A Study Of PF-04449913 Administered Alone In Select Solid Tumors
- Registration Number
- NCT01286467
- Lead Sponsor
- Pfizer
- Brief Summary
This study examines the effect of a small molecule inhibitor to the Sonic Hedgehog pathway on select solid tumors.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 23
- Histological or cytological diagnosis of advanced/metastatic solid tumor
- Adequate Bone Marrow Function
- Adequate Renal Function
- Adequate Liver Function
- Patients with known symptomatic brain metastases requiring steroids
- Current active treatment on another clinical trial
- Major surgery or radiation therapy within 4-weeks of starting study treatment
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1 PF-04449913 -
- Primary Outcome Measures
Name Time Method Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Baseline up to end of Cycle 1 (Study Day 28) Any DLT event in Cycle 1: (1) Grade 4 neutropenia lasting more than 7 days; (2) Febrile neutropenia; (3) Grade \>=3 neutropenic infection; (4) Grade \>=3 thrombocytopenia with bleeding; (5) Grade 4 thrombocytopenia lasting more than 7 days; (6) Grade \>=3 non-hematologic toxicity; (7) Failure to deliver at least 80% of the planned doses due to toxicities attributable to PF-04449913
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Treatment-emergent Adverse Events (AEs), by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) Grade Baseline up to 28 days post last dose of study medication (maximum duration: 14 cycles [each cycle of 28 days]) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent AEs are events occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. If the same participant in a given treatment had more than one occurrence in the same preferred term event category, only the worst CTCAE grade was reported. Grades as per NCI CTCAE, v4.0 were classified as: Grade 1- mild, Grade 2- moderate, Grade 3- severe, Grade 4- life threatening, and Grade 5- death.
Percentage of Participants With Treatment-related AEs, by NCI CTCAE (Version 4.0) Grade Baseline up to 28 days post last dose of study medication (maximum duration: 14 cycles [each cycle of 28 days]) An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-related AEs are events that were assessed by the investigator as related to study medication. If the same participant in a given treatment had more than one occurrence in the same preferred term event category, only the worst CTCAE grade was reported. Grades as per NCI CTCAE, v4.0 were classified as: Grade 1- mild, Grade 2- moderate, Grade 3- severe, Grade 4- life threatening, and Grade 5- death.
Hedgehog Biomarker Modulation: Relative GLI1 Gene Expression (Ratio) to Baseline for Normal Skin on Cycle 1/Day 15 Baseline and Cycle 1/Day 15 Ribonucleic acid (RNA) was extracted from skin samples and complementary deoxyribonucleic acid (cDNA) was prepared. Gene expression was measured using custom Taqman low density array (TLDA) cards run on the Applied Biosystems ViiATM 7 system. The ratio for each participant at each dosing level was calculated at C1D15 to baseline assay readout (C1D1), and the mean of it is reported in this outcome measure.
Maximum Observed Plasma Concentration (Cmax) on Cycle 1/Day 1 Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1 Cmax of PF-04449913 on Cycle 1/Day 1 has been reported.
Maximum Observed Plasma Concentration (Cmax) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Cmax of PF-04449913 on Cycle 1/Day 25 has been reported.
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Cycle 1/Day 1 Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1 Tmax of PF-04449913 on Cycle 1/Day 1 has been reported.
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Tmax of PF-04449913 on Cycle 1/Day 25 has been reported.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) on Cycle 1/Day 1 Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1 AUCtau of PF-04449913 on Cycle 1/Day 1 has been reported. AUCtau is defined as area under the curve from time 0 to tau, where tau is the dosing interval of 24 hours.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 AUCtau of PF-04449913 on Cycle 1/Day 25 has been reported. AUCtau is defined as area under the curve from time 0 to tau, where tau is the dosing interval of 24 hours.
Plasma Decay Half-life (t1/2) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Apparent Oral Clearance (CL/F) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Apparent Volume of Distribution (Vz/F) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Accumulation Ratio (Rac) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1, and pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Accumulation ratio was calculated as AUCtau at steady state (Cycle 1/Day 25)/AUCtau on Study Day 1
Average Concentration at Steady State (Cavg) on Cycle 1/Day 25 Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25 Number of Participants With Increase From Baseline in Corrected QT Using Fridericia's Formula (QTcF) Interval Baseline up to Cycle 14 (each cycle 28 days) Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole (QT) was corrected for heart rate (QTc). QTc using Fridericia's formula (QTcF) was calculated. Participants with maximum increase from baseline of less than (\<) 30 millisecond (msec), 30 to \<60 msec and \>=60 msec were summarized.
Duration of Response (DR) Baseline up to Cycle 14 (each cycle 28 days) Duration from date of first documentation of objective response to date of first documentation of disease progression or death. Progression was defined using RECIST 1.1 as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. DR was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first objective response that was subsequently confirmed plus 1).
Number of Participants With Decrease From Baseline in QTcF Interval Baseline up to Cycle 14 (each cycle 28 days) Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. QTcF was calculated. Participants with maximum decrease from baseline of \<30 msec, 30 to \<60 msec and \>=60 msec were summarized.
Percentage of Participants With Objective Response Baseline up to Cycle 14 (each cycle 28 days) Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Confirmed responses were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target measurable lesions.
Progression-Free Survival (PFS) Baseline up to Cycle 14 (each cycle 28 days) Time from Cycle 1/Day 1 to first documentation of disease progression or to death due to any cause, whichever occurred first. Progression was defined using RECIST 1.1 as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. PFS (days) was calculated as (first event date minus the date of first dose of study medication plus 1).
Number of Participants With Post-baseline QTcF Interval Greater Than or Equal to 500 Msec Baseline up to Cycle 14 (each cycle 28 days) Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. Participants with post-baseline absolute QTcF values \>=500 msec were summarized.
Time to Progression (TTP) Baseline up to Cycle 14 (each cycle 28 days) Time from Cycle 1/Day 1 to first documentation of disease progression. Progression was defined using RECIST 1.1 as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. TTP (days) was calculated as (first event date minus the date of first dose of study medication plus 1).
Trial Locations
- Locations (9)
Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Keck Hospital of University of Southern California
🇺🇸Los Angeles, California, United States
University of Southern California/Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Los Angeles County-University of Southern California Medical Center
🇺🇸Los Angeles, California, United States
University of Southern California/Norris Comprehensive Cancer Center/Investigational Drug Service
🇺🇸Los Angeles, California, United States
University of Colorado Denver
🇺🇸Aurora, Colorado, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Brigham and Women's Hospital (BWH)
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute (DFCI)
🇺🇸Boston, Massachusetts, United States