Clinical trial NCT00953758: A Study Of PF-04449913 In Select Hematologic Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hematologic Malignancies
Keywords: Chronic Myeloid Leukemia Myelofibrosis Myelodysplastic Syndrome Acute myeloid Leukemia Hedgehog inhibitor
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2009-08-06
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With First Cycle Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 Day 1 to end of Cycle 1 (28 days)
Secondary outcomes:
measure: 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
timeFrame: Baseline up to 28 days post last dose of study medication (maximum duration: 537 days)
measure: Percentage of Participants With Treatment-related Adverse Events (AEs), by NCI CTCAE Version 3.0) Grade
timeFrame: Baseline up to 28 days post last dose of study medication (maximum duration: 537 days)
measure: Number of Participants With Vital Signs Values Meeting Categorical Summarization Criteria
timeFrame: Screening up to maximum of 537 days
measure: Number of Participants With Laboratory Test Abnormalities
timeFrame: Screening to EOT (maximum duration: 537 days)
measure: Hedgehog Biomarker Modulation: Relative GLI1 Gene Expression to Baseline for Normal Skin on Cycle 1 Day 21
timeFrame: Baseline, Cycle 1 Day 21
measure: Maximum Observed Plasma Concentration (Cmax) on Lead-in
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
measure: Maximum Observed Plasma Concentration (Cmax) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) on Lead-in
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Apparent Oral Clearance (CL/F) on Lead-in
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
measure: Apparent Oral Clearance (CL/F) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Apparent Volume of Distribution (Vz/F) on Lead-in
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
measure: Plasma Decay Half-life (t1/2) on Lead-in
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
measure: Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUCinf) on Lead-in
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24, 48, 96 and 120 hours post-dose during the lead-in period (Day -6)
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Average Plasma Concentration (Cavg) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Minimum Plasma Concentration (Cmin) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Pre-dose Concentration (Ctrough) on Cycle 1 Day 21
timeFrame: Pre-dose on Cycle 1 Day 21
measure: Accumulation Ratio (Rac)
timeFrame: 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
measure: Linearity Ratio (Rss)
timeFrame: 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
measure: Renal Clearance on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Amount of Unchanged Drug Excreted in Urine (Over the Dosing Interval) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Percentage of Dose Excreted Unchanged in Urine (Over the Dosing Interval) on Cycle 1 Day 21
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on Cycle 1 Day 21
measure: Percentage of Participants With Objective Response (OR)
timeFrame: Baseline to end of study (up to 537 days)
measure: Time to Progression (TTP)
timeFrame: Baseline to end of study, up to 36 months
measure: Duration of Response (DR)
timeFrame: Baseline to end of study, up to 36 months
measure: Progression-Free Survival (PFS)
timeFrame: Baseline to end of study, up to 36 months
measure: Number of Participants With Increase From Baseline in Corrected QT Interval Using Fridericia's Formula (QTcF)
timeFrame: 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)
measure: Number of Participants With Decrease From Baseline in QTcF Interval
timeFrame: Baseline up to maximum of 537 days
measure: Number of Participants With Post-baseline QTcF Interval >= 500 Msec
timeFrame: Baseline up to maximum of 537 days
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD Medical Center - La Jolla
state: California
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: San Diego
country: United States
facility: UCSD Medical Center - Hillcrest
state: California
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center, Seattle Cancer Care Alliance
state: Washington
city: Bologna
country: Italy
facility: U.O. di Ematologia
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.