A Study Evaluating PF-03084014 In Patients With Advanced Breast Cancer With Or Without Notch Alterations

PHASE 2 STUDY OF SINGLE-AGENT PF-03084014 IN PATIENTS WITH ADVANCED TRIPLE-NEGATIVE BREAST CANCER WITH OR WITHOUT GENOMIC ALTERATIONS IN NOTCH RECEPTORS

This study is designed to evaluate the preliminary anti-tumor activity and tolerability of PF-03084014 when administered as a single agent in the treatment of patients with advanced triple receptor-negative breast cancer (mTNBC) harboring genomic alterations in Notch receptors (NA+), and in a smaller subset of mTNBC patients whose tumor tests negative for genomic alterations in Notch receptors (NA-)

Study Overview

• Status: Terminated
• Conditions: Triple Negative Breast Neoplasms
• Intervention / Treatment: Drug: PF-03084014; Drug: PF-03084014; Drug: PF-03084014

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem, Klinikai Kozpont, Onkologiai Intezet
• Italy
  • Lecce, Italy, 73100
    • Presidio Ospedaliero Vito Fazzi
  • Milan, Italy, 20141
    • Istitutio Europeo di Oncologia
• Poland
  • Krakow, Poland, 31108
    • Vesalius
  • Krakow, Poland, 31216
    • Vesalius Poradnia Onkologiczna i Hematologiczna
  • Poznan, Poland, 60-569
    • Szpital Kliniczny Przemienienia Panskiego, Uniwersutetu Medycznego im. Karola Marcinkowskiego
• Spain
  • A Coruna, Spain, 15006
    • Complejo Hospitalario Universitario A Coruna (Hospital Teresa Herrera)
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08041
    • Hospital de La Santa Creu i Sant Pau
  • Barcelona, Spain, 08908
    • Instituto Catalan de Oncologia de L'Hospitalet de Llobregat (ICO)
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
  • Surrey, United Kingdom, SM2 5PT
    • The Royal Marsden NHS Foundation Trust
  • Scotland
    • Glasgow, Scotland, United Kingdom, G12 0YN
      • Beatson West of Scotland Cancer Centre
    • Glasgow, Scotland, United Kingdom, G52 3NQ
      • Ross Hall Hospital
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
    • Stanford, California, United States, 94305
      • Stanford Women's Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
    • New Lenox, Illinois, United States, 60451
      • University of Chicago Comprehensive Cancer Center at Silver Cross Hospital
    • Zion, Illinois, United States, 60099
      • Midwestern Regional Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute (DFCI)
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital (BWH)
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Cancer Center Basking Ridge
    • Paramus, New Jersey, United States, 07652
      • The Valley Hospital - Luckow Pavilion
    • Paramus, New Jersey, United States, 07652
      • Valley Medical Group
    • Westwood, New Jersey, United States, 07675
      • Valley Medical Group
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Cancer Center Commack
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Cancer Center West Harrison
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • Rockville Centre, New York, United States, 11570
      • Memorial Sloan Kettering Cancer Center Rockville Centre
    • Sleepy Hollow, New York, United States, 10591
      • Memorial Sloan Kettering Cancer Center Sleepy Hollow

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Histological or cytological diagnosis of triple negative breast cancer (TNBC) with evidence of a) metastatic or b) locally recurrent advanced disease that is not amenable to resection or radiotherapy with curative intent.
• Availability of an original diagnostic tumor tissue or the most recent metastatic tumor biopsies (archival biopsy or de novo biopsy) and a peripheral blood sample for Notch receptors genomic profiling

Exclusion Criteria:

• Known brain metastases.
• Prior treatment with gamma secretase inhibitor or other Notch signaling inhibitor.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-03084014; PF-03084014 will be administered orally, continuously, twice daily at 150 mg, but the dose can be reduced to 100 mg or 80 mg.	Drug: PF-03084014; Tablet, 50 mg, twice a day; Drug: PF-03084014; Tablet, 100 mg, twice a day; Drug: PF-03084014; Tablet, 10 mg, twice a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response (OR) Rate in Participants With Advanced Triple Receptor-Negative Breast Cancer (mTNBC) Harboring Activating Genomic Alterations in Notch Receptors (NA+)	OR status based on assessment of confirmed complete remission (CR) or confirmed partial remission (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR: Complete disappearance of all target lesions with the exception of nodal disease and all target nodes decreased to normal size (short axis less than [<]10 millimeter [mm]). PR: Greater than or equal to (>=)30% decrease under baseline of the sum of diameters of all target measurable lesions. OR=CR+PR.	Cycle 3 Day 1, Cycle 5 Day 1, and every 6 weeks for subsequent cycles ntil disease progression, patient refusal for further follow up, or start of another anti-cancer treatment, whichever occurred first.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OR Rate in Participants With mTNBC Whose Tumors Tested Negative for Eenomic Alterations in Notch Receptor (NA-)	OR status based on assessment of confirmed CR or confirmed PR according to RECIST 1.1. CR: Complete disappearance of all target lesions with the exception of nodal disease and all target nodes decreased to normal size (short axis <10 mm). PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. OR=CR+PR.	Cycle 3 Day 1, Cycle 5 Day 1, and every 6 weeks for subsequent cycles ntil disease progression, patient refusal for further follow up, or start of another anti-cancer treatment, whichever occurred first.
Progression-Free Survival (PFS) in Participants With NA+ or NA mTNBC	The period from study entry until disease progression, death, whichever occurred first as per RECIST version 1.1.	2 years
Duration of Response (DR) in Participants With NA+ or NA mTNBC	Time from the first documentation of objective tumor response to objective tumor progression or death due to any cause. DR was calculated for the subgroup of patients with a confirmed objective tumor response. Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.	2 years
One-Year Survival Probability in Participants With NA+ or NA mTNBC	Overall survival (OS) status (alive or not) at 1 year after study entry. The the survival probability at 1 year was summarized as a product limit estimator based on the Kaplan-Meier method to account for censored events.	1 year
Overall Survival (OS) in Participants With NA+ or NA mTNBC	OS was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.	2 years
Type of Notch Genomic Alterations in Participants With NA+ mTNBC	Type of notch genomic alterations identified by NGS assay in patients with NA+ mTNBC	2 years
Pre-dose Serum Concentration (Ctrough) for PF-03084014		Day 1 of Cycle 1, 2, 3, and 5
Pharmacodynamic (PD) Effects of PF-03084014 in Tumor Specimens and Peripheral Blood	Original diagnostic tumor tissue or the most recent metastatic tumor (archival or de novo biopsy), plasma, and peripheral blood samples were collected for biomarker assessments of circulating analytes, immunohistochemistry for notch receptors expression, expression of notch pathway components and modulators, mutational analysis of pathway and disease associated genes.	Day 1 of Cycle 1, 2, 3, and 5
Alterations in Genes, Proteins, and RNAs Relevant to the Notch Signaling Pathway, to TNBC Biology, and to Sensitivity/Resistance to PF-03084014 in Tumor Specimens and Peripheral Blood.	Original diagnostic tumor tissue or the most recent metastatic tumor (archival or de novo biopsy), plasma, and peripheral blood samples were collected for biomarker assessments of circulating analytes, immunohistochemistry for notch receptors expression, expression of notch pathway components and modulators, mutational analysis of pathway and disease associated genes.	Day 1 of Cycle 1, 2, 3, and 5
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An 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. Treatment-emergent AEs were defined as all deaths, regardless of cause, from treatment start until 28 days after the last dose and non-fatal events occurring after treatment start regardless of cause, up until 28 days after the last dose or until start of new anti-cancer treatment, whichever was first.	2 years
Number of Participants With Treatment-Emergent AEs by CTCAE Grade	An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. AEs were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	2 years
Number of Participants With Laboratory Test (Hematology) Abnormalities	Number of participants with CTCAE version 4.03 grade 1 to 4 hematological test abnormalities.	Day 1 of Cycles 1, 2, 3, 4, 5, and subsequent cycles.
Number of Participants With Laboratory Test (Chemistry) Abnormalities	Number of participants with CTCAE version 4.03 grade 1 to 4 chemistry test abnormalities	Day 1 and Day 15 of Cycles 1, 2, 3, 4, 5, and subsequent cycles up to Cycle 8 and Day 8 of Cycle 1
Number of Participants With Laboratory Test (Urinalysis) Abnormalities	Number of participants with CTCAE version 4.03 grade 1 to 4 urinalysis test abnormalities for urine protein.	Day 1 of Cycle 1
Number of Notch Genomic Alterations in Participants With NA+ mTNBC	Number of notch genomic alterations identified by NGS assay in patients with NA+ mTNBC	2 years

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2015
• Primary Completion (Actual): January 14, 2016
• Study Completion (Actual): January 14, 2016

Study Registration Dates

• First Submitted: November 20, 2014
• First Submitted That Met QC Criteria: November 20, 2014
• First Posted (Estimate): November 24, 2014

Study Record Updates

• Last Update Posted (Actual): January 8, 2019
• Last Update Submitted That Met QC Criteria: December 19, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: PF-03084014; Notch Alterations
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms
• Other Study ID Numbers: A8641020; 2014-002286-30 (EudraCT 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.