This study examines the effect of a small molecule inhibitor to the Sonic Hedgehog pathway on select hematologic malignancies.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
47
Escalating doses of PF-04449913 administered as tablets PO QD continuously in 28 day cycles
UCSD Medical Center - La Jolla
La Jolla, California, United States
Moores UCSD Cancer Center
La Jolla, California, United States
UCSD Medical Center - Hillcrest
San Diego, California, United States
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States
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
Time frame: Cycle 1 Day 1 to end of Cycle 1 (28 days)
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.
Time frame: 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.
Time frame: Baseline up to 28 days post last dose of study medication (maximum duration: 537 days)
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University of Washington Medical Center, Seattle Cancer Care Alliance
Seattle, Washington, United States
U.O. di Ematologia
Bologna, Italy
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.
Time frame: 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).
Time frame: 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.
Time frame: Baseline, Cycle 1 Day 21
Maximum Observed Plasma Concentration (Cmax) on Lead-in
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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 \[Day -6\]).
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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").
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to maximum of 537 days