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

• Sponsor: Swedish Orphan Biovitrum (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00460421
• Collaborator: (none)
• Enrollment: 27
• Locations: 7
• Arm: 1
• Duration (Months): 57
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

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)

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Palifermin; Radiation: Total Body irradiation; Drug: Chemotherapy	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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 Start Date: Aug 1, 2006
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Palifermin Dose Escalation 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).	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).; Other Names: Kepivance ; Radiation: Total Body irradiation; Drug: Chemotherapy; High dose etoposide, Cyclophosphamide

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. Pharmacokinetics of Palifermin, Volume of Distribution at Steady State (Vss) After the 1st IV Bolus Injection for Multiple Dose Levels [Day -10]

6. 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.

7. 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.

8. 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.

9. 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.

10. 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)]

11. 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)

12. 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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 16 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

1. Identification of an HLA-compatible donor per institutional standards

2. 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.

3. Serum amylase and lipase: ≤ 1.2 x IULN

4. Negative serum/urine pregnancy test for females with childbearing potential within 4 days before administration of the first palifermin dose

5. 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center	Tucson	Arizona	United States
2	Loma Linda University	Loma Linda	California	United States
3	Children´s Hospital	Los Angeles	California	United States
4	Regents of University of California	Los Angeles	California	United States
5	Children´s Hospital of Orange	Orange	California	United States
6	Children´s Memorial	Chicago	Illinois	United States
7	University of Texas	Dallas	Texas	United States

Sponsors and Collaborators

• Swedish Orphan Biovitrum

Investigators

• Study Director: Maarten de Chateau, MD, PhD, Swedish Orphan Biovitrum AB

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Swedish Orphan Biovitrum
• ClinicalTrials.gov Identifier: NCT00460421
• Other Study ID Numbers: 20010133; NCT00896506
• First Posted: Apr 16, 2007
• Last Update Posted: Dec 5, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by Swedish Orphan Biovitrum: Oral Mucositis; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Palifermin; Kepivance
• Additional relevant MeSH terms: Leukemia

Study Results

Participant Flow

Recruitment Details	This phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of palifermin in pediatric subjects with acute leukemias undergoing myeloblative therapy and allogeneic hematopoietic stem cell transplant (HSCT) was performed in 7 centers in USA between 2006 and 2011.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Period Title: Overall Study
STARTED	9	9	9
COMPLETED	9	9	9
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day	Total
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Total of all reporting groups
Overall Participants	9	9	9	27
Age (Count of Participants)
<=18 years	9 100%	9 100%	9 100%	27 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.4 (6.3)	7.4 (5.6)	8.0 (6.6)	7.6 (5.9)
Sex: Female, Male (Count of Participants)
Female	3 33.3%	4 44.4%	5 55.6%	12 44.4%
Male	6 66.7%	5 55.6%	4 44.4%	15 55.6%
Region of Enrollment (participants) [Number]
United States	9 100%	9 100%	9 100%	27 100%

Outcome Measures

1. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Number [percentage of participants]	0 0%	0 0%	0 0%

2. Secondary Outcome

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))

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Number [percentage of participants]	0 0%	0 0%	0 0%

3. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Number [percentage of participants]	100 1111.1%	100 1111.1%	100 1111.1%

4. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Number [percentage of participants]	100 1111.1%	100 1111.1%	100 1111.1%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. This set consists of all subjects who receive at least one dose of palifermin and who have a sufficient number of serum concentration data points to allow calculation of the pharmacokinetic variables.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Median (Full Range) [mL/hr/kg]	1954.84	2164.87	3932.30

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. This set consists of all subjects who receive at least one dose of palifermin and who have a sufficient number of serum concentration data points to allow calculation of the pharmacokinetic variables.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Median (Full Range) [mL/kg]	2552.79	5134.84	8580.91

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. This set consists of all subjects who receive at least one dose of palifermin and who have a sufficient number of serum concentration data points to allow calculation of the pharmacokinetic variables.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Median (Full Range) [hour]	2.91	3.05	3.68

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. This set consists of all subjects who receive at least one dose of palifermin and who have a sufficient number of serum concentration data points to allow calculation of the pharmacokinetic variables.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Median (Full Range) [hour]	3.40	3.89	2.99

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. This set consists of all subjects who receive at least one dose of palifermin and who have a sufficient number of serum concentration data points to allow calculation of the pharmacokinetic variables.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Median (Full Range) [ng*hr/mL]	16.54	18.14	38.44

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. This set consists of all subjects who receive at least one dose of palifermin and who have a sufficient number of serum concentration data points to allow calculation of the pharmacokinetic variables.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Median (Full Range) [ng*hr/mL]	18.32	17.97	34.74

11. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts
Measure Participants	9	9	9
Number [percentage of participants]	0 0%	11 122.2%	0 0%

12. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day	All Subjects
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	All subjects from each age group (1-2, 3-11, 12-16 years)
Measure Participants	9	9	9	27
Median (Full Range) [months]	NA	NA	NA	36

13. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set. This set consisted of subjects who received at least one dose of palifermin.

Arm/Group Title	Palifermin 40 µg/kg/Day	Palifermin 60 µg/kg/Day	Palifermin 80 µg/kg/Day	All Subjects
Arm/Group Description	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	Three subjects from each age group (1-2, 3-11, 12-16 years) were sequentially enrolled into the 3 planned dosing cohorts	All subjects from each age group (1-2, 3-11, 12-16 years)
Measure Participants	9	9	9	27
Median (Full Range) [months]	NA	NA	NA	36

Adverse Events

Time Frame	Adverse events collected from signed informed consent to Day 30, i.e. a period of up to 71 days.
Arm/Group Title	All Subjects
Arm/Group Description	All subjects from each age group (1-2, 3-11, 12-16 years)
All Cause Mortality
	All Subjects
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	5/27 (18.5%)
Cardiac disorders
Cardiac arrest	1/27 (3.7%)	1
Gastrointestinal disorders
Diarrhoea	2/27 (7.4%)	2
Vomiting	1/27 (3.7%)	1
Ascites	1/27 (3.7%)	1
Gastrointestinal haemorrhage	1/27 (3.7%)	1
General disorders
Pyrexia	2/27 (7.4%)	2
Infections and infestations
Enterococcal infection	1/27 (3.7%)	1
Septic chock	1/27 (3.7%)	1
Investigations
Urine output decreased	1/27 (3.7%)	1
Nervous system disorders
Cerebral haemorrhage	1/27 (3.7%)	1
Convulsion	1/27 (3.7%)	1
Haemorrhage intracranial	1/27 (3.7%)	1
Renal and urinary disorders
Renal failure	2/27 (7.4%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/27 (3.7%)	1
Vascular disorders
Hypotension	1/27 (3.7%)	1
Venoocclusive disease	2/27 (7.4%)	2
Other (Not Including Serious) Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	3/27 (11.1%)
Cardiac disorders
Pericardial effusion	2/27 (7.4%)
Tachycardia	7/27 (25.9%)
Ear and labyrinth disorders
Ear pain	2/27 (7.4%)
Eye disorders
Dry eye	2/27 (7.4%)
Gastrointestinal disorders
Abdominal pain	15/27 (55.6%)
Ascites	2/27 (7.4%)
Constipation	5/27 (18.5%)
Diarrhoea	19/27 (70.4%)
Dyspepsia	2/27 (7.4%)
Flatulence	2/27 (7.4%)
Gastritis	2/27 (7.4%)
Gingival hyperplasia	2/27 (7.4%)
Haematemesis	2/27 (7.4%)
Lip dry	2/27 (7.4%)
Mouth haemorrhage	2/27 (7.4%)
Nausea	21/27 (77.8%)
Oesophagitis	2/27 (7.4%)
Oral pain	2/27 (7.4%)
Perianal erythema	2/27 (7.4%)
Proctalgia	4/27 (14.8%)
Vomiting	23/27 (85.2%)
General disorders
Catheter related complication	6/27 (22.2%)
Catheter site pain	5/27 (18.5%)
Chills	3/27 (11.1%)
Face oedema	3/27 (11.1%)
Fatigue	7/27 (25.9%)
Irritability	4/27 (14.8%)
Oedema	4/27 (14.8%)
Oedema peripheral	5/27 (18.5%)
Pain	4/27 (14.8%)
Pyrexia	22/27 (81.5%)
Hepatobiliary disorders
Hepatomegaly	2/27 (7.4%)
Hyperbilirubinaemia	5/27 (18.5%)
Immune system disorders
Acute graft versus host disease in skin	5/27 (18.5%)
Infections and infestations
Alpha haemolytic streptococcal infection	3/27 (11.1%)
Bacteraemia	2/27 (7.4%)
Clostridium difficile colitis	3/27 (11.1%)
Enterococcal sepsis	3/27 (11.1%)
Fungal infection	2/27 (7.4%)
Parotitis	3/27 (11.1%)
Pneumonia	2/27 (7.4%)
Sinusitis	3/27 (11.1%)
Staphylococcal infection	4/27 (14.8%)
Urinary tract infection enterococcal	2/27 (7.4%)
Injury, poisoning and procedural complications
Contusion	2/27 (7.4%)
Excoriation	4/27 (14.8%)
Head injury	2/27 (7.4%)
Investigations
Blood bilirubin increased	2/27 (7.4%)
Occult blood positive	2/27 (7.4%)
Weight decreased	2/27 (7.4%)
Weight increased	4/27 (14.8%)
Metabolism and nutrition disorders
Anorexia	18/27 (66.7%)
Decreased appetite	2/27 (7.4%)
Fluid retention	5/27 (18.5%)
Hyperglycaemia	5/27 (18.5%)
Hyperkalaemia	3/27 (11.1%)
Hypoalbuminaemia	3/27 (11.1%)
Hypocalcaemia	5/27 (18.5%)
Hypokalaemia	9/27 (33.3%)
Hypomagnesaemia	10/27 (37%)
Hyponatraemia	5/27 (18.5%)
Hypophosphataemia	3/27 (11.1%)
Musculoskeletal and connective tissue disorders
Back pain	4/27 (14.8%)
bone pain	2/27 (7.4%)
Pain in extremity	8/27 (29.6%)
Pain in jaw	2/27 (7.4%)
Nervous system disorders
Dizziness	2/27 (7.4%)
Headache	11/27 (40.7%)
Lethargy	2/27 (7.4%)
Psychiatric disorders
Agitation	4/27 (14.8%)
Anxiety	6/27 (22.2%)
Insomnia	4/27 (14.8%)
Renal and urinary disorders
Dysuria	2/27 (7.4%)
Haematuria	3/27 (11.1%)
Renal tubular acidosis	2/27 (7.4%)
Reproductive system and breast disorders
Scrotal erythema	2/27 (7.4%)
Testicular pain	3/27 (11.1%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	2/27 (7.4%)
Cough	12/27 (44.4%)
Dyspnoea	3/27 (11.1%)
Epistaxis	7/27 (25.9%)
Oropharyngeal pain	14/27 (51.9%)
Pleural effusion	2/27 (7.4%)
Rhinorrhoea	2/27 (7.4%)
Tachypnoea	4/27 (14.8%)
Upper respiratory tract congestion	3/27 (11.1%)
Skin and subcutaneous tissue disorders
Alopecia	3/27 (11.1%)
Dermatitis diaper	2/27 (7.4%)
Dry skin	2/27 (7.4%)
Erythema	3/27 (11.1%)
Ingrowing nail	2/27 (7.4%)
Petechiae	2/27 (7.4%)
Pruritus	16/27 (59.3%)
Rash	15/27 (55.6%)
Skin disorder	3/27 (11.1%)
Skin lesion	2/27 (7.4%)
Urticaria	2/27 (7.4%)
Vascular disorders
Hypertension	16/27 (59.3%)
Hypotension	7/27 (25.9%)

Limitations/Caveats

The original protocol included a long term follow-up (LTFU) phase up to 10 years. This was reduced in a protocol amendment to up to the time when the last enrolled subject had completed the day +100 follow-up.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits sponsor a limited period of time to review material discussing trial results (approximately up to 90 days). Sponsor may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, investigator agrees not to publish any results before the first multi-center publication.