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

Study Overview
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Brief Summary
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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-)

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

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: PF-03084014
* Drug: PF-03084014
* Drug: PF-03084014


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-03084014<br>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<br>* Tablet, 10 mg, twice a day.<br>Drug: PF-03084014<br>* Tablet, 50 mg, twice a day<br>Drug: PF-03084014<br>* Tablet, 100 mg, twice a day<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-03084014, Notch Alterations