A Study Of PF-04449913 Administered Alone In Select Solid Tumors

A PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF PF 04449913, AN ORAL HEDGEHOG INHIBITOR, ADMINISTERED AS SINGLE AGENT IN SELECT SOLID TUMORS

This study examines the effect of a small molecule inhibitor to the Sonic Hedgehog pathway on select solid tumors.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: PF-04449913

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • Keck Hospital of University of Southern California
    • Los Angeles, California, United States, 90033
      • Los Angeles County-University of Southern California Medical Center
    • Los Angeles, California, United States, 90033
      • University of Southern California/Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • University of Southern California/Norris Comprehensive Cancer Center/Investigational Drug Service
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Aurora, Colorado, United States, 80045
      • Anschutz Cancer Pavilion
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute (DFCI)
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital (BWH)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histological or cytological diagnosis of advanced/metastatic solid tumor
• Adequate Bone Marrow Function
• Adequate Renal Function
• Adequate Liver Function

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: PF-04449913; Escalating dose of PF-04449913 administered as tablets PO QD in 28-day cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With First Cycle Dose Limiting Toxicities (DLTs)	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	Baseline up to end of Cycle 1 (Study Day 28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Baseline up to 28 days post last dose of study medication (maximum duration: 14 cycles [each cycle of 28 days])
Percentage of Participants With Treatment-related AEs, by NCI CTCAE (Version 4.0) Grade	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.	Baseline up to 28 days post last dose of study medication (maximum duration: 14 cycles [each cycle of 28 days])
Hedgehog Biomarker Modulation: Relative GLI1 Gene Expression (Ratio) to Baseline for Normal Skin on 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.	Baseline and Cycle 1/Day 15
Maximum Observed Plasma Concentration (Cmax) on Cycle 1/Day 1	Cmax of PF-04449913 on Cycle 1/Day 1 has been reported.	Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1
Maximum Observed Plasma Concentration (Cmax) on Cycle 1/Day 25	Cmax of PF-04449913 on Cycle 1/Day 25 has been reported.	Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Cycle 1/Day 1	Tmax of PF-04449913 on Cycle 1/Day 1 has been reported.	Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Cycle 1/Day 25	Tmax of PF-04449913 on Cycle 1/Day 25 has been reported.	Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) 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.	Pre dose, 1, 2, 4, 6, 10 and 24 hours post dose on Cycle 1/Day 1
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) 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.	Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25
Plasma Decay Half-life (t1/2) on Cycle 1/Day 25	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25
Apparent Oral Clearance (CL/F) 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.	Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25
Apparent Volume of Distribution (Vz/F) 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.	Pre dose, 1, 2, 4, 10, 24, 48, 72 and 96 hours post dose on Cycle 1/Day 25
Accumulation Ratio (Rac) on Cycle 1/Day 25	Accumulation ratio was calculated as AUCtau at steady state (Cycle 1/Day 25)/AUCtau on Study Day 1	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
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	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.	Baseline up to Cycle 14 (each cycle 28 days)
Number of Participants With Decrease From Baseline in QTcF Interval	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.	Baseline up to Cycle 14 (each cycle 28 days)
Number of Participants With Post-baseline QTcF Interval Greater Than or Equal to 500 Msec	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.	Baseline up to Cycle 14 (each cycle 28 days)
Percentage of Participants With Objective Response	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.	Baseline up to Cycle 14 (each cycle 28 days)
Progression-Free Survival (PFS)	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).	Baseline up to Cycle 14 (each cycle 28 days)
Time to Progression (TTP)	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).	Baseline up to Cycle 14 (each cycle 28 days)
Duration of Response (DR)	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).	Baseline up to Cycle 14 (each cycle 28 days)

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

General Publications

• Fostvedt LK, Shaik N, Martinelli G, Wagner AJ, Ruiz-Garcia A. Exposure-response modeling of the effect of glasdegib on cardiac repolarization in patients with cancer. Expert Rev Clin Pharmacol. 2021 Jul;14(7):927-935. doi: 10.1080/17512433.2021.1925538. Epub 2021 May 18.
• Wagner AJ, Messersmith WA, Shaik MN, Li S, Zheng X, McLachlan KR, Cesari R, Courtney R, Levin WJ, El-Khoueiry AB. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015 Mar 1;21(5):1044-51. doi: 10.1158/1078-0432.CCR-14-1116. Epub 2014 Nov 11.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2011
• Primary Completion (Actual): May 10, 2012
• Study Completion (Actual): December 28, 2012

Study Registration Dates

• First Submitted: January 14, 2011
• First Submitted That Met QC Criteria: January 27, 2011
• First Posted (Estimated): January 31, 2011

Study Record Updates

• Last Update Posted (Actual): March 6, 2024
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Solid tumor; Pharmacodynamics; Hedgehog Inhibitor; PF-04449913
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: B1371002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• 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.