1.5 ULN
  10. 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention
  11. QTc interval ≤470 msec and without history of Torsades de pointes
  12. Not pregnant or nursing, fertile patients must use effective contraception 2 weeks before, during, and for 7 months after completion of study treatment

    • A fertile female patient whose result of the urine test or serum pregnancy test was negative within 72 hours of the first dose. If the test results are positive or not-confirmatory negative, a serum pregnancy test should be performed.
    • The fertile women are required to use proper contraception (inscribed in 11.13 section) during clinical trials and up to seven months after final administration, or agree to be surgically infertile or to stop having heterosexual sex.

    The definition of infertile women is as follows, and the woman who do not fall under this category are judged to be fertile women.

    • Women who have undergone infertility surgery (bilateral tubal resection, bilateral oophorectomy, or uterine resection)
    • Women aged 55 or older who have no natural menstruation for more than 12 months before random assignment
    • Women under the age of 55 with no natural menstruation and a menopause follicle hormone (FSH) concentration of 30 IU/L (or meet the standards of post-menopausal in the local lab) for a period of more than 12 months before randomization
  13. No other concurrent severe and/or uncontrolled medical disease which could compromise study participation
  14. Adequate treatment washout period before enrollment are below Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy ≥ 4 weeks (if palliative stereotactic radiation therapy ≥ 2 weeks)
  15. For patients with Germline BRCA1/2 mutations, the patients whose use of PARP inhibitors outside this clinical trial after the treatment of the platinum chemotherapy is inappropriate, impossible, or difficult to implement due to the patient's rejection, judged by the investigator or the patient for various reasons (including economic reasons)

Exclusion Criteria:

  1. Progression of tumor between start of platinum-based chemotherapy for recurrent, metastatic, or unresectable TNBC and randomization.
  2. Severe Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within the past year)
  3. Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic gallstones, liver metastasis or stable chronic liver disease per investigator assessment).
  4. Any previous treatment with a PARP inhibitor, including talazoparib
  5. Clinically significant uncontrolled medical conditions are not permitted that would limit ability to comply with study procedures, and any other medical condition that places the patient at unacceptable risk of toxicity.
  6. Presence of symptomatic CNS metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery). Patients with treated brain metastases should be neurologically stable (for 4 weeks post treatment and prior to study enrollment) and without steroid therapy over physiologic dose (> 10mg prednisolone/day) for at least 2 weeks before administration of study drug.
  7. Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
  8. Known active hepatitis B or C infection
  9. Significantly altered mental status prohibiting the understanding of the study, or with psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
  10. Multiple primary malignancies within 5 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral breast cancer.
  11. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
  12. Patients who are pregnant or nursing, or plan to be pregnant during the scheduled clinical trial period from the screening visit to 7 months after the last administration of the medication.
  13. Previous allogeneic bone marrow transplant.
  14. Patients with a known hypersensitivity to talazoparib or any of the excipients of the product.
  15. Patients who received live-attenuated vaccination with 30 days before the first administration of study drug
  16. Unresolved systemic active infection
  17. Patients with history of HIV infection

Sites / Locations

  • Yonsei University College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Maintenance therapy with talazoparib

Maintenance therapy with placebo

Arm Description

Maintenance therapy with talazoparib (1mg once daily) (once daily 1.0 mg oral administration), 103patients

Maintenance therapy with placebo (once daily 1.0 mg oral administration), 103patients

Outcomes

Primary Outcome Measures

Progression-free survival
Progression-free survival (PFS) after randomization by RECIST 1.1 PFS is defined as time interval from cycle 1 day 1 to tumor progression/death/last follow-up.

Secondary Outcome Measures

Overall survival (OS)
OS is defined as time interval from cycle 1 day 1 to tumor death/last follow-up.
progression-free survival 2
PFS2 is defined as time interval from cycle 1 day 1 to second tumor progression or death.
Objective response rate
ORR is defined as rate of patients with complete remission (CR) or partial remission (PR) based on RESIST1.1.
Adverse events by CTCAE 5.0 criteria
Safety is based on CTCAE 5.0.
Quality of life (QoL)
Quality of life (QoL) measured by EORTC-QLQ-C30
Progression-free survival(PFS) analysis
Progression-free survival(PFS) analysis using visceral metastasis status as covariate
Quality of life (QoL)
Quality of life (QoL) measured by EuroQoL EQ-5D

Full Information

First Posted
February 9, 2021
Last Updated
February 14, 2021
Sponsor
Yonsei University
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1. Study Identification

Unique Protocol Identification Number
NCT04755868
Brief Title
Talazoparib Maintenance Therapy in Triple-negative Breast Cancer
Official Title
A Randomized Phase II Clinical Trial of Talazoparib Maintenance Therapy in Triple-negative Breast Cancer Patients Who Showed Platinum-sensitivity on First- or Second-line Platinum-based Chemotherapy
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
March 2021 (Anticipated)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yonsei University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators propose a randomized phase II clinical trial of talazoparib maintenance therapy in TNBC patients whose tumor showed clinical benefit (platinum-sensitivity) to first- or second-line platinum-based chemotherapy (monotherapy or combination with other agents). Patients are eligible when they meet at least one of two following platinum-sensitivity criteria: They should have received 6 tri-weekly doses or 18 weekly doses of platinum-based therapy in non-progression status (at least stable disease) at the time of enrollment; They should remain in complete or partial response status after 4-6 tri-weekly doses or 12-18 weekly doses of platinum-based chemotherapy. Eligible patients are enrolled to the trial within 4 to 8 weeks after last chemotherapy and 1:1 randomized to receive talazoparib versus placebo maintenance therapy. The primary endpoint is PFS by RECIST 1.1 after randomization. The secondary endpoints include OS, time from randomization to second progression or death (PFS2), and objective response rate (ORR) by RECIST 1.1, adverse events by CTCAE 5.0 criteria, quality of life evaluated by EORTC-QLQ-C30, and EuroQoL EQ-5D.
Detailed Description
Randomized double-blind placebo controlled phase II trial This is a double-blind, placebo-controlled randomized phase II study, and the TNBC patients showing platinum-sensitivity after first- or second-line platinum-based chemotherapy will be screened. The total doses of platinum-based chemotherapy will be 4 or 6 doses for tri-weekly regimens and 12 or 18 doses for weekly regimen before randomization . The platinum sensitivity is determined as follows, Remaining stable disease after 6 tri-weekly doses or 18 weekly doses of platinum-based therapy (stable disease after 6 cycles) Remaining complete or partial response status after 4-6 tri-weekly doses or 12-18 weekly doses of platinum-based chemotherapy (partial or complete response after 4-6 cycles) The platinum sensitivity of the patients will be determined before enrollment to the clinical trial by review of central investigation institution (Yonsei Cancer Center) based on the the image reading results and, if necessary, the raw imaging data to determine that there is no tumor progression, tumor size increase, or new lesions. The platinum-based chemotherapy can be either monotherapy or combination doublet chemotherapy of carboplatin or cisplatin with following combination partners: Paclitaxel, Docetaxel, Gemcitabine, Eribulin, Vinorelbine, Capecitabine, and Nab-paclitaxel. The combined targeted therapy agents including bevacizumab will be allowed but should be discontinued before randomization. The patient with any BRCA1/2 mutation status is eligible. Germline BRCA1/2 test will be performed with reimbursement from South Korean health insurance in the study subject, if the subjects are under the age of 60 or have family history of BRCA-related cancers before enrollment. The testing results will be verified by the investigator. If the germline BRCA1/2 test is not covered by national health insurance (patients over 60 years of age and no family history), the BRCA1/2 germline testing will be performed with study support. The germline BRCA mutation status will be determined before randomization if the patient do not have BRCA mutation results before. The eligible patients will be assigned to each treatment arm after 1:1 randomization. The patients will be stratified on randomization with following factors. 1st line platinum-based chemotherapy versus 2nd line platinum-based chemotherapy* Response (CR/PR vs. stable disease) to the prior platinum-based chemotherapy BRCA status: wild-type (including benign variants and variants of unknown significance) versus BRCA1/2-mutated (pathogenic mutation) For the patient who recurred within 12 months after the last dose of (neo)adjuvant chemotherapy for operable stage breast cancer, the (neo)adjuvant chemotherapy will be considered as one line of chemotherapy. The Arm A (Experimental arm) Maintenance therapy with talazoparib (1mg once daily) (once daily 1.0 mg oral administration), 103patients The Arm B (Control arm) Maintenance therapy with placebo (once daily 1.0 mg oral administration), 103patients The maintenance talazoparib will be initiated 4 to 8 weeks after the last dose of platinum-based chemotherapy. The talazoparib treatment will continue until disease progression by RECIST 1.1, unacceptable toxicity, or death. Computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis will be performed at baseline, and every 8 weeks until disease progression after then.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
TNBC - Triple-Negative Breast Cancer
Keywords
BRCA +, Breast cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
206 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Maintenance therapy with talazoparib
Arm Type
Experimental
Arm Description
Maintenance therapy with talazoparib (1mg once daily) (once daily 1.0 mg oral administration), 103patients
Arm Title
Maintenance therapy with placebo
Arm Type
Active Comparator
Arm Description
Maintenance therapy with placebo (once daily 1.0 mg oral administration), 103patients
Intervention Type
Drug
Intervention Name(s)
Talazoparib
Intervention Description
The Arm A (Experimental arm) Maintenance therapy with talazoparib (1mg once daily) (once daily 1.0 mg oral administration), 103patients
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The Arm B (Control arm) Maintenance therapy with placebo (once daily 1.0 mg oral administration), 103patients
Primary Outcome Measure Information:
Title
Progression-free survival
Description
Progression-free survival (PFS) after randomization by RECIST 1.1 PFS is defined as time interval from cycle 1 day 1 to tumor progression/death/last follow-up.
Time Frame
2 months
Secondary Outcome Measure Information:
Title
Overall survival (OS)
Description
OS is defined as time interval from cycle 1 day 1 to tumor death/last follow-up.
Time Frame
2 months
Title
progression-free survival 2
Description
PFS2 is defined as time interval from cycle 1 day 1 to second tumor progression or death.
Time Frame
2 months
Title
Objective response rate
Description
ORR is defined as rate of patients with complete remission (CR) or partial remission (PR) based on RESIST1.1.
Time Frame
2 months
Title
Adverse events by CTCAE 5.0 criteria
Description
Safety is based on CTCAE 5.0.
Time Frame
2 months
Title
Quality of life (QoL)
Description
Quality of life (QoL) measured by EORTC-QLQ-C30
Time Frame
2 months
Title
Progression-free survival(PFS) analysis
Description
Progression-free survival(PFS) analysis using visceral metastasis status as covariate
Time Frame
2 months
Title
Quality of life (QoL)
Description
Quality of life (QoL) measured by EuroQoL EQ-5D
Time Frame
2 months

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Female patients with ≥19 years of age
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically or cytologically confirmed TNBC patients receiving first- or second-line chemotherapy for recurrent, metastatic, or unresectable disease. The triple-negative breast cancer is defined as ER negative, PR negative, and HER2 negative receptor status ER and PR negative defined as IHC nuclear staining < 1% AND HER2 negative defined as: IHC 0, 1+ without ISH OR IHC 2+ and ISH non-amplified (average HER2 gene copy number < 4 signals/cell using single-probe ISH or HER2/CEP17 ratio < 2.0 and average HER2 gene copy number < 4 signals/cell in dual-probe ISH) OR ISH non-amplified without IHC Female patients with ≥19 years of age Patients on first- or second-line platinum-based (cisplatin or carboplatin) chemotherapy regimen for recurrent, metastatic, or unresectable TNBC showing platinum-sensitivity during chemotherapy The platinum-based chemotherapy can be either monotherapy or combination doublet chemotherapy of carboplatin or cisplatin with following combination partners: Paclitaxel, Docetaxel, Gemcitabine, Eribulin, Vinorelbine, Capecitabine, and Nab-paclitaxel. For the patient who recurred within 12 months after the last dose of (neo)adjuvant chemotherapy for operable stage breast cancer, the (neo)adjuvant chemotherapy will be considered as one line of chemotherapy. The combined targeted therapy agents including bevacizumab will be allowed but should be discontinued before randomization. The platinum sensitivity is determined as follows, Remaining stable disease after 6 tri-weekly doses or 18 weekly doses of platinum-based therapy (stable disease after 6 cycles) Remaining complete or partial response status after 4-6 tri-weekly doses or 12-18 weekly doses of platinum-based chemotherapy (partial or complete response after 4-6 cycles) Patients who can receive germline BRCA1/2 mutation test or patients with previously known germline BRCA1/2 mutation status. Provision of informed consent prior to any study specific procedures Measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT as defined by RECIST 1.1 Patients who have received platinum as potentially curative treatment for a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for breast cancer are eligible with at least 12 months elapsed between the last dose of curative platinum-based treatment and initiation of the platinum-based chemotherapy for recurrent, metastatic, or unresectable breast cancer. ECOG performance status 0 or 1 Adequate organ function within 14 days before enrollment for treatment A. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 B. Platelets ≥ 100,000 cells/mm3 C. Hemoglobin ≥ 9.0g/dL with no blood transfusions (packed red blood cells) in the past 7 days D. Bilirubin ≤ 2.0 x ULN E. AST (SGOT) ≤ 3 x ULN (5.0 x ULN if hepatic metastases) F. ALT (SGPT) ≤ 3 x ULN (5.0 x ULN if hepatic metastases) G. Creatinine clearance ≥ 30mL/min as calculated using the Cockcroft-Gault equation or serum creatinine ≤ 1.5 ULN 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention QTc interval ≤470 msec and without history of Torsades de pointes Not pregnant or nursing, fertile patients must use effective contraception 2 weeks before, during, and for 7 months after completion of study treatment A fertile female patient whose result of the urine test or serum pregnancy test was negative within 72 hours of the first dose. If the test results are positive or not-confirmatory negative, a serum pregnancy test should be performed. The fertile women are required to use proper contraception (inscribed in 11.13 section) during clinical trials and up to seven months after final administration, or agree to be surgically infertile or to stop having heterosexual sex. The definition of infertile women is as follows, and the woman who do not fall under this category are judged to be fertile women. Women who have undergone infertility surgery (bilateral tubal resection, bilateral oophorectomy, or uterine resection) Women aged 55 or older who have no natural menstruation for more than 12 months before random assignment Women under the age of 55 with no natural menstruation and a menopause follicle hormone (FSH) concentration of 30 IU/L (or meet the standards of post-menopausal in the local lab) for a period of more than 12 months before randomization No other concurrent severe and/or uncontrolled medical disease which could compromise study participation Adequate treatment washout period before enrollment are below Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy ≥ 4 weeks (if palliative stereotactic radiation therapy ≥ 2 weeks) For patients with Germline BRCA1/2 mutations, the patients whose use of PARP inhibitors outside this clinical trial after the treatment of the platinum chemotherapy is inappropriate, impossible, or difficult to implement due to the patient's rejection, judged by the investigator or the patient for various reasons (including economic reasons) Exclusion Criteria: Progression of tumor between start of platinum-based chemotherapy for recurrent, metastatic, or unresectable TNBC and randomization. Severe Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within the past year) Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic gallstones, liver metastasis or stable chronic liver disease per investigator assessment). Any previous treatment with a PARP inhibitor, including talazoparib Clinically significant uncontrolled medical conditions are not permitted that would limit ability to comply with study procedures, and any other medical condition that places the patient at unacceptable risk of toxicity. Presence of symptomatic CNS metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery). Patients with treated brain metastases should be neurologically stable (for 4 weeks post treatment and prior to study enrollment) and without steroid therapy over physiologic dose (> 10mg prednisolone/day) for at least 2 weeks before administration of study drug. Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. Known active hepatitis B or C infection Significantly altered mental status prohibiting the understanding of the study, or with psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Multiple primary malignancies within 5 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral breast cancer. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Patients who are pregnant or nursing, or plan to be pregnant during the scheduled clinical trial period from the screening visit to 7 months after the last administration of the medication. Previous allogeneic bone marrow transplant. Patients with a known hypersensitivity to talazoparib or any of the excipients of the product. Patients who received live-attenuated vaccination with 30 days before the first administration of study drug Unresolved systemic active infection Patients with history of HIV infection
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joohyuk sohn
Phone
+82-2-2228-8135
Email
oncosohn@yuhs.ac
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joohyuk sohn
Organizational Affiliation
Severance Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yonsei University College of Medicine
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joohyuk sohn
Phone
+82-2-2228-8135
Email
oncosohn@yuhs.ac

12. IPD Sharing Statement

Plan to Share IPD
No

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Talazoparib Maintenance Therapy in Triple-negative Breast Cancer

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