A Study Evaluating The PF-03084014 In Combination With Docetaxel In Patients With Advanced Breast Cancer

Study Overview
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Brief Summary
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This study is aimed to determine the tolerability of the PF-03084014 plus docetaxel combination in patients with advanced breast cancer. Preliminary information about the efficacy of the combination will also be collected.

Official Title
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Phase 1b Study Of Docetaxel + Pf 03084014 In Metastatic Or Locally Recurrent/Advanced Triple Negative Breast Cancer

Conditions
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Breast Cancer Metastatic

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of breast cancer with evidence of a) metastatic or b) locally recurrent/advanced disease. Exclusion Criteria: Prior treatment with a gamma secretase inhibitors or other Notch signaling inhibitors.

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 plus docetaxel<br>PF 03084014 will be administered orally, continuously, twice daily at doses from 80 to 150 mg in combination with docetaxel given every 3 weeks at doses from 75 to 100 mg/m^2 | 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>Drug: Docetaxel<br>* Solution for IV infusion 75 mg/m^2, every 3 weeks<br>* Other names: Taxotere;Drug: Docetaxel<br>* Solution for IV infusion 100 mg/m^2, every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1 | Any DLT event in Cycle 1: Grade 4 neutropenia lasting more than (>)7 days; febrile neutropenia (Grade more than or equal to [>=] 3 and body temperature >=38.5 degrees Celsius); Grade >=3 neutropenic infection; Grade >=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia without bleeding; Grade >=3 toxicities (except those that had not been maximally treated); Grade 3 prolongation of time from electrocardiogram (ECG) Q wave to the end of the T wave corresponding to electrical systole (QT) corrected for heart rate (QTc) which persisted after correction of reversible causes; delay of 2 weeks in receiving next scheduled cycle due to persisting treatment-related toxicities; and failure to deliver at least 80% of planned dose during first cycle due to treatment-related toxicities. | Cycle 1 Days 1-21 | 
| Progression-free Survival (PFS) at 6 Months - Expansion Cohort | The period from study entry until disease progression, death or date of last contact. Assessment of response was made using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Baseline till 6 months post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All Causality and Treatment-related Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent AEs (TEAEs) are defined as newly occurring AEs or those worsening after first dose. AEs comprised both SAEs and non-SAEs. 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. Causality assessment was made by the investigator. Grading was per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death related to AE. | Baseline up to 28-35 days after treatment discontinuation (up to Day 280) | 
| Number of Participants With Laboratory Abnormalities | Number of participants with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, coagulation, liver function, renal function, electrolytes, clinical chemistry, and urinalysis (dipstick). | Baseline up to 28-35 days after treatment discontinuation (up to Day 280) | 
| Percentage of Participants With Objective Response (OR) | OR was based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeters [mm]). No new lesions. PR was defined as more than or equal to (>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Baseline, every 6 weeks from Cycle 2 onwards up to 26 months | 
| Area Under the Concentration-time Curve (AUC) From Time 0 to Time of Last Measured Concentration (AUClast) of PF-03084014 in Dose-finding Cohort | Serum PF-03084014 pharmacokinetic (PK) parameters were calculated following twice daily (BID) doses of PF-03084014 given alone (Cycle 1 Day 21) and in combination with docetaxel (Cycle 1 Day 2 and Cycle 2 Day 1). | Cycle (C) 1 Days (D) 1, 2, 8, and 21; Day 1 of subsequent cycles and at EOT (max reached: Cycle 12) | 
| AUClast and AUC From Time 0 Extrapolated to Infinite Time (AUCinf) of Docetaxel in Dose-finding Cohort | Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Maximum Serum or Plasma Concentration (Cmax) and Predose Concentration (Ctrough) of PF-03084014 in Dose-finding Cohort | Serum PF-03084014 PK parameters were calculated following BID doses of PF-03084014 given alone (Cycle 1 Day 21) and in combination with docetaxel (Cycle 1 Day 2 and Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Cmax of Docetaxel in Dose-finding Cohort | Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Time to Cmax (Tmax) of PF-03084014 in Dose-finding Cohort | Serum PF-03084014 PK parameters were calculated following BID doses of PF-03084014 given alone (Cycle 1 Day 21) and in combination with docetaxel (Cycle 1 Day 2 and Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Tmax of Docetaxel in Dose-finding Cohort | Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Systemic Clearance (CL) of Docetaxel in Dose-finding Cohort | Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Terminal Half-life (t1/2) of Docetaxel in Dose-finding Cohort | Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| Volume of Distribution (Vss) of Docetaxel in Dose-finding Cohort | Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1) | C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) | 
| AUClast of PF-03084014 in the Expansion Cohort |  | C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) | 
| Cmax of PF-03084014 in the Expansion Cohort |  | C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) | 
| Tmax of PF-03084014 in the Expansion Cohort |  | C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) | 
| Ctrough of PF-03084014 in the Expansion Cohort |  | C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) | 
| Duration of Response (DR) | Duration of response (DR) defined as time from start of first documented objective tumor response [Complete Response (CR) or Partial Response (PR)] to first documented objective tumor progression or death due to any cause, whichever occurs first. DR = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.02. CR: disappearance of all target lesions. PR: at least 30% decrease in the sum of diameters of target lesions. | Baseline up to 28-35 days after treatment discontinuation (up to Day 280) | 
| Number of Participants With QTc Values Meeting Categorical Summarization Criteria | Criteria for categorical summarization of the time corresponding to the beginning of depolarization to repolarization of the ventricles (QT) corrected for heart rate (QTc) using Bazett's correction (QTcB) or Fridericia's correction (QTcF) included: maximum QTcB or QTcF less than or equal to (<=) 450 milliseconds (msec), 450 to <=480 msec, 480 to <=500 msec, more than (>) 500 msec; maximum QTcB or QTcF changes (increases/decreases) from baseline (BL) less than (<) 30 msec, 30 to <60 msec, more than or equal to (>=) 60 msec. | Screening, C1D1, C1D21, Day 1 of subsequent cycles, and EOT (maximum reached: C12) | 
| Percentage Change From Baseline in Notch 1 to 4 Ribonucleic Acid (RNA) in Blood | As PF-03084014 acts on the Notch pathway as an inhibitor, it is of interest to investigate its effects, if any, on the Notch family of receptors, mainly Notch 1-4. | C1D1, C1D2, C1D8, C1D21 and EOT (maximum reached: C12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer metastatic, docetaxel, PF-03084014