A Study Of PF-04449913 In Select Hematologic Malignancies

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

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

Study Overview

• Status: Completed
• Conditions: Hematologic Malignancies
• Intervention / Treatment: Drug: PF-04449913

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy, 40138
    • U.O. di Ematologia
• United States
  • California
    • La Jolla, California, United States, 92093
      • Moores UCSD Cancer Center
    • La Jolla, California, United States, 92037
      • UCSD Medical Center - La Jolla
    • San Diego, California, United States, 92103
      • UCSD Medical Center - Hillcrest
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas M.D. Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • University of Washington Medical Center, Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with select advanced hematologic malignancies who are refractory, resistant or intolerant to prior therapies. They may be newly diagnosed and previously untreated, but not eligible for standard treatment options, or for whom standard therapies are not anticipated to result in a durable response.
• ECOG performance status 0 to 2
• Adequate organ function

Exclusion Criteria:

• Patients with active CNS disease
• Patient with active malignancy with the exception of basal cell carcinoma, non melanoma skin cancer, carcinoma in situ cervical or skin cancer
• Active GVHD other than Grade 1 skin involvement
• Known malabsorption syndrome
• Patient has an active, life threatening or clinically significant uncontrolled systemic infection

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 doses of PF-04449913 administered as tablets PO QD continuously 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 >=3 non-hematologic toxicity that had been maximally treated, 2) prolonged myelosupression that lasted greater than (>) 42 days from the point of detection in a normal bone marrow (less than [<] 500 per microliter [/uL] or platelet count <10,000/uL, or hemoglobin <8 gram per deciliter [g/dL] with <5% blasts and no evidence of disease or dysplasia), 3) inability to deliver >= 80% of the planned doses due to PF-04449913 related non-hematologic and hematologic toxicities	Cycle 1 Day 1 to end of Cycle 1 (28 days)

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 (CTC) for AEs (CTCAE) (Version 3.0) 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 which occurred between first dose of study drug and 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 1 occurrence in the same preferred term event category, only the worst CTCAE grade (1 = mild AE, 2 = moderate AE, 3 = severe AE, 4 = life-threatening or disabling AE, 5 = death related to AE) was reported.	Baseline up to 28 days post last dose of study medication (maximum duration: 537 days)
Percentage of Participants With Treatment-related Adverse Events (AEs), by NCI CTCAE Version 3.0) Grade	An AE was any untoward medical occurrence in a participant. 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 1 occurrence in the same preferred term event category, only the worst CTCAE grade (1 = mild AE, 2 = moderate AE, 3 = severe AE, 4 = life-threatening or disabling AE, 5 = death related to AE) was reported.	Baseline up to 28 days post last dose of study medication (maximum duration: 537 days)
Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria	Participants with systolic blood pressure (BP) less than (<) 90 millimeters of mercury (mmHg), maximum increase and decrease from baseline systolic BP of more than or equal to (>=) 30 mmHg, diastolic BP <50 mmHg, maximum increase and decrease from baseline diastolic BP >=20 mmHg, and a heart rate of more than (>) 120 beats per minute (bpm) at any time post dose were summarized.	Screening up to maximum of 537 days
Number of Participants With Laboratory Test Abnormalities	Number of participants with laboratory test abnormalities without regard to baseline abnormality as per the pre defined criteria were reported. Laboratory test parameters included hematology, coagulation, liver function, renal function, electrolytes, clinical chemistry, and urinalysis (dipstick and microscopy).	Screening to EOT (maximum duration: 537 days)
Hedgehog Biomarker Modulation: Relative GLI1 Gene Expression to Baseline for Normal Skin on Cycle 1 Day 21	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.	Baseline, Cycle 1 Day 21
Maximum Observed Plasma Concentration (Cmax) on Lead-in		Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
Maximum Observed Plasma Concentration (Cmax) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Lead-in		Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Apparent Oral Clearance (CL/F) on Lead-in	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
Apparent Oral Clearance (CL/F) on Cycle 1 Day 21	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Apparent Volume of Distribution (Vz/F) on Lead-in	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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.	Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
Plasma Decay Half-life (t1/2) on Lead-in	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUCinf) on Lead-in		Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Average Plasma Concentration (Cavg) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Minimum Plasma Concentration (Cmin) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Pre-dose Concentration (Ctrough) on Cycle 1 Day 21		Pre-dose on Cycle 1 Day 21
Accumulation Ratio (Rac)	Accumulation ratio was calculated as AUCtau at steady state (Cycle 1/Day 21)/AUCtau on Cycle 1 Day 1.	Pre-dose, 1 hour post-dose on Cycle 1 Day 1; Pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose on Cycle 1 Day 21
Linearity Ratio (Rss)	Linearity ratio was calculated as AUCtau at steady state (Cycle 1/Day 21)/AUCinf after single dose (Lead-in Period [Day -6]).	Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96, 120 hours post-dose during the lead-in period (Day -6); Pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose on Cycle 1 Day 21
Renal Clearance on Cycle 1 Day 21	Renal clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by the kidneys.	Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Amount of Unchanged Drug Excreted in Urine (Over the Dosing Interval) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Percentage of Dose Excreted Unchanged in Urine (Over the Dosing Interval) on Cycle 1 Day 21		Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
Percentage of Participants With Objective Response (OR)	Percentage of participants with OR based on assessment of disease response according to disease specific response criteria (hematologic, cytogenetic and molecular responses). Results were analyzed based on malignancies, according to the planned analysis.	Baseline to end of study (up to 537 days)
Time to Progression (TTP)	Time in months from start of study treatment to first documentation of objective disease progression or death due to cancer, whichever comes first. TTP was calculated as (first event date - date of first dose of study medication + 1)/30.4. Disease progression was determined from oncologic assessment data (where data met the criteria for disease progression: categorized as early progressor from chronic phase [CP], progressor to accelerated phase [AP] or blast crisis [BC] from CP or return to CP, progressor to AP to BC, loss of confirmed complete hematologic response, or loss of major cytogenetic response).	Baseline to end of study, up to 36 months
Duration of Response (DR)	Time in months from the first documentation of objective response to objective disease progression or death due to any cancer. DR was calculated as [date of first documentation of progression or death due to cancer - date of first disease response + 1]/30.4. DR was calculated for the subgroup of participants with an objective disease response.	Baseline to end of study, up to 36 months
Progression-Free Survival (PFS)	Time in months from start of study treatment to first documentation of objective disease progression or death due to any cause. PFS was calculated as [first event date - date of first dose of study medication + 1]/30.4. Disease progression was determined from oncologic assessment data (where data met the criteria for disease progression: categorized as early progressor from CP, progressor to AP or BC from CP or return to CP, progressor to AP to BC, loss of confirmed complete hematologic response, or loss of major cytogenetic response; or from adverse event data (where the outcome was "Death").	Baseline to end of study, up to 36 months
Number of Participants With Increase From Baseline in Corrected QT Interval Using Fridericia's Formula (QTcF)	Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and the average was calculated. The time from ECG 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 <30 millisecond (msec), 30 to <60 msec and >=60 msec were summarized.	Screening; predose, 1, 4, 24 hours (hr) postdose on Day -6; predose, 1 hr postdose on Cycle 1 Day 1; 1 hr postdose on Cycle 1 Days 8, 15; Day 1 of every subsequent cycle; predose, 1, 2, 4, 24 hr postdose for Cycle 1 Day 21; EOT (max reached: Cycle 20)
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 the 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 maximum of 537 days
Number of Participants With Post-baseline QTcF Interval >= 500 Msec	Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and the average was calculated. QTcF was calculated. Participants with post-baseline absolute QTcF values >=500 msec were summarized.	Baseline up to maximum of 537 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.
• Martinelli G, Oehler VG, Papayannidis C, Courtney R, Shaik MN, Zhang X, O'Connell A, McLachlan KR, Zheng X, Radich J, Baccarani M, Kantarjian HM, Levin WJ, Cortes JE, Jamieson C. Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol. 2015 Aug;2(8):e339-46. doi: 10.1016/S2352-3026(15)00096-4. Epub 2015 Jul 26.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2010
• Primary Completion (Actual): September 26, 2012
• Study Completion (Actual): February 27, 2013

Study Registration Dates

• First Submitted: August 4, 2009
• First Submitted That Met QC Criteria: August 5, 2009
• First Posted (Estimated): August 6, 2009

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Chronic Myeloid Leukemia Myelofibrosis Myelodysplastic Syndrome Acute myeloid Leukemia Hedgehog inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: B1371001; 2009-011285-29 (EudraCT Number)

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.