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)

Breast Neoplasms Clinical Trial

— ABRAZO  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02034916
• Other study ID #: 673-201
• Secondary ID: 2013-003076-12C3
• Status: Terminated
• Phase: Phase 2
• Start date: December 13, 2013
• Est. completion date: October 31, 2018

Study information

• Verified date: October 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 84
• Est. completion date: October 31, 2018
• Est. primary completion date: September 1, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• BRCA 1 Gene Mutation
• BRCA 2 Gene Mutation
• Breast Neoplasms

Intervention

Drug:
• talazoparib

Locations

Country	Name	City	State
France	Centre Oscar Lambret	Lille Cédex
France	Centre Leon Berard	Lyon Cedex 08
France	Institut Paoli Calmettes	Marseille
France	Hopital Prive du Confluent	Nantes BP 20215
France	Hopitaux Universitaires de Strasbourg - Hopital Civil	Strasbourg
France	Institut Universitaire du Cancer Toulouse - Oncopole	Toulouse
France	CHU Bretonneau Centre Henry Kaplan	Tours Cedex 9
Germany	Helios Klinikum Berlin-Buch	Berlin
Germany	University Hospital Carl Gustav Carus	Dresden	Saxony
Germany	University Hospital Duesseldorf	Duesseldorf
Germany	Universitaetsklinikum Erlangen	Erlangen	Bavaria
Germany	Kliniken Essen Mitte Klinik fuer Gynaekologie und Gynaekologische Onkologie	Essen
Germany	Universitaetsklinikum Schleswig-Holstein	Kiel
Germany	IOZ Muenchen - lnerdisziplinaeres Onkologisches Zentrum	Muenchen	Bavaria
Germany	Klinikum rechts der Isar der TU Muenchen	Muenchen	Bavaria
Germany	University of Munich (LMU) Grosshadern Hospital	Munich	Bavaria
Germany	g.SUND Gynaekologie Kompetenzzentrum Stralsund	Stralsund
Germany	Klinikum Mutterhaus Der Borromaeerinnen Ggmbh	Trier	Rheinland-pfalz
Germany	Universitaets-Frauenklinik	Tuebingen
Spain	Complejo Hospitalario Universitario A Coruna	A Coruna
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	MD Anderson Cancer Center International Espana	Madrid
Spain	Hospital Universitario San Juan de Alicante	San Juan de Alicante
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	Cambridge University Hospital NHS Foundation Trust	Cambridge	England
United Kingdom	Sarah Cannon Research Institute UK	London	England
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Lancashire Teaching Hospitals NHS Foundation Trust	Preston	Lancashire
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton
United States	Anne Arundel Medical Center (AAMC)	Annapolis	Maryland
United States	Anne Arundel Medical Center (AAMC), Annapolis Oncology and Hematology	Annapolis	Maryland
United States	Anne Arundel Medical Center (AAMC), Research Pharmacy	Annapolis	Maryland
United States	Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins	Baltimore	Maryland
United States	Sylvester at Deerfield Beach	Deerfield Beach	Florida
United States	Marin Cancer Care, Inc.	Greenbrae	California
United States	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida
United States	Memorial Regional Hospital	Hollywood	Florida
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	ICRC	Indianapolis	Indiana
United States	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Investigational Drug Services	Indianapolis	Indiana
United States	IU Health University Hospital	Indianapolis	Indiana
United States	Sidney & Lois Eskenazi Hospital	Indianapolis	Indiana
United States	Springmill Medical Clinic	Indianapolis	Indiana
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	TRIO-US Central Administration	Los Angeles	California
United States	UCLA West Medical Pharmacy Attn: Steven L. Wong, PharmD	Los Angeles	California
United States	UCLA West Medical Pharmacy, Attn: Steven L. Wong, Pharm.D.	Los Angeles	California
United States	Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Green Spring Station	Lutherville	Maryland
United States	University of Miami Hospital & Clinics	Miami	Florida
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	The Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Evelyn H. Lauder Breast Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Stanford Women's Cancer Center	Palo Alto	California
United States	Memorial Breast Cancer Center at Memorial Hospital West	Pembroke Pines	Florida
United States	Memorial Cancer Institute at Memorial Hospital West	Pembroke Pines	Florida
United States	Memorial Hospital West	Pembroke Pines	Florida
United States	Sylvester at Plantation	Plantation	Florida
United States	UCLA Hematology Oncology- Porter Ranch	Porter Ranch	California
United States	Torrance Health Association, DBA Torrance Memorial Physician Network/Cancer Care Associates	Redondo Beach	California
United States	Memorial Sloan Kettering Rockville Centre	Rockville Centre	New York
United States	University of California, San Francisco: Helen Diller Comprehensive Cancer Center	San Francisco	California
United States	UCLA Hematology-Oncology	Santa Monica	California
United States	Stanford Cancer Institute	Stanford	California
United States	Stanford Hospital and Clinics	Stanford	California

Sponsors (3)

Lead Sponsor	Collaborator
Pfizer	Medivation, Inc., Myriad Genetic Laboratories, Inc.

Countries where clinical trial is conducted

United States,  France,  Germany,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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])
Other	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])
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).	From randomization until data cutoff date (01 Sep 2016)
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.	From randomization until data cutoff date (01 Sep 2016)
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.	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])
Secondary	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])
Secondary	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])
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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])
Secondary	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)
Secondary	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)
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.	Baseline up to end of study (up to a maximum duration of 42.8 months): based on data cutoff date (31 Oct 2018)
Secondary	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)