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

Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00460421
• Other study ID #: 20010133
• Status: Completed
• Phase: Phase 1
• First received: April 12, 2007
• Last updated: November 4, 2014
• Start date: August 2006
• Est. completion date: May 2011

Study information

• Verified date: November 2014
• Source: Swedish Orphan Biovitrum
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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)

Other known NCT identifiers

• NCT00896506

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 16 Years

Eligibility

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)

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Leukemia

Intervention

Drug:
• Palifermin
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).

Radiation:
• Total Body irradiation

Drug:
• Chemotherapy
High dose etoposide, Cyclophosphamide

Locations

Country	Name	City	State
United States	Children´s Memorial	Chicago	Illinois
United States	University of Texas	Dallas	Texas
United States	Loma Linda University	Loma Linda	California
United States	Children´s Hospital	Los Angeles	California
United States	Regents of University of California	Los Angeles	California
United States	Children´s Hospital of Orange	Orange	California
United States	Arizona Cancer Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Swedish Orphan Biovitrum

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Approximately 1 month duration (Day -10 through Day +16)	Yes
Secondary	Incidence of Serum Palifermin Antibody Formation	The percentage of participants developing palifermin antibodies during the study was assessed.	Approximately 4 month duration (Through Day + 100 (+/- 40 days))	Yes
Secondary	Incidence of Severe Adverse Events (AEs)	The percentage of participants with a severe AE during the study was assessed.	Approximately 1 1/2 months duration (Through Day +30/End of Treatment)	Yes
Secondary	Incidence of Laboratory Abnormalities	The percentage of participants with a laboratory value outside the normal ranges during the study.	Approximately 1 1/2 months duration (Through Day +30/End of Treatment)	Yes
Secondary	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.	Day -10	No
Secondary	Pharmacokinetics of Palifermin, Volume of Distribution at Steady State (Vss) After the 1st IV Bolus Injection for Multiple Dose Levels		Day -10	No
Secondary	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.	Day -10	No
Secondary	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.	Day -8	No
Secondary	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.	Day -10	No
Secondary	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.	Day -8	No
Secondary	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)	Yes
Secondary	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)	Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)	Yes
Secondary	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)	Up to 4 years duration (Assessments performed on months 6, 9, 12 (+/- 30 Days) for the first year and then annually)	Yes