Back to resultsA Phase 1 Dose-escalation Study to Evaluate the Safety and Pharmacokinetics (PK) of Palifermin in Subjects With Acute Leukemias Undergoing HSCT
Primary Purpose
Leukemia
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Palifermin
Total Body irradiation
Chemotherapy
Sponsored by
About this trial
This is an interventional prevention trial for Leukemia focused on measuring Oral Mucositis, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Palifermin, Kepivance
Eligibility Criteria
Inclusion Criteria:
- Acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) requiring HSCT
- Age ≥ 1 and ≤ 16 years at screening
- Lansky performance status > 60%
Candidate for allogeneic HSCT protocol:
- Adequate kidney function: Serum creatinine: ≤ 1.5 mg/dL or creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73m2
- Adequate liver function: Serum total bilirubin: ≤ 2.0 mg/dl; aspartate transaminase (AST)/alanine aminotransferase (ALT) ≤ 4.0 x institutional upper limits of normal (IULN); Albumin ≥ 2 g/dL
- Adequate cardiac function: shortening fraction > 29% documented by echocardiogram, or ejection fraction ≥ 50% documented by multigated acquisition scan (MUGA).
- Adequate pulmonary function documented by corrected lung diffusion capacity test (DLCO) > 50% or oxygen saturation of ≥ 92% on room air if unable to perform pulmonary function tests
- Negative for human immunodeficiency virus (HIV), hepatitis C virus (HCV), human T cell lymphotropic virus (HTLV)
- Identification of an HLA-compatible donor per institutional standards
- Assent from a minor (if the child is capable of giving assent) per Department of Health and Human Services (DHHS) guidelines listed in 21CFR 50.55 and local Institutional Review Board (IRB) standards.
- Serum amylase and lipase: ≤ 1.2 x IULN
- Negative serum/urine pregnancy test for females with childbearing potential within 4 days before administration of the first palifermin dose
- Agreement by males and females of reproductive potential to use an effective means of contraception 30 days prior to enrollment through Day +30 (end of treatment)
Exclusion Criteria:
- Prior treatment with palifermin or other keratinocyte growth factors
- Received an investigational product or device, with the exception investigational stem cell separators, in another clinical trial within 30 days before enrollment.
- Known to have a life threatening infection not responding well to treatment
- Past history of veno-occlusive disease of the liver
- Known sensitivity to any Escherichia coli-derived products with grade 3 to 4 allergies to L-asparaginase [grade 1 to 2 allergies to L-asparaginase will be allowed].
- Receiving glutamine or any other medication to reduce the incidence of oral mucositis (OM) within 30 days before enrollment
- Previous or concurrent malignancy other than entry diagnostic criteria and/or solid organ transplantation and/or treatment of congenital immunodeficiency
- History of pancreatitis
- Breastfeeding (giving)
Sites / Locations
- Arizona Cancer Center
- Loma Linda University
- Children´s Hospital
- Regents of University of California
- Children´s Hospital of Orange
- Children´s Memorial
- University of Texas
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Palifermin Dose Escalation
Arm Description
A 3 dose escalation design. Sucessive cohorts of patient (9 patients per group) will each be administered Palifermin as an IV bolus injection (40, 60 or 80 µg) once daily for 3 consecutive days before the start of conditioning regimen (chemotherapy and total body irradiation) and after HCST (Day -10, -9, -8 and Day 0, +1, +2 respectively).
Outcomes
Primary Outcome Measures
Incidence of Dose Limiting Toxicities (DLTs)
A DLT is appearance of side effects during treatment severe enough to prevent further increase in dosage or strength of treatment agent, or to prevent continuation of treatment at any dosage level.
A DLT was defined as: Grade 3 or 4 AE [based on Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE) v3.0] considered by the investigator to be related to palifermin with the exceptions: Grade 3 erythema, pruritus or rash that resolves within 7 days of the last dose of palifermin.
The percentage of particiapnts with a DLT during the study was assessed.
Secondary Outcome Measures
Incidence of Serum Palifermin Antibody Formation
The percentage of participants developing palifermin antibodies during the study was assessed.
Incidence of Severe Adverse Events (AEs)
The percentage of participants with a severe AE during the study was assessed.
Incidence of Laboratory Abnormalities
The percentage of participants with a laboratory value outside the normal ranges during the study.
Pharmacokinetics of Palifermin, Clearence (CL) After the 1st Intravenous (IV) Bolus Injection for Multiple Dose Levels
Clearence was estimated as dose divided by the area under serum concentration-time curve from time zero to infinity where the dose was given in amount palifermin actually administered.
Pharmacokinetics of Palifermin, Volume of Distribution at Steady State (Vss) After the 1st IV Bolus Injection for Multiple Dose Levels
Pharmacokinetics of Palifermin, Terminal Half-life (t½,z) After the 1st IV Bolus Injection for Multiple Dose Levels
The terminal half-life was calculated as ln(2)/lambda,z where lambda,z was estimated using at least three quantifiable serum concentrations of the terminal log-linear phase.
Pharmacokinetics of Palifermin, t½,z After the 3rd IV Bolus Injection for Multiple Dose Levels
The terminal half-life was calculated as ln(2)/lambda,z where lambda,z was estimated using at least three quantifiable serum concentrations of the terminal log-linear phase.
Pharmacokinetics of Palifermin, Area Under the Concentration Time Curve From Zero to the End of the Dosing Interval (AUCtau) After the 1st IV Bolus Injection for Multiple Dose Levels
The AUC was estimated using the linear/log trapezoidal method for AUC0-tau from time zero to the end of the dosing interval (24 hours (hrs) post-dose)
Data collected at time points: 0, 2 minutes (min), 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6, hrs, 10, hrs and 24 hrs post-dose.
Pharmacokinetics of Palifermin, AUCtau After the 3rd IV Bolus Injection for Multiple Dose Levels
The AUC was estimated using the linear/log trapezoidal method for AUC0-tau from time zero to the end of the dosing interval (24 hours (hrs) post-dose)
Data collected at time points: 0, 2 minutes (min), 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6, hrs, 10, hrs and 24 hrs post-dose.
Long-Term Follow-Up: Incidence of Secondary Malignancies
Long-Term Follow-Up: Progression Free Survival
Progression free survival (PFS) was defined as the number of days between the date of first investigational product administration and the date when physical or radiological evidence of disease progression is determined or death (regardless of cause)
Long-Term Follow-Up: Overall Survival
Overall survival was defined as the number of days from the date of first investigational product administration to the date of death (regardless of cause)
Full Information
NCT ID
NCT00460421
First Posted
April 12, 2007
Last Updated
November 4, 2014
Sponsor
Swedish Orphan Biovitrum
1. Study Identification
Unique Protocol Identification Number
NCT00460421
Brief Title
A Phase 1 Dose-escalation Study to Evaluate the Safety and Pharmacokinetics (PK) of Palifermin in Subjects With Acute Leukemias Undergoing HSCT
Official Title
A Phase 1 Dose-escalation Study to Evaluate the Safety and Pharmacokinetics (PK) of Palifermin in Pediatric Subjects With Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
Study Type
Interventional
2. Study Status
Record Verification Date
November 2014
Overall Recruitment Status
Completed
Study Start Date
August 2006 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
May 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Swedish Orphan Biovitrum
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
20010133 is an open-label, dose escalation study in pediatric patients with acute leukemias receiving myelotoxic therapy (high dose etoposide, cyclophosphamide and total body irradiation [TBI]) followed by hematopoietic stem cell transplant (HSCT). The study will evaluate the safety and pharmacokinetics of palifermin in pediatric patients. Three doses (40 μg/kg/day, 60 μg/kg/day, and 80 μg/kg/day) are to be evaluated in each age group (1 to 2, 3 to 11, and 12 to 16 years, respectively) using a conventional dose escalation design. Palifermin is administered for 3 consecutive days (Day -10 to Day -8, respectively) before the start of the conditioning regimen and for 3 consecutive days (Day 0 to Day +2) following HSCT. Patients will be enrolled simultaneously to each age group to identify a safe, well tolerated, efficacious dose in each age group. Patients will also be followed for secondary malignancies, progression-free survival (PFS) and overall survival (OS)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia
Keywords
Oral Mucositis, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Palifermin, Kepivance
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Palifermin Dose Escalation
Arm Type
Experimental
Arm Description
A 3 dose escalation design. Sucessive cohorts of patient (9 patients per group) will each be administered Palifermin as an IV bolus injection (40, 60 or 80 µg) once daily for 3 consecutive days before the start of conditioning regimen (chemotherapy and total body irradiation) and after HCST (Day -10, -9, -8 and Day 0, +1, +2 respectively).
Intervention Type
Drug
Intervention Name(s)
Palifermin
Other Intervention Name(s)
Kepivance
Intervention Description
Palifermin will be administered as an IV bolus injection (40, 60 or 80 µg/kg/day)once daily for 3 consecutive days before the start of conditioning regimen and after HCST (Day -10, -9, -8 and Day 0, +1, +2 respectively).
Intervention Type
Radiation
Intervention Name(s)
Total Body irradiation
Intervention Type
Drug
Intervention Name(s)
Chemotherapy
Intervention Description
High dose etoposide, Cyclophosphamide
Primary Outcome Measure Information:
Title
Incidence of Dose Limiting Toxicities (DLTs)
Description
A DLT is appearance of side effects during treatment severe enough to prevent further increase in dosage or strength of treatment agent, or to prevent continuation of treatment at any dosage level.
A DLT was defined as: Grade 3 or 4 AE [based on Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE) v3.0] considered by the investigator to be related to palifermin with the exceptions: Grade 3 erythema, pruritus or rash that resolves within 7 days of the last dose of palifermin.
The percentage of particiapnts with a DLT during the study was assessed.
Time Frame
Approximately 1 month duration (Day -10 through Day +16)
Secondary Outcome Measure Information:
Title
Incidence of Serum Palifermin Antibody Formation
Description
The percentage of participants developing palifermin antibodies during the study was assessed.
Time Frame
Approximately 4 month duration (Through Day + 100 (+/- 40 days))
Title
Incidence of Severe Adverse Events (AEs)
Description
The percentage of participants with a severe AE during the study was assessed.
Time Frame
Approximately 1 1/2 months duration (Through Day +30/End of Treatment)
Title
Incidence of Laboratory Abnormalities
Description
The percentage of participants with a laboratory value outside the normal ranges during the study.
Time Frame
Approximately 1 1/2 months duration (Through Day +30/End of Treatment)
Title
Pharmacokinetics of Palifermin, Clearence (CL) After the 1st Intravenous (IV) Bolus Injection for Multiple Dose Levels
Description
Clearence was estimated as dose divided by the area under serum concentration-time curve from time zero to infinity where the dose was given in amount palifermin actually administered.
Time Frame
Day -10
Title
Pharmacokinetics of Palifermin, Volume of Distribution at Steady State (Vss) After the 1st IV Bolus Injection for Multiple Dose Levels
Time Frame
Day -10
Title
Pharmacokinetics of Palifermin, Terminal Half-life (t½,z) After the 1st IV Bolus Injection for Multiple Dose Levels
Description
The terminal half-life was calculated as ln(2)/lambda,z where lambda,z was estimated using at least three quantifiable serum concentrations of the terminal log-linear phase.
Time Frame
Day -10
Title
Pharmacokinetics of Palifermin, t½,z After the 3rd IV Bolus Injection for Multiple Dose Levels
Description
The terminal half-life was calculated as ln(2)/lambda,z where lambda,z was estimated using at least three quantifiable serum concentrations of the terminal log-linear phase.
Time Frame
Day -8
Title
Pharmacokinetics of Palifermin, Area Under the Concentration Time Curve From Zero to the End of the Dosing Interval (AUCtau) After the 1st IV Bolus Injection for Multiple Dose Levels
Description
The AUC was estimated using the linear/log trapezoidal method for AUC0-tau from time zero to the end of the dosing interval (24 hours (hrs) post-dose)
Data collected at time points: 0, 2 minutes (min), 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6, hrs, 10, hrs and 24 hrs post-dose.
Time Frame
Day -10
Title
Pharmacokinetics of Palifermin, AUCtau After the 3rd IV Bolus Injection for Multiple Dose Levels
Description
The AUC was estimated using the linear/log trapezoidal method for AUC0-tau from time zero to the end of the dosing interval (24 hours (hrs) post-dose)
Data collected at time points: 0, 2 minutes (min), 15 min, 30 min, 60 min, 2 hrs, 4 hrs, 6, hrs, 10, hrs and 24 hrs post-dose.
Time Frame
Day -8
Title
Long-Term Follow-Up: Incidence of Secondary Malignancies
Time Frame
Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
Title
Long-Term Follow-Up: Progression Free Survival
Description
Progression free survival (PFS) was defined as the number of days between the date of first investigational product administration and the date when physical or radiological evidence of disease progression is determined or death (regardless of cause)
Time Frame
Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
Title
Long-Term Follow-Up: Overall Survival
Description
Overall survival was defined as the number of days from the date of first investigational product administration to the date of death (regardless of cause)
Time Frame
Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) requiring HSCT
Age ≥ 1 and ≤ 16 years at screening
Lansky performance status > 60%
Candidate for allogeneic HSCT protocol:
Adequate kidney function: Serum creatinine: ≤ 1.5 mg/dL or creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73m2
Adequate liver function: Serum total bilirubin: ≤ 2.0 mg/dl; aspartate transaminase (AST)/alanine aminotransferase (ALT) ≤ 4.0 x institutional upper limits of normal (IULN); Albumin ≥ 2 g/dL
Adequate cardiac function: shortening fraction > 29% documented by echocardiogram, or ejection fraction ≥ 50% documented by multigated acquisition scan (MUGA).
Adequate pulmonary function documented by corrected lung diffusion capacity test (DLCO) > 50% or oxygen saturation of ≥ 92% on room air if unable to perform pulmonary function tests
Negative for human immunodeficiency virus (HIV), hepatitis C virus (HCV), human T cell lymphotropic virus (HTLV)
Identification of an HLA-compatible donor per institutional standards
Assent from a minor (if the child is capable of giving assent) per Department of Health and Human Services (DHHS) guidelines listed in 21CFR 50.55 and local Institutional Review Board (IRB) standards.
Serum amylase and lipase: ≤ 1.2 x IULN
Negative serum/urine pregnancy test for females with childbearing potential within 4 days before administration of the first palifermin dose
Agreement by males and females of reproductive potential to use an effective means of contraception 30 days prior to enrollment through Day +30 (end of treatment)
Exclusion Criteria:
Prior treatment with palifermin or other keratinocyte growth factors
Received an investigational product or device, with the exception investigational stem cell separators, in another clinical trial within 30 days before enrollment.
Known to have a life threatening infection not responding well to treatment
Past history of veno-occlusive disease of the liver
Known sensitivity to any Escherichia coli-derived products with grade 3 to 4 allergies to L-asparaginase [grade 1 to 2 allergies to L-asparaginase will be allowed].
Receiving glutamine or any other medication to reduce the incidence of oral mucositis (OM) within 30 days before enrollment
Previous or concurrent malignancy other than entry diagnostic criteria and/or solid organ transplantation and/or treatment of congenital immunodeficiency
History of pancreatitis
Breastfeeding (giving)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maarten de Chateau, MD, PhD
Organizational Affiliation
Swedish Orphan Biovitrum AB
Official's Role
Study Director
Facility Information:
Facility Name
Arizona Cancer Center
City
Tucson
State/Province
Arizona
Country
United States
Facility Name
Loma Linda University
City
Loma Linda
State/Province
California
Country
United States
Facility Name
Children´s Hospital
City
Los Angeles
State/Province
California
Country
United States
Facility Name
Regents of University of California
City
Los Angeles
State/Province
California
Country
United States
Facility Name
Children´s Hospital of Orange
City
Orange
State/Province
California
Country
United States
Facility Name
Children´s Memorial
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
University of Texas
City
Dallas
State/Province
Texas
Country
United States
12. IPD Sharing Statement
Learn more about this trial
A Phase 1 Dose-escalation Study to Evaluate the Safety and Pharmacokinetics (PK) of Palifermin in Subjects With Acute Leukemias Undergoing HSCT
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