Clinical trial NCT00460421: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Keywords: Oral Mucositis
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Palifermin
Kepivance
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
First posted: 2007-04-16
Enrollment: 27
Sex: ALL
Minimum age (years): 1
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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)


Eligibility criteria: Inclusion Criteria:

1. Acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) requiring HSCT
2. Age ≥ 1 and ≤ 16 years at screening
3. Lansky performance status \> 60%
4. 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)
5. Identification of an HLA-compatible donor per institutional standards
6. 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.
7. Serum amylase and lipase: ≤ 1.2 x IULN
8. Negative serum/urine pregnancy test for females with childbearing potential within 4 days before administration of the first palifermin dose
9. 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:

1. Prior treatment with palifermin or other keratinocyte growth factors
2. Received an investigational product or device, with the exception investigational stem cell separators, in another clinical trial within 30 days before enrollment.
3. Known to have a life threatening infection not responding well to treatment
4. Past history of veno-occlusive disease of the liver
5. Known sensitivity to any Escherichia coli-derived products with grade 3 to 4 allergies to L-asparaginase \[grade 1 to 2 allergies to L-asparaginase will be allowed\].
6. Receiving glutamine or any other medication to reduce the incidence of oral mucositis (OM) within 30 days before enrollment
7. Previous or concurrent malignancy other than entry diagnostic criteria and/or solid organ transplantation and/or treatment of congenital immunodeficiency
8. History of pancreatitis
9. Breastfeeding (giving)

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLTs)
timeFrame: Approximately 1 month duration (Day -10 through Day +16)
Secondary outcomes:
measure: Incidence of Serum Palifermin Antibody Formation
timeFrame: Approximately 4 month duration (Through Day + 100 (+/- 40 days))
measure: Incidence of Severe Adverse Events (AEs)
timeFrame: Approximately 1 1/2 months duration (Through Day +30/End of Treatment)
measure: Incidence of Laboratory Abnormalities
timeFrame: Approximately 1 1/2 months duration (Through Day +30/End of Treatment)
measure: Pharmacokinetics of Palifermin, Clearence (CL) After the 1st Intravenous (IV) Bolus Injection for Multiple Dose Levels
timeFrame: Day -10
measure: Pharmacokinetics of Palifermin, Volume of Distribution at Steady State (Vss) After the 1st IV Bolus Injection for Multiple Dose Levels
timeFrame: Day -10
measure: Pharmacokinetics of Palifermin, Terminal Half-life (t½,z) After the 1st IV Bolus Injection for Multiple Dose Levels
timeFrame: Day -10
measure: Pharmacokinetics of Palifermin, t½,z After the 3rd IV Bolus Injection for Multiple Dose Levels
timeFrame: Day -8
measure: 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
timeFrame: Day -10
measure: Pharmacokinetics of Palifermin, AUCtau After the 3rd IV Bolus Injection for Multiple Dose Levels
timeFrame: Day -8
measure: Long-Term Follow-Up: Incidence of Secondary Malignancies
timeFrame: Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
measure: Long-Term Follow-Up: Progression Free Survival
timeFrame: Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
measure: Long-Term Follow-Up: Overall Survival
timeFrame: Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University
state: California
city: Los Angeles
country: United States
facility: Children´s Hospital
state: California
city: Los Angeles
country: United States
facility: Regents of University of California
state: California
city: Orange
country: United States
facility: Children´s Hospital of Orange
state: California
city: Chicago
country: United States
facility: Children´s Memorial
state: Illinois
city: Dallas
country: United States
facility: University of Texas
state: Texas
Study officials:
affiliation: Swedish Orphan Biovitrum AB
name: Maarten de Chateau, MD, PhD
role: STUDY_DIRECTOR
References: