A Study Of PF-04449913 In Select Hematologic Malignancies
- Registration Number
- NCT00953758
- Lead Sponsor
- Pfizer
- Brief Summary
This study examines the effect of a small molecule inhibitor to the Sonic Hedgehog pathway on select hematologic malignancies.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 47
- 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
- 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 & 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) Cycle 1 Day 1 to end of Cycle 1 (28 days) 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
- Secondary Outcome Measures
Name Time Method Hedgehog Biomarker Modulation: Relative GLI1 Gene Expression to Baseline for Normal Skin on Cycle 1 Day 21 Baseline, 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.
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 Baseline up to 28 days post last dose of study medication (maximum duration: 537 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 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.
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 Percentage of Participants With Treatment-related Adverse Events (AEs), by NCI CTCAE Version 3.0) Grade Baseline up to 28 days post last dose of study medication (maximum duration: 537 days) 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.
Apparent Oral Clearance (CL/F) on Cycle 1 Day 21 Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose 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.
Apparent Volume of Distribution (Vz/F) 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) 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.
Plasma Decay Half-life (t1/2) 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) Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
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) Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria Screening up to maximum of 537 days 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.
Number of Participants With Laboratory Test Abnormalities Screening to EOT (maximum duration: 537 days) 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 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 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 Apparent Oral Clearance (CL/F) 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) 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.
Percentage of Participants With Objective Response (OR) Baseline to end of study (up to 537 days) 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.
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) 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 Accumulation ratio was calculated as AUCtau at steady state (Cycle 1/Day 21)/AUCtau on Cycle 1 Day 1.
Linearity Ratio (Rss) 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 Linearity ratio was calculated as AUCtau at steady state (Cycle 1/Day 21)/AUCinf after single dose (Lead-in Period \[Day -6\]).
Renal Clearance on Cycle 1 Day 21 Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose 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 to Progression (TTP) Baseline to end of study, up to 36 months 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).
Duration of Response (DR) Baseline to end of study, up to 36 months 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.
Progression-Free Survival (PFS) Baseline to end of study, up to 36 months 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").
Number of Participants With Increase From Baseline in Corrected QT Interval Using Fridericia's Formula (QTcF) 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) 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.
Number of Participants With Decrease From Baseline in QTcF Interval Baseline up to maximum of 537 days 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.
Number of Participants With Post-baseline QTcF Interval >= 500 Msec Baseline up to maximum of 537 days 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.
Trial Locations
- Locations (6)
University of Washington Medical Center, Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
UCSD Medical Center - Hillcrest
🇺🇸San Diego, California, United States
UCSD Medical Center - La Jolla
🇺🇸La Jolla, California, United States
The University of Texas M.D. Anderson Cancer Center
🇺🇸Houston, Texas, United States
U.O. di Ematologia
🇮🇹Bologna, Italy
Moores UCSD Cancer Center
🇺🇸La Jolla, California, United States