A Study Of PF-04449913 In Select Hematologic Malignancies

Hematologic Malignancies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00953758
• Other study ID #: B1371001
• Secondary ID: 2009-011285-29
• Status: Completed
• Phase: Phase 1
• Start date: March 3, 2010
• Est. completion date: February 27, 2013

Study information

• Verified date: November 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: February 27, 2013
• Est. primary completion date: September 26, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hematologic Malignancies
• Hematologic Neoplasms
• Neoplasms

Intervention

Drug:
• PF-04449913
Escalating doses of PF-04449913 administered as tablets PO QD continuously in 28 day cycles

Locations

Country	Name	City	State
Italy	U.O. di Ematologia	Bologna
United States	The University of Texas M.D. Anderson Cancer Center	Houston	Texas
United States	Moores UCSD Cancer Center	La Jolla	California
United States	UCSD Medical Center - La Jolla	La Jolla	California
United States	UCSD Medical Center - Hillcrest	San Diego	California
United States	University of Washington Medical Center, Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Pre-dose Concentration (Ctrough) on Cycle 1 Day 21		Pre-dose on Cycle 1 Day 21
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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

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