A Study Evaluating The PF-03084014 In Combination With Docetaxel In Patients With Advanced Breast Cancer
- Registration Number
- NCT01876251
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Female
- Target Recruitment
- 30
- Diagnosis of breast cancer with evidence of a) metastatic or b) locally recurrent/advanced disease.
- Prior treatment with a gamma secretase inhibitors or other Notch signaling inhibitors.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description PF-03084014 plus docetaxel PF-03084014 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 PF-03084014 plus docetaxel Docetaxel 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
- Primary Outcome Measures
Name Time Method Progression-free Survival (PFS) at 6 Months - Expansion Cohort Baseline till 6 months post-dose 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.
Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1 Cycle 1 Days 1-21 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With All Causality and Treatment-related Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs Baseline up to 28-35 days after treatment discontinuation (up to Day 280) 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.
Maximum Serum or Plasma Concentration (Cmax) and Predose Concentration (Ctrough) of PF-03084014 in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Tmax of PF-03084014 in the Expansion Cohort C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) Number of Participants With Laboratory Abnormalities Baseline up to 28-35 days after treatment discontinuation (up to Day 280) 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).
Volume of Distribution (Vss) of Docetaxel in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
AUClast of PF-03084014 in the Expansion Cohort C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) Percentage Change From Baseline in Notch 1 to 4 Ribonucleic Acid (RNA) in Blood C1D1, C1D2, C1D8, C1D21 and EOT (maximum reached: C12) 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.
Time to Cmax (Tmax) of PF-03084014 in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Tmax of Docetaxel in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Terminal Half-life (t1/2) of Docetaxel in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Cmax of PF-03084014 in the Expansion Cohort C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) Cmax of Docetaxel in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Systemic Clearance (CL) of Docetaxel in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Ctrough of PF-03084014 in the Expansion Cohort C1D1, C1D21, and Day 1 of subsequent cycles and at EOT (max reached: C12) Percentage of Participants With Objective Response (OR) Baseline, every 6 weeks from Cycle 2 onwards up to 26 months 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.
Area Under the Concentration-time Curve (AUC) From Time 0 to Time of Last Measured Concentration (AUClast) of PF-03084014 in Dose-finding Cohort Cycle (C) 1 Days (D) 1, 2, 8, and 21; Day 1 of subsequent cycles and at EOT (max reached: Cycle 12) 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).
AUClast and AUC From Time 0 Extrapolated to Infinite Time (AUCinf) of Docetaxel in Dose-finding Cohort C1D1, 2, 8, and 21; D1 of subsequent cycles and at EOT (max reached: C12) 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)
Duration of Response (DR) Baseline up to 28-35 days after treatment discontinuation (up to Day 280) 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.
Number of Participants With QTc Values Meeting Categorical Summarization Criteria Screening, C1D1, C1D21, Day 1 of subsequent cycles, and EOT (maximum reached: C12) 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.
Trial Locations
- Locations (15)
Instituto Europeo di Oncologia
🇮🇹Milano, Italy
Karmanos Cancer Institute (KCI)
🇺🇸Detroit, Michigan, United States
Barbara Ann Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Jules Bordet Institut
🇧🇪Bruxelles, Belgium
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Stanford Hospital & Clinics-DRUG SHIPMENT ADDRESS only
🇺🇸Stanford, California, United States
University of Alabama at Birmingham, IDS Pharmacy
🇺🇸Birmingham, Alabama, United States
Stanford Cancer Institute
🇺🇸Stanford, California, United States
Stanford Hospital & Clinics
🇺🇸Stanford, California, United States
UNC Cancer Hospital Infusion Pharmacy
🇺🇸Chapel Hill, North Carolina, United States
Stanford Women's Cancer Center
🇺🇸Stanford, California, United States
UNC Hospitals, The University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Grand Hopital de Charleroi
🇧🇪Charleroi, Belgium
Instituto Catalan de Oncologia de L'Hospitalet de Llobregat(ICO)
🇪🇸Barcelona, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain