A Phase 1 Dose-escalation Study to Evaluate the Safety and Pharmacokinetics (PK) of Palifermin in Subjects With Acute Leukemias Undergoing HSCT

Phase 1

Completed

Conditions: Leukemia

Interventions: Drug: Palifermin
Radiation: Total Body irradiation
Drug: Chemotherapy

Registration Number: NCT00460421

Lead Sponsor: Swedish Orphan Biovitrum

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)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Palifermin Dose Escalation	Chemotherapy	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).
Palifermin Dose Escalation	Total Body irradiation	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).
Palifermin Dose Escalation	Palifermin	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).

Primary Outcome Measures

Name	Time	Method
Incidence of Dose Limiting Toxicities (DLTs)	Approximately 1 month duration (Day -10 through Day +16)	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

Name	Time	Method
Incidence of Serum Palifermin Antibody Formation	Approximately 4 month duration (Through Day + 100 (+/- 40 days))	The percentage of participants developing palifermin antibodies during the study was assessed.
Pharmacokinetics of Palifermin, Volume of Distribution at Steady State (Vss) After the 1st IV Bolus Injection for Multiple Dose Levels	Day -10
Pharmacokinetics of Palifermin, Terminal Half-life (t½,z) After the 1st IV Bolus Injection for Multiple Dose Levels	Day -10	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.
Long-Term Follow-Up: Incidence of Secondary Malignancies	Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)
Incidence of Severe Adverse Events (AEs)	Approximately 1 1/2 months duration (Through Day +30/End of Treatment)	The percentage of participants with a severe AE during the study was assessed.
Incidence of Laboratory Abnormalities	Approximately 1 1/2 months duration (Through Day +30/End of Treatment)	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	Day -10	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, t½,z After the 3rd IV Bolus Injection for Multiple Dose Levels	Day -8	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	Day -10	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	Day -8	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: Progression Free Survival	Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)	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	Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)	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)

Trial Locations

Locations (7): University of Texas
🇺🇸
Dallas, Texas, United States
Arizona Cancer Center
🇺🇸
Tucson, Arizona, United States
Loma Linda University
🇺🇸
Loma Linda, California, United States
Children´s Hospital of Orange
🇺🇸
Orange, California, United States
Children´s Hospital
🇺🇸
Los Angeles, California, United States
Children´s Memorial
🇺🇸
Chicago, Illinois, United States
Regents of University of California
🇺🇸
Los Angeles, California, United States