A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)

A PHASE 2, 2-STAGE, 2-COHORT STUDY OF TALAZOPARIB (BMN 673) ADMINISTERED TO GERMLINE BRCA MUTATION SUBJECTS WITH LOCALLY ADVANCED AND/OR METASTATIC BREAST CANCER

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02034916

Acronym

ABRAZO

Enrollment

Registered

2014-01-14

Start date

2013-12-13

Completion date

2018-10-31

Last updated

2019-10-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

BRCA 1 Gene Mutation, BRCA 2 Gene Mutation, Breast Neoplasms

Keywords

Breast cancer, BRCA mutation, PARP inhibitor, BRCA 1, BRCA 2

Brief summary

The purpose of this 2-stage, 2-cohort Phase 2 trial is to evaluate the safety and efficacy of talazoparib (also known as BMN 673) in subjects with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease: * Cohort 1) Subjects with a documented PR or CR to a prior platinum-containing regimen for metastatic disease with disease progression \> 8 weeks following the last dose of platinum; or * Cohort 2) Subjects who have received \> 2 prior chemotherapy regimens for metastatic disease and who have had no prior platinum therapy for metastatic disease

Interventions

DRUGtalazoparib

Study design

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Histologically or cytologically confirmed carcinoma of the breast * Locally advanced and/or metastatic disease * Deleterious or pathogenic germline BRCA 1 or BRCA 2 mutation * Prior chemotherapy: Cohort 1) PR or CR to prior platinum-containing regimen for metastatic disease with disease progression \> 8 weeks following the last dose of platinum; or Cohort 2) \> 2 prior chemotherapy regimens for metastatic disease and no prior platinum for metastatic disease * ECOG performance status ≤ 1 * Have adequate organ function

Exclusion criteria

* Prior enrollment into a clinical trial of a PARP inhibitor * CNS metastasis except adequately treated brain metastasis documented by baseline CT or MRI scan that has not progressed since previous scans and that does not require corticosteroids for management of CNS symptoms * Prior malignancy except for prior BRCA-associated cancer as long as there is no current evidence of the prior cancer, carcinoma in situ of the cervix or non-melanoma skin cancer, and a cancer diagnosed and definitively treated \>5 years prior to study enrollment with no subsequent evidence of recurrence * Known to be HIV positive, active hepatitis C virus, or active hepatitis B virus * Known hypersensitivity to any of the components of talazoparib

Design outcomes

Primary

Measure	Time frame	Description
Objective Response Rate (ORR)	From randomization until data cutoff date (01 Sep 2016)	ORR: Percentage of participants with a confirmed best overall complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1). CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to less than (\<) 10 millimeter (mm) in short axis. PR: Greater than or equal to (\>=) 30 percent (%) decrease in sum of diameters of target lesions, compared to the sum at baseline. Response evaluation was done by an independent radiology facility (IRF).

Secondary

Measure	Time frame	Description
Clinical Benefit Rate-24 (CBR-24)	From randomization until data cutoff date (01 Sep 2016)	CBR24: Percentage of participants with a best response of CR, PR or stable disease (SD) sustained for at least 24 weeks, as assessed by IRF using RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to \<10 mm in short axis. PR: \>=30% decrease in sum of diameters of target lesions, compared to the sum at baseline. SD: Neither PR nor progression of disease (PD) criteria met. SD follow PR only when sum increases by less than 20% from the nadir, but previously seen 30% decrease from baseline no longer hold. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions.
Duration of Response (DOR)	From first documentation of CR or PR until PD, last tumor assessment without PD before new anticancer treatment initiation or death due to any cause, whichever occurred first (up to the data cutoff date [01 Sep 2016])	DOR: Time from first documentation of CR or PR, to PD by IRF assessment using RECIST 1.1, or to death due to any cause, whichever occurred first. CR: Disappearance of all non-nodal target and non-target lesions, with target and non-target lymph nodes reduction to \<10 mm in short axis. PR: \>=30% decrease in sum of diameters of target lesions, compared to the sum at baseline. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions. Participants with no PD or death at the analysis date were censored at last tumor assessment date prior to on or before initiation of a new anticancer therapy or before the data cutoff date.
Progression Free Survival (PFS)	From first dose of study drug until PD, last tumor assessment without PD before new anticancer treatment initiation or death due to any cause, whichever occurred first (up to the data cutoff date [01 Sep 2016])	PFS was defined as the time in months from the first dose of study drug to the first documentation of PD by investigator assessment using RECIST 1.1 or death on study due to any cause on or before the data cutoff date, whichever occurred first. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions. Participants with no PFS event at the analysis were censored at last tumor assessment date prior to data cutoff or date of new anticancer treatment initiation, whichever occurred first.
Overall Survival (OS)	From first dose of study drug until death due to any cause (up to the data cutoff date [01 Sep 2016])	OS was defined as the time from first dose of study drug to death due to any cause. For participants without a death date at the time of data cutoff or permanently lost to follow-up, OS was right-censored at the date the participant was last known to be alive on or before the data cutoff date.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; an important medical event or reaction, including events requiring medical intervention to prevent worsening to any of the previously noted seriousness criteria. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious AEs.
Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	A treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A treatment-related SAE was a treatment-related AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; an important medical event or reaction, including events requiring medical intervention to prevent worsening to any of the previously noted seriousness criteria. Related TEAEs are TEAEs that were judged by the investigators as possibly, probably, or definitely related to study drug. AEs included both SAES and non SAES.
Number of Participants With Outcome in Response to Adverse Events (AEs)	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Outcome of an AE was response to a question answered by the investigator: 'Is the AE leading to study discontinuation or death?' as 'yes'.
Number of Participants With At Least 1 Concomitant Medication	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	Number of participants taking any non-study medications, therapies, including herbal supplements during the treatment-emergent period for the management of an adverse event or for the treatment of any other disease.
Trough Concentration Versus Time Summary of Talazoparib	Predose on Day 1 of Cycle 1, 2, 3, and 4 (data cutoff date: 01 Sep 2016)	Concentrations below the limit of quantitation values less than or equal to (\<=) 25 picogram per milliliter (pg/mL) were set as zero. Pharmacokinetic (PK) analysis was not done separately for each reporting arm and cohorts were combined for PK analysis.
Number of Participants With Toxicity Grades Increase of 2 or More in Laboratory Parameter (Hematology Parameter)	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	Laboratory tests included hematology (hemoglobin \[low\], leucocytes \[low\], lymphocytes \[low\], neutrophils \[low\], platelets \[low\]). Toxicity grades were evaluated based on national cancer institute- common terminology criteria for adverse events (NCI-CTCAE) version 4.03. Number of participants with increase of 2 or more CTCAE toxicity grades above baseline, for hematology laboratory parameter is reported in this outcome measure.
Number of Participants With Toxicity Grades Increase of 2 or More in Laboratory Parameter (Chemistry Parameter)	Baseline up to 30 days after the last dose of study drug or before initiation of a new anticancer treatment, whichever occurred first (up to data cutoff date [01 Sep 2016])	Laboratory tests included serum chemistry (alanine aminotransferase \[high\], albumin \[low\], alkaline phosphatase \[high\], aspartate aminotransferase \[high\], bilirubin \[high\], calcium \[low\], glucose \[high\], magnesium \[low\], phosphate \[low\], potassium \[high\], potassium \[low\], sodium \[high\], sodium \[low\]). Toxicity grades were evaluated based on national cancer institute- common terminology criteria for adverse events (NCI-CTCAE) version 4.03. Number of participants with increase of 2 or more CTCAE toxicity grades above baseline, for chemistry laboratory parameter is reported in this outcome measure.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	Criteria for clinically significant vital signs changes: 1) Blood pressure: systolic blood pressure (SBP): greater than or equal to (\>=30) millimeters of mercury (mmHg) increase from baseline, diastolic blood pressure (DBP): \>=20 mmHg decrease from baseline; 2) Heart rate (HR): absolute HR greater than (\>) 120 beats per minute (bpm) and \>30 bpm increase from baseline, absolute HR less than (\<) 50 bpm and \>20 bpm decrease from baseline; 3) Weight: \>10% decrease from baseline. Number of participants with any clinically significant change from baseline for blood pressure, heart rate and weight are reported in this outcome measure.
Number of Participants With Clinically Significant Change From Baseline in Physical Findings	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)	Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.

Other

Measure	Time frame	Description
Time to Deterioration in Global Health Status/Quality of Life (QOL) and Functional Status as Assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)	Baseline up to death, disease progression or end of treatment (30 days after last dose of study drug or before initiation of a new anticancer therapy, whichever occurred first [up to data cutoff date: 01 Sep 2016])	Time to deterioration was defined as the time from baseline to day to death, first occurrence of progression, or a \>=10 point change from baseline in any of the functional status score and global health status/QOL score based on the EORTC-QLQ-C30, whichever occurred first. EORTC-QLQ-C30 questionnaire is a standardized instrument developed to assess the quality of life of people with cancer. EORTC-QLQ-C30 functional subscale includes 5 items: physical, role, emotional, cognitive, and social functioning. All of the single items of functional status subscale measures and global health status/QOL subscale range from 0 to 100, where higher scores represent a better level of functioning/quality of life.
Time to Deterioration in Disease Specific Symptoms as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC-QLQ-BR23)	Baseline up to death, disease progression or end of treatment (30 days after last dose of study drug or before initiation of a new anticancer therapy, whichever occurred first [up to data cutoff date: 01 Sep 2016])	Time to deterioration was defined as the time from baseline to day to death, first occurrence of progression, or a \>=10 point change from baseline in any of the symptom score based on the EORTC-QLQ-BR23, whichever occurred first. EORTC-QLQ-BR23 is a disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess the quality of life of participants with breast cancer. EORTC-QLQ-BR23 symptoms subscale includes 4 items: systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss. Each item is rated by choosing 1 of 4 possible responses that record the level of intensity (1= not at all, 2= a little, 3= quite a bit, and 4= very much) within each scale.

Countries

France, Germany, Spain, United Kingdom, United States

Participant flow

Pre-assignment details

In this study, enrollment of participants was to be done in 2 stages for each of the 2 cohorts. Sufficient responses in each cohort were observed such that enrollment could proceed to Stage 2 for both cohorts. However, due to Sponsor decision, enrollment in the overall trial was terminated early.

Participants by arm

Arm	Count
Cohort 1: Talazoparib 1 mg Participants who responded to a prior platinum-containing treatment for metastatic breast cancer, with disease progression of at least 8 weeks following the last dose of platinum, received talazoparib 1.0 mg orally, once daily for 21 days in repeated 21-day cycles until disease progression, occurrence of unacceptable toxicity or permanent treatment discontinuation. Participants were followed-up for survival and new anticancer treatment at every 60 days after the last dose of study drug for the first year, every 90 days thereafter.	49
Cohort 2: Talazoparib 1 mg Participants with more than 2 prior non-platinum chemotherapy treatment for metastatic breast cancer, received talazoparib 1.0 mg orally, once daily for 21 days in repeated 21-day cycles until disease progression, occurrence of unacceptable toxicity or permanent treatment discontinuation. Prior adjuvant or neo-adjuvant therapy with a platinum was allowed if first disease recurrence was for more than 6 months since last dose of adjuvant/neo-adjuvant platinum treatment. Participants were followed-up for survival and new anticancer treatment at every 60 days after the last dose of study drug for the first year, every 90 days thereafter.	35
Total	84

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	39	28
Overall Study	Lost to Follow-up	4	1
Overall Study	Study terminated by sponsor	4	5
Overall Study	Withdrawal by Subject	2	1

Baseline characteristics

Characteristic	Cohort 1: Talazoparib 1 mg	Cohort 2: Talazoparib 1 mg	Total
Age, Continuous	50.1 years STANDARD_DEVIATION 11.48	53.4 years STANDARD_DEVIATION 11.05	51.5 years STANDARD_DEVIATION 11.35
Sex: Female, Male Female	48 Participants	34 Participants	82 Participants
Sex: Female, Male Male	1 Participants	1 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	47 / 48	34 / 35
serious Total, serious adverse events	16 / 48	7 / 35

Outcome results

Primary

Objective Response Rate (ORR)

ORR: Percentage of participants with a confirmed best overall complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1). CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to less than (\<) 10 millimeter (mm) in short axis. PR: Greater than or equal to (\>=) 30 percent (%) decrease in sum of diameters of target lesions, compared to the sum at baseline. Response evaluation was done by an independent radiology facility (IRF).

Time frame: From randomization until data cutoff date (01 Sep 2016)

Population: Tumor-evaluable population (TEP) included all treated participants who had a baseline and at least 1 post-baseline tumor assessment or who discontinued the study before first scheduled post-baseline tumor scan plus (+) 1 week window.

Arm	Measure	Value (NUMBER)
Cohort 1: Talazoparib 1 mg	Objective Response Rate (ORR)	20.8 percentage of participants
Cohort 2: Talazoparib 1 mg	Objective Response Rate (ORR)	37.1 percentage of participants

Secondary

Clinical Benefit Rate-24 (CBR-24)

CBR24: Percentage of participants with a best response of CR, PR or stable disease (SD) sustained for at least 24 weeks, as assessed by IRF using RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to \<10 mm in short axis. PR: \>=30% decrease in sum of diameters of target lesions, compared to the sum at baseline. SD: Neither PR nor progression of disease (PD) criteria met. SD follow PR only when sum increases by less than 20% from the nadir, but previously seen 30% decrease from baseline no longer hold. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions.

Time frame: From randomization until data cutoff date (01 Sep 2016)

Arm	Measure	Value (NUMBER)
Cohort 1: Talazoparib 1 mg	Clinical Benefit Rate-24 (CBR-24)	27.1 percentage of participants
Cohort 2: Talazoparib 1 mg	Clinical Benefit Rate-24 (CBR-24)	45.7 percentage of participants

Secondary

Duration of Response (DOR)

DOR: Time from first documentation of CR or PR, to PD by IRF assessment using RECIST 1.1, or to death due to any cause, whichever occurred first. CR: Disappearance of all non-nodal target and non-target lesions, with target and non-target lymph nodes reduction to \<10 mm in short axis. PR: \>=30% decrease in sum of diameters of target lesions, compared to the sum at baseline. PD: \>=20% increase (\>=5 mm absolute increase) in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), or unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions. Participants with no PD or death at the analysis date were censored at last tumor assessment date prior to on or before initiation of a new anticancer therapy or before the data cutoff date.

Time frame: From first documentation of CR or PR until PD, last tumor assessment without PD before new anticancer treatment initiation or death due to any cause, whichever occurred first (up to the data cutoff date [01 Sep 2016])

Population: TEP included all treated participants who had a baseline and at least 1 post-baseline tumor assessment or who discontinued the study before first scheduled post-baseline tumor scan + 1 week window. Here 'Number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm	Measure	Value (MEDIAN)
Cohort 1: Talazoparib 1 mg	Duration of Response (DOR)	5.8 months
Cohort 2: Talazoparib 1 mg	Duration of Response (DOR)	3.8 months

Secondary

Number of Participants With At Least 1 Concomitant Medication

Number of participants taking any non-study medications, therapies, including herbal supplements during the treatment-emergent period for the management of an adverse event or for the treatment of any other disease.

Time frame: Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)