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) (ABRAZO)

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

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

Study Overview

• Status: Terminated
• Conditions: Breast Neoplasms; BRCA 1 Gene Mutation; BRCA 2 Gene Mutation
• Intervention / Treatment: Drug: talazoparib

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lille Cédex, France, 59020
    • Centre Oscar Lambret
  • Lyon Cedex 08, France, 69373
    • Centre Leon Berard
  • Marseille, France, 13273 Cedex 9
    • Institut Paoli Calmettes
  • Nantes BP 20215, France, 44202 Cedex 2
    • Hôpital Privé du Confluent
  • Strasbourg, France, 67091Cedex
    • Hôpitaux Universitaires de Strasbourg - Hôpital Civil
  • Toulouse, France, 31059 Cedex 9
    • Institut Universitaire du Cancer Toulouse - Oncopole
  • Tours Cedex 9, France, 37044
    • CHU Bretonneau Centre Henry Kaplan
• Germany
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin-Buch
  • Duesseldorf, Germany, 40225
    • University Hospital Duesseldorf
  • Essen, Germany, 45136
    • Kliniken Essen Mitte Klinik fuer Gynaekologie und Gynaekologische Onkologie
  • Kiel, Germany, 24105
    • Universitaetsklinikum Schleswig-Holstein
  • Stralsund, Germany, 18435
    • g.SUND Gynaekologie Kompetenzzentrum Stralsund
  • Tuebingen, Germany, 72076
    • Universitaets-Frauenklinik
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Universitaetsklinikum Erlangen
    • Muenchen, Bavaria, Germany, 80336
      • IOZ Muenchen - lnerdisziplinaeres Onkologisches Zentrum
    • Muenchen, Bavaria, Germany, 81675
      • Klinikum rechts der Isar der TU Muenchen
    • Munich, Bavaria, Germany, 81377
      • University of Munich (LMU) Grosshadern Hospital
  • Rheinland-pfalz
    • Trier, Rheinland-pfalz, Germany, 54290
      • Klinikum Mutterhaus der Borromaeerinnen gGmbH
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • University Hospital Carl Gustav Carus
• Spain
  • A Coruna, Spain, 15006
    • Complejo Hospitalario Universitario A Coruña
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Jaen, Spain, 23007
    • Complejo Hospitalario de Jaén
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center International Espana
  • San Juan de Alicante, Spain, 03550
    • Hospital Universitario San Juan de Alicante
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden NHS Foundation Trust
  • England
    • Cambridge, England, United Kingdom, CB2 0QQ
      • Cambridge University Hospital NHS Foundation Trust
    • London, England, United Kingdom, W1G 6AD
      • Sarah Cannon Research Institute UK
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Lancashire Teaching Hospitals NHS Foundation Trust
• United States
  • California
    • Greenbrae, California, United States, 94904
      • Marin Cancer Care, Inc.
    • Los Angeles, California, United States, 90095
      • TRIO-US Central Administration
    • Los Angeles, California, United States, 90095-7349
      • UCLA West Medical Pharmacy, Attn: Steven L. Wong, Pharm.D.
    • Los Angeles, California, United States, 90095-1772
      • UCLA West Medical Pharmacy Attn: Steven L. Wong, PharmD
    • Palo Alto, California, United States, 94304
      • Stanford Women's Cancer Center
    • Porter Ranch, California, United States, 91326
      • UCLA Hematology Oncology- Porter Ranch
    • Redondo Beach, California, United States, 90277
      • Torrance Health Association, DBA Torrance Memorial Physician Network/Cancer Care Associates
    • San Francisco, California, United States, 94115
      • University of California, San Francisco: Helen Diller Comprehensive Cancer Center
    • Santa Monica, California, United States, 90404
      • UCLA Hematology-Oncology
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Florida
    • Deerfield Beach, Florida, United States, 33442
      • Sylvester at Deerfield Beach
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Hospital
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute at Memorial Regional Hospital
    • Miami, Florida, United States, 33136
      • University of Miami Hospital & Clinics
    • Pembroke Pines, Florida, United States, 33028
      • Memorial Cancer Institute at Memorial Hospital West
    • Pembroke Pines, Florida, United States, 33028
      • Memorial Hospital West
    • Pembroke Pines, Florida, United States, 33028
      • Memorial Breast Cancer Center at Memorial Hospital West
    • Plantation, Florida, United States, 33324
      • Sylvester at Plantation
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • IU Health University Hospital
    • Indianapolis, Indiana, United States, 46290
      • Springmill Medical Clinic
    • Indianapolis, Indiana, United States, 46202
      • Investigational Drug Services
    • Indianapolis, Indiana, United States, 46202-5116
      • ICRC
    • Indianapolis, Indiana, United States, 46202
      • Sidney & Lois Eskenazi Hospital
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Medical Center (AAMC), Annapolis Oncology and Hematology
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Medical Center (AAMC), Research Pharmacy
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Medical Center (AAMC)
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins
    • Lutherville, Maryland, United States, 21093
      • Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Green Spring Station
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Evelyn H. Lauder Breast Center
    • Rockville Centre, New York, United States, 11570
      • Memorial Sloan Kettering Rockville Centre
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC
    • Nashville, Tennessee, United States, 37203
      • The Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: talazoparib; 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 Cohort 2) Subjects who have received > 2 prior chemotherapy regimens for metastatic disease and who have had no prior platinum therapy for metastatic disease	Drug: talazoparib; Other Names: MDV3800; BMN673

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	From randomization until data cutoff date (01 Sep 2016)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization until data cutoff date (01 Sep 2016)
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.	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])
Progression Free Survival (PFS)	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.	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])
Overall Survival (OS)	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.	From first dose of study drug until death due to any cause (up to the data cutoff date [01 Sep 2016])
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	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 With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	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 With Outcome in Response to Adverse Events (AEs)	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'.	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 With Toxicity Grades Increase of 2 or More in Laboratory Parameter (Hematology Parameter)	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.	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 With Toxicity Grades Increase of 2 or More in Laboratory Parameter (Chemistry Parameter)	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.	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])
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	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.	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 With Clinically Significant Change From Baseline in Physical Findings	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.	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 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.	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)
Trough Concentration Versus Time Summary of Talazoparib	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.	Predose on Day 1 of Cycle 1, 2, 3, and 4 (data cutoff date: 01 Sep 2016)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	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 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)	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.	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])

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Medivation, Inc.; Myriad Genetic Laboratories, Inc.

Publications and helpful links

General Publications

• Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke EM, Mina LA, Balmana J, Fasching PA, Hurvitz SA, Wardley AM, Chappey C, Hannah AL, Robson ME; ABRAZO Study Group. A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin Cancer Res. 2019 May 1;25(9):2717-2724. doi: 10.1158/1078-0432.CCR-18-1891. Epub 2018 Dec 18.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 13, 2013
• Primary Completion (ACTUAL): September 1, 2016
• Study Completion (ACTUAL): October 31, 2018

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: January 10, 2014
• First Posted (ESTIMATE): January 14, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 14, 2019
• Last Update Submitted That Met QC Criteria: October 10, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: PARP inhibitor; Breast cancer; BRCA mutation; BRCA 1; BRCA 2
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: 673-201; 2013-003076-12 (EUDRACT_NUMBER); C3441008 (OTHER: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.