Phase II Study Incorporating Pegylated Interferon In the Treatment For Children With High-Risk Melanoma

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00539591
• Collaborator: Schering-Plough (Industry)
• Enrollment: 29
• Locations: 3
• Arms: 2
• Duration (Months): 187
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The main goal of this study is to estimate the tumor response rate of temozolomide administered in combination with peginterferon alfa-2b to pediatric patients with unresectable Stage III, metastatic, or recurrent cutaneous melanoma.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Peginterferon alfa-2b; Drug: Temozolomide; Drug: Recombinant interferon alfa-2b	Phase 2

Detailed Description

This study is for children with malignant melanoma and high risk features (at high risk of melanoma returning or spreading to other parts of the body) or who have recurrent disease. The study has two treatment groups based on the stage of the disease. Patients with stage IIC, IIIA or IIIB melanoma whose tumors have been removed by surgery will be treated in study group A. These patients will receive 4 weeks of high dose interferon alfa-2b followed by 48 weeks of peginterferon. Patients with stage IIIC or IV melanoma, stage III melanoma that could not be removed by surgery and those with recurrent disease will be treated in study group B. These patients will receive peginterferon alfa-2b and temozolomide.

Stratum A: Resected Stages IIC, IIIA, and IIIB patients

Induction therapy (weeks 1-4): Subjects will receive recombinant interferon alfa-2b 20 million units/m2 per day intravenously over 20-30 minutes on 5 consecutive days per week for 4 weeks. Subjects will receive peginterferon alfa-2b 1 mcg/kg/week subcutaneously for a total of 48 weeks.

Stratum B: Resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent patients

Stratum B is divided into 2 groups based on the presence (Stratum B1) or absence (Stratum B2) of measurable disease. Subjects will receive 8 weekly doses of peginterferon alfa-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75mg/m2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course will be 8 weeks. Strata B2 (no measurable disease) will proceed with 7 courses as outlined.

Surgery interventions -Associated with both Strata A and B Surgery description: All subjects with initial presentation of melanoma (T1-4) will be treated with primary wide local excision with a minimum of 1cm margin (if anatomically feasible) surrounding the primary lesion or biopsy scar. For lesions with Breslow's thickness of > 1mm or <or= with ulceration or Clark's level IV/V, a 2 cm margin is preferred when anatomically feasible. Subjects with sentinel lymph node(s) positive for disease, will undergo complete lymph node dissection of the involved nodal basin.

Additional objectives include:

• To assess the safety of temozolomide administered in combination with peginterferon α-2b to pediatric patients with resected AJCC Stage IIIC, unresectable Stage III, metastatic, or recurrent cutaneous melanoma (Stratum B).

• To study the feasibility and safety of administering peginterferon α-2b weekly for 48 weeks following an initial induction phase with intravenous high dose interferon α-2b for 4 weeks to pediatric patients with resected thick melanomas (> 4mm) with ulcerations (AJCC Stage IIC) and resected melanomas with regional lymph node metastases (AJCC Stage IIIA and IIIB) (Stratum A).

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study Incorporating Pegylated Interferon In the Treatment For Children With High-Risk Melanoma
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Jun 1, 2015
• Anticipated Study Completion Date: May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Temozolomide/peginterferon alfa-2b Stratum B: Resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent patients Stratum B is divided into 2 groups based on the presence (Stratum B1) or absence (Stratum B2) of measurable disease. Subjects will receive 8 weekly doses of peginterferon alfa-2b 0.5 mcg/kg/dose subcutaneously (SQ) in combination with temozolomide 75mg/m2/dose by mouth (PO) daily for 6 weeks followed by 2 week break. The duration of each treatment course will be 8 weeks. Strata B2 (no measurable disease) will proceed with 7 courses as outlined.	Drug: Peginterferon alfa-2b; Given either IV or SQ. Therapeutic drug class: interferon.; Other Names: PEG-Intron(R) pegylated interferon alfa-2b ; Drug: Temozolomide; Given PO. Therapeutic drug class: antineoplastic agent.; Other Names: Temodar(R), SCH 52365
Experimental: Peginterferon alfa-2b/non-pegylated interferon alfa-2b Stratum A: Resected Stages IIC, IIIA, and IIIB patients will receive recombinant interferon alfa-2b 20 million units/m2/day intravenously (IV) 5 consecutive days per week for 4 weeks followed by peginterferon alfa-2b 1mcg/kg subcutaneously (SQ) once a week for 48 weeks.	Drug: Peginterferon alfa-2b; Given either IV or SQ. Therapeutic drug class: interferon.; Other Names: PEG-Intron(R) pegylated interferon alfa-2b ; Drug: Temozolomide; Given PO. Therapeutic drug class: antineoplastic agent.; Other Names: Temodar(R), SCH 52365 ; Drug: Recombinant interferon alfa-2b; Given IV. Therapeutic drug classes: antineoplastic agent, immunomodulatory agent, interferon; Other Names: Intron® non-pegylated interferon alfa-2b

Outcome Measures

Primary Outcome Measures

1. Tumor Response Rate [8 weeks]

   Tumor response rate of stratum B1 participants was evaluated after 1 treatment course of temozolomide plus peginterferon ɑ-2b. Complete response (CR) and partial response (PR) confirmed with repeated scan at least 4 weeks apart following completion of course 1 therapy. CR defined as disappearance of all target and non-target lesions with no new lesions detected. If available, no disease must be detected by immunocytology or serum tumor markers. PR defined as at least 30% decrease in disease measurement compared to disease measurement at study entry with no new lesions detected. Progressive disease (PD) defined as at least 20% increase in the disease measurement compared to the smallest disease measurement recorded since start of treatment, or appearance of one or more new lesions. Stable disease defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD compared to smallest disease measurement since start of treatment.

2. Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Strata B1 and B2 [52 weeks]

   The objective was to assess the safety of temozolomide administered in combination with peginterferon a-2b in Stratum B participants. Accrual was suspended any time during therapy if 2 or more of 6, 4 or more of 12, 6 or more of 18, 8 or more of 24, 10 or more of 30 participants experienced target toxicity defined as: Grade 4 non-hematologic (non-hem) toxicity that does not resolve to ≤grade 1 within 2 weeks from the time next dose is due and is determined to be probably or definitely related to protocol therapy Grade 4 non-hem toxicity that is NOT constitutional symptoms (fever, chills, fatigue and/or pain) Grade 3 elevations in creatinine or BUN that are determined to be probably or definitely related to protocol therapy Grade 4 cardiopulmonary toxicity that is determined to be probably or definitely related to protocol therapy Grade 4 mood alteration (suicidal ideation; danger to self or others)

3. Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients [52 weeks]

   The objective was to study the feasibility and safety of administering peginterferon a-2b weekly for 48 weeks following the initial induction phase to Stratum A participants. Accrual was suspended during the 48-week course if 2 or more of 6, 4 or more of 12, 6 or more of 18, 8 or more of 24, 10 or more of 30 participants experienced target toxicity defined as: Grade 4 non-hematologic (non-hem) toxicity that does not resolve to ≤grade 1 within 2 weeks from the time next dose is due and is determined to be probably or definitely related to protocol therapy Grade 4 non-hem toxicity that is NOT constitutional symptoms (fever, chills, fatigue and/or pain) Grade 3 elevations in creatinine or BUN that are determined to be probably or definitely related to protocol therapy Grade 4 cardiopulmonary toxicity that is determined to be probably or definitely related to protocol therapy Grade 4 mood alteration (suicidal ideation; danger to self or others)

4. Probability of Event-free Survival (EFS) of Stratum A Participants [3 years from diagnosis]

   The probability of EFS was estimated as time to first event (relapse, death or second malignancy). As of April 2016, 21 out of 23 participants had no events. The EFS rate was estimated by Kaplan-Meier method.

Other Outcome Measures

1. Median Steady State Trough Concentration of Pegylated Interferon ɑ-2B [Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28]

   The pharmacokinetic (PK) analysis of pegylated ɑ-2b included only patients within Stratum A who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

2. Area Under the Curve (AUC) of Pegylated Interferon ɑ-2B [Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28]

   Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM. AUC is given as Time 0 through infinity.

3. ɑ Half Life of Pegylated Interferon ɑ-2B [Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28]

   Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

4. Volume of Central Compartment (Vc) of Pegylated Interferon ɑ-2B [Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28]

   Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

5. Apparent Clearance (CL) of Pegylated Interferon ɑ-2B [Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28]

   Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

6. Area Under the Curve (AUC) of Interferon ɑ-2b [Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion]

   Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM. AUC is given as Time 0 to infinity.

7. Half-Life of Interferon ɑ-2b [Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion]

   Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

8. Volume of Central Compartment (Vc) of Interferon ɑ-2b [Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion]

   Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

9. Systemic Clearance (CL) of Interferon ɑ-2B [Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion]

   Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.

10. Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) [Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Quality of Life Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for child report = 83.0 ± 14.8.

11. Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) [Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Quality of Life Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for child report = 83.0 ± 14.8.

12. Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) [Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Quality of Live Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for parent report = 87.6 ± 12.3.

13. Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum B) [Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Quality of Live Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for parent report = 87.6 ± 12.3.

14. Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) [Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.

15. Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B) [Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.

16. Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) [Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.

17. Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum B) [Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post]

    QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.

18. BASC-2 Psychological Assessment (Stratum A) [Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy]

    The Behavioral Assessment System for Children, 2nd Edition (BASC-2) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The behavior system index (BSI) T-score (range 0-100) is reported for the BASC-2 assessment. Higher scores reflect greater behavioral problems.

19. BASC-2 Psychological Assessment (Stratum B) [Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy]

    The Behavioral Assessment System for Children, 2nd Edition (BASC-2) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The behavior system index (BSI) T-score (range 0-100) is reported for the BASC-2 assessment. Higher scores reflect greater behavioral problems.

20. BRIEF Psychological Assessment (Stratum A) [Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy]

    The Behavioral Rating Inventory of Executive Function (BRIEF) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The global executive composite (GEC) T-score (range 0-100) is reported for the BRIEF assessment. Higher scores reflect poorer executive function.

21. BRIEF Psychological Assessment (Stratum B) [Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy]

    The Behavioral Rating Inventory of Executive Function (BRIEF) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The global executive composite (GEC) T-score (range 0-100) is reported for the BRIEF assessment. Higher scores reflect poorer executive function.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• AJCC stage IIC, III, IV or recurrent cutaneous melanoma

• Adequate bone marrow function

• Age less than or equal to 21 years of age at diagnosis

• Adequate liver and kidney function

Exclusion Criteria:

• Prior Therapy with dacarbazine or temozolomide

• Patients who have uncontrolled infection

• Patients with autoimmune hepatitis

• Patients who have a history of depression or other psychiatric diseases requiring hospitalization

• Patients taking systemic corticosteroids including oral steroids (i.e. prednisone, dexamethasone) or topical steroid creams/ointments. Steroid containing inhalers, steroid replacement for adrenal insufficiency and steroid premedication for prevention of transfusion or imaging contrast-agent related allergic reaction will be permitted.

• Patients with hypersensitivity reaction to non-pegylated interferon α-2b are not eligible for study

• Patients with diabetes mellitus not adequately controlled with medication

• Patients with hypo- or hyperthyroidism not adequately controlled with medication.

• Patients with a history of myocardial infarction, severe or unstable angina, or severe peripheral vascular disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rady Children's Hospital	San Diego	California	United States	92123
2	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
3	The Children's Cancer Hospital at UT M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• St. Jude Children's Research Hospital
• Schering-Plough

Investigators

• Principal Investigator: Alberto Pappo, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00539591
• Other Study ID Numbers: MEL06; NCI-2011-01192
• First Posted: Oct 4, 2007
• Last Update Posted: Apr 5, 2022
• Last Verified: Apr 1, 2022

• Keywords provided by St. Jude Children's Research Hospital: Cutaneous Melanoma
• Additional relevant MeSH terms: Melanoma; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b; Temozolomide

Study Results

Participant Flow

Recruitment Details	A total of 29 patients were enrolled between May 9, 2008 and August 22, 2012. Of the 29 participants, 21 were enrolled at St. Jude Children's Research Hospital (SJCRH), 7 at MD Anderson, and 1 at Rady Children's Hospital. Twenty-three participants met stratum A eligibility, 2 met stratum B1 eligibility and 4 met stratum B2 eligibility.

Arm/Group Title	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b	Temozolomide/Peginterferon ɑ-2b With Measureable Disease	Temozolomide/Peginterferon ɑ-2b Without Measureable Disease
Arm/Group Description	Stratum A: American Joint Committee on Cancer (AJCC) resected Stages IIC, IIIA, and IIIB Participants received recombinant interferon ɑ-2b 20 million units/m^2/day intravenously 5 consecutive days per week for 4 weeks followed by peginterferon ɑ-2b 1 mcg/kg subcutaneously once a week for 48 weeks.	Stratum B1: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants with measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks.	Stratum B2: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants without measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks. Stratum B2 (no measurable disease) proceeded with 7 courses as outlined.
Period Title: Overall Study
STARTED	23	2	4
COMPLETED	18	0	1
NOT COMPLETED	5	2	3

Baseline Characteristics

Arm/Group Title	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b	Temozolomide/Peginterferon ɑ-2b With Measureable Disease	Temozolomide/Peginterferon ɑ-2b Without Measureable Disease	Total
Arm/Group Description	Stratum A: American Joint Committee on Cancer (AJCC) resected Stages IIC, IIIA, and IIIB Participants received recombinant interferon ɑ-2b 20 million units/m^2/day intravenously 5 consecutive days per week for 4 weeks followed by peginterferon ɑ-2b 1 mcg/kg subcutaneously once a week for 48 weeks.	Stratum B1: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants with measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks.	Stratum B2: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants without measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks. Stratum B2 (no measurable disease) proceeded with 7 courses as outlined.	Total of all reporting groups
Overall Participants	23	2	4	29
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	10.3 (2.4)	11.9 (3.96)	18.4 (3.6)	10.77 (2.4)
Sex: Female, Male (Count of Participants)
Female	15 65.2%	0 0%	1 25%	16 55.2%
Male	8 34.8%	2 100%	3 75%	13 44.8%

Outcome Measures

1. Primary Outcome

Title	Tumor Response Rate
Description	Tumor response rate of stratum B1 participants was evaluated after 1 treatment course of temozolomide plus peginterferon ɑ-2b. Complete response (CR) and partial response (PR) confirmed with repeated scan at least 4 weeks apart following completion of course 1 therapy. CR defined as disappearance of all target and non-target lesions with no new lesions detected. If available, no disease must be detected by immunocytology or serum tumor markers. PR defined as at least 30% decrease in disease measurement compared to disease measurement at study entry with no new lesions detected. Progressive disease (PD) defined as at least 20% increase in the disease measurement compared to the smallest disease measurement recorded since start of treatment, or appearance of one or more new lesions. Stable disease defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD compared to smallest disease measurement since start of treatment.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum B1
Arm/Group Description	Stratum B: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants, divided into 2 groups based on presence (B1) or absence (B2) of measurable disease Stratum B1 had presence of measurable disease. Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks. Interventions: Temozolomide, peginterferon ɑ-2b
Measure Participants	2
Progressive Disease	2 8.7%
Clinical Remission	0 0%

2. Primary Outcome

Title	Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Strata B1 and B2
Description	The objective was to assess the safety of temozolomide administered in combination with peginterferon a-2b in Stratum B participants. Accrual was suspended any time during therapy if 2 or more of 6, 4 or more of 12, 6 or more of 18, 8 or more of 24, 10 or more of 30 participants experienced target toxicity defined as: Grade 4 non-hematologic (non-hem) toxicity that does not resolve to ≤grade 1 within 2 weeks from the time next dose is due and is determined to be probably or definitely related to protocol therapy Grade 4 non-hem toxicity that is NOT constitutional symptoms (fever, chills, fatigue and/or pain) Grade 3 elevations in creatinine or BUN that are determined to be probably or definitely related to protocol therapy Grade 4 cardiopulmonary toxicity that is determined to be probably or definitely related to protocol therapy Grade 4 mood alteration (suicidal ideation; danger to self or others)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

This toxicity report was based on intention to treat population (ITT), all patients enrolled were included. The study did not meet its accrual goals within the planned timeframe due to slow accrual.

Arm/Group Title	Temozolomide/Peginterferon ɑ-2b With Measureable Disease	Temozolomide/Peginterferon ɑ-2b Without Measureable Disease
Arm/Group Description	Stratum B1: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants with measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks.	Stratum B2: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants without measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks. Stratum B2 (no measurable disease) proceeded with 7 courses as outlined.
Measure Participants	2	4
Number [participants]	0 0%	0 0%

3. Primary Outcome

Title	Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients
Description	The objective was to study the feasibility and safety of administering peginterferon a-2b weekly for 48 weeks following the initial induction phase to Stratum A participants. Accrual was suspended during the 48-week course if 2 or more of 6, 4 or more of 12, 6 or more of 18, 8 or more of 24, 10 or more of 30 participants experienced target toxicity defined as: Grade 4 non-hematologic (non-hem) toxicity that does not resolve to ≤grade 1 within 2 weeks from the time next dose is due and is determined to be probably or definitely related to protocol therapy Grade 4 non-hem toxicity that is NOT constitutional symptoms (fever, chills, fatigue and/or pain) Grade 3 elevations in creatinine or BUN that are determined to be probably or definitely related to protocol therapy Grade 4 cardiopulmonary toxicity that is determined to be probably or definitely related to protocol therapy Grade 4 mood alteration (suicidal ideation; danger to self or others)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Number of participants for the analysis was based on the intent to treat population, all patients enrolled were included. Participants were enrolled on Stratum A until the accrual goals were met on Stratum B.

Arm/Group Title	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A: American Joint Committee on Cancer (AJCC) resected Stages IIC, IIIA, and IIIB Participants received recombinant interferon ɑ-2b 20 million units/m^2/day intravenously 5 consecutive days per week for 4 weeks followed by peginterferon ɑ-2b 1 mcg/kg subcutaneously once a week for 48 weeks.
Measure Participants	23
Grade 4 non-hem toxicity	2 8.7%
Grade 4 non-hem/NOT constitutional	0 0%
Grade 3 elevations in creatinine or BUN	0 0%
Grade 4 cardiopulmonary toxicity	0 0%
Grade 4 mood alteration	1 4.3%

4. Primary Outcome

Title	Probability of Event-free Survival (EFS) of Stratum A Participants
Description	The probability of EFS was estimated as time to first event (relapse, death or second malignancy). As of April 2016, 21 out of 23 participants had no events. The EFS rate was estimated by Kaplan-Meier method.
Time Frame	3 years from diagnosis

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A: American Joint Committee on Cancer (AJCC) resected Stages IIC, IIIA, and IIIB Participants received recombinant interferon ɑ-2b 20 million units/m^2/day intravenously 5 consecutive days per week for 4 weeks followed by peginterferon ɑ-2b 1 mcg/kg subcutaneously once a week for 48 weeks.
Measure Participants	23
Number (95% Confidence Interval) [probability]	0.913

5. Other Pre-specified Outcome

Title	Median Steady State Trough Concentration of Pegylated Interferon ɑ-2B
Description	The pharmacokinetic (PK) analysis of pegylated ɑ-2b included only patients within Stratum A who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28

Outcome Measure Data

Analysis Population Description

Only one patient had evaluable data in Stratum B and is not included in the final analysis, because data from more than one patient are required for nonlinear-mixed effects modeling.

Arm/Group Title	Peginterferon ɑ-2b/Non-Pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A participants who received pegylated interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	16
Median (Full Range) [pcg/ml]	52.8

6. Other Pre-specified Outcome

Title	Area Under the Curve (AUC) of Pegylated Interferon ɑ-2B
Description	Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM. AUC is given as Time 0 through infinity.
Time Frame	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28

Outcome Measure Data

Analysis Population Description

Only one Stratum B patient had evaluable data and is not included in final analysis, because data from more than one patient are required for nonlinear-mixed effects modeling. Two patients in Week 5 and three in Week 28 were excluded due to inadequate sampling to characterize an AUC value.

Arm/Group Title	Week 5 - First Dose	Week 28 - Steady State
Arm/Group Description	Stratum A participants who received pegylated interferon ɑ-2b and had pharmacokinetic studies performed are included.	Stratum A participants who received pegylated interferon ɑ-2b and had pharmacokinetic studies performed.
Measure Participants	7	6
Median (Full Range) [pcg * hr/ml]	50556	48480

7. Other Pre-specified Outcome

Title	ɑ Half Life of Pegylated Interferon ɑ-2B
Description	Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28

Outcome Measure Data

Analysis Population Description

Only one Stratum B patient had evaluable data and is not included in final analysis, because data from more than one patient are required for nonlinear-mixed effects modeling. Two patients in Week 5 and three in Week 28 were excluded due to inadequate sampling to characterize an AUC value.

Arm/Group Title	Peginterferon ɑ-2b/Non-Pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A participants who received pegylated interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	9
Median (Full Range) [hours]	24.8

8. Other Pre-specified Outcome

Title	Volume of Central Compartment (Vc) of Pegylated Interferon ɑ-2B
Description	Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28

Outcome Measure Data

Analysis Population Description

Only one Stratum B patient had evaluable data and is not included in final analysis, because data from more than one patient are required for nonlinear-mixed effects modeling due to differences in clinical variables. Two patients in Week 5 and three in Week 28 were excluded due to inadequate sampling to characterize an AUC value.

Arm/Group Title	Peginterferon ɑ-2b/Non-Pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A participants who received pegylated interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	9
Median (Full Range) [ml/kg]	772

9. Other Pre-specified Outcome

Title	Apparent Clearance (CL) of Pegylated Interferon ɑ-2B
Description	Pharmacokinetic (PK) analysis of pegylated ɑ-2b included only Stratum A patients who had PK studies performed. Samples were analyzed for pegylated interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28

Outcome Measure Data

Analysis Population Description

Only one Stratum B patient had evaluable data and is not included in final analysis due to differences in clinical variables, because data from more than one patient are required for nonlinear-mixed effects modeling. Two patients in Week 5 and three in Week 28 were excluded due to inadequate sampling to characterize an AUC value.

Arm/Group Title	Peginterferon ɑ-2b/Non-Pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A participants who received pegylated interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	9
Median (Full Range) [ml/hr/kg]	19.8

10. Other Pre-specified Outcome

Title	Area Under the Curve (AUC) of Interferon ɑ-2b
Description	Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM. AUC is given as Time 0 to infinity.
Time Frame	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion

Outcome Measure Data

Analysis Population Description

The pharmacokinetic(PK) analysis of pegylated ɑ-2b included only patients within Stratum A who had PK studies performed. Only one patient had evaluable data in Stratum B and is not included in the final analysis due to differences in clinical variables.

Arm/Group Title	Peginterferon ɑ-2b/Non-Pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A participants who received interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	16
Median (Full Range) [pcg * hr/ml]	5026

11. Other Pre-specified Outcome

Title	Half-Life of Interferon ɑ-2b
Description	Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis of pegylated ɑ-2b included only patients within Stratum A who had PK studies performed. Only one patient had evaluable data in Stratum B and is not included in the final analysis due to differences in clinical variables.

Arm/Group Title	Peginterferon ɑ-2b/Non-Pegylated Interferon ɑ-2b
Arm/Group Description	Stratum A participants who received interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	16
ɑ half-life	0.7
ß half-life	14.7

12. Other Pre-specified Outcome

Title	Volume of Central Compartment (Vc) of Interferon ɑ-2b
Description	Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis of pegylated ɑ-2b included only patients within Stratum A who had PK studies performed. Only one patient had evaluable data in Stratum B and is not included in the final analysis due to differences in clinical variables.

Arm/Group Title	Interferon ɑ-2b
Arm/Group Description	Participants who received interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	16
Median (Full Range) [l/m^2]	25.1

13. Other Pre-specified Outcome

Title	Systemic Clearance (CL) of Interferon ɑ-2B
Description	Samples were analyzed for interferon ɑ-2b concentrations by using the VeriKine Human Interferon Alpha ELISA Kit following the manufacturer's instructions, and concentration-time data were analyzed by nonlinear-mixed effects modeling as implemented in NONMEM.
Time Frame	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis of pegylated ɑ-2b included only patients within Stratum A who had PK studies performed. Only one patient had evaluable data in Stratum B and is not included in the final analysis due to differences in clinical variables.

Arm/Group Title	Interferon ɑ-2b
Arm/Group Description	Participants who received interferon ɑ-2b and had pharmacokinetic studies performed are included.
Measure Participants	16
Median (Full Range) [l/hr/m^2]	15.3

14. Other Pre-specified Outcome

Title	Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A)
Description	QoL assessments were completed using Pediatrics Quality of Life Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for child report = 83.0 ± 14.8.
Time Frame	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

This QOL analysis included patients only within Stratum A.

Arm/Group Title	Pretherapy	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed before start of therapy.	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	15	15	17	14	14	17	15	13	15
Mean (Standard Deviation) [units on a scale]	75.5 (18.4)	71.6 (18.7)	77.2 (16.3)	79.3 (17.4)	77.8 (20.6)	80.6 (15.6)	80.4 (16.1)	87.5 (12.5)	91.0 (7.1)

15. Other Pre-specified Outcome

Title	Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B)
Description	QoL assessments were completed using Pediatrics Quality of Life Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for child report = 83.0 ± 14.8.
Time Frame	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

Only one patient had evaluable data in Stratum B. The raw score, rather than the mean +/- SD, is presented. Data was not collected at Week 24, and the patient was taken off study prior to 6 months after end of therapy.

Arm/Group Title	Pretherapy	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed before start of therapy.	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	1	1	1	1	1	0	1	0	0
Number [units on a scale]	90.3	93.1	72.8	79.2	68.1	65.6

16. Other Pre-specified Outcome

Title	Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A)
Description	QoL assessments were completed using Pediatrics Quality of Live Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for parent report = 87.6 ± 12.3.
Time Frame	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

This QOL analysis included patients only within Stratum A.

Arm/Group Title	Pretherapy	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed before start of therapy.	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	16	15	17	13	16	17	15	15	15
Mean (Standard Deviation) [units on a scale]	70.3 (19.1)	71.8 (16.4)	74.4 (17.9)	79.1 (16.6)	79.0 (19.0)	82.2 (14.5)	87.5 (15.3)	86.0 (17.6)	87.3 (17.5)

17. Other Pre-specified Outcome

Title	Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum B)
Description	QoL assessments were completed using Pediatrics Quality of Live Inventory (PedsQL v4.0). Scale range is 0-100 with higher scores reflecting better quality of life. PedsQL 4.0 healthy sample normative mean ± SD for parent report = 87.6 ± 12.3.
Time Frame	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

Only one patient had evaluable data in Stratum B. The raw score, rather than the mean +/- SD, is presented. Data was not collected after Week 4.

Arm/Group Title	Pretherapy	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed before start of therapy.	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	1	1	1	0	0	0	0	0	0
Number [units on a scale]	77.6	72.2	89.1

18. Other Pre-specified Outcome

Title	Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A)
Description	QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.
Time Frame	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

PedsQL v3.0 was not completed pretherapy. This QOL analysis included patients only within Stratum A.

Arm/Group Title	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	17	19	17	17	16	17	15	15
Mean (Standard Deviation) [units on a scale]	71.1 (17.2)	76.1 (15.4)	79.2 (19.2)	78.5 (14.7)	77.1 (16.0)	77.0 (16.5)	83.7 (18.0)	85.4 (8.9)

19. Other Pre-specified Outcome

Title	Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B)
Description	QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.
Time Frame	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

PedsQL v3.0 was not completed pretherapy. Only one patient had evaluable data in Stratum B. The raw score, rather than the mean +/- SD, is presented. Data was not collected at Week 24, and the patient was taken off study prior to 6 months after end of therapy.

Arm/Group Title	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	1	1	1	1	0	1	0	0
Number [units on a scale]	92.8	90.1	93.2	79.6	67.4

20. Other Pre-specified Outcome

Title	Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A)
Description	QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.
Time Frame	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

PedsQL v3.0 was not completed pretherapy. This QOL analysis included patients only within Stratum A.

Arm/Group Title	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	19	19	17	18	16	16	15	15
Mean (Standard Deviation) [units on a scale]	73.2 (13.9)	75.1 (15.2)	81.4 (11.6)	78.7 (17.7)	81.6 (17.1)	85.6 (13.8)	85.0 (11.5)	89.1 (11.6)

21. Other Pre-specified Outcome

Title	Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum B)
Description	QoL assessments were completed using Pediatrics Cancer Quality of Life Inventory (PedsQL v3.0). Scale range is 0-100 with higher scores reflecting better quality of life.
Time Frame	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post

Outcome Measure Data

Analysis Population Description

PedsQL v3.0 was not completed pretherapy. Only one patient had evaluable data in Stratum B. The raw score, rather than the mean +/- SD, is presented. Data was not collected after Week 4.

Arm/Group Title	Week 2	Week 4	Week 8	Week 12	Week 24	End of Therapy	6 Months After End of Therapy	12 Months After End of Therapy
Arm/Group Description	QoL assessment completed at Week 2.	QoL assessment completed at Week 4.	QoL assessment completed at Week 8.	QoL assessment completed at Week 12.	QoL assessment completed at Week 24.	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.	QoL assessment completed 12 months after end of therapy.
Measure Participants	1	1	0	0	0	0	0	0
Number [units on a scale]	67.7	71.4

22. Other Pre-specified Outcome

Title	BASC-2 Psychological Assessment (Stratum A)
Description	The Behavioral Assessment System for Children, 2nd Edition (BASC-2) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The behavior system index (BSI) T-score (range 0-100) is reported for the BASC-2 assessment. Higher scores reflect greater behavioral problems.
Time Frame	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy

Outcome Measure Data

Analysis Population Description

This QOL analysis included patients only within Stratum A.

Arm/Group Title	Pretherapy	Week 4	Week 24	End of Therapy	6 Months After End of Therapy
Arm/Group Description	Psychological assessment completed before start of therapy.	Psychological assessment completed at Week 4	Psychological assessment completed at Week 24	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.
Measure Participants	21	21	19	18	16
Mean (Standard Deviation) [T score]	44.9 (8.1)	45.9 (8.3)	44.2 (6.9)	47.2 (11.1)	42.3 (7.2)

23. Other Pre-specified Outcome

Title	BASC-2 Psychological Assessment (Stratum B)
Description	The Behavioral Assessment System for Children, 2nd Edition (BASC-2) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The behavior system index (BSI) T-score (range 0-100) is reported for the BASC-2 assessment. Higher scores reflect greater behavioral problems.
Time Frame	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy

Outcome Measure Data

Analysis Population Description

Only one patient had evaluable data in Stratum B, but scores were not available for this instrument due to the age of the patient.

Arm/Group Title	Pretherapy	Week 4	Week 24	End of Therapy	6 Months After End of Therapy
Arm/Group Description	Psychological assessment completed before start of therapy.	Psychological assessment completed at Week 4	Psychological assessment completed at Week 24	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.
Measure Participants	0	0	0	0	0

24. Other Pre-specified Outcome

Title	BRIEF Psychological Assessment (Stratum A)
Description	The Behavioral Rating Inventory of Executive Function (BRIEF) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The global executive composite (GEC) T-score (range 0-100) is reported for the BRIEF assessment. Higher scores reflect poorer executive function.
Time Frame	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy

Outcome Measure Data

Analysis Population Description

This QOL analysis included patients only within Stratum A.

Arm/Group Title	Pretherapy	Week 4	Week 24	End of Therapy	6 Months After End of Therapy
Arm/Group Description	Psychological assessment completed before start of therapy.	Psychological assessment completed at Week 4	Psychological assessment completed at Week 24	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.
Measure Participants	17	17	13	14	11
Mean (Standard Deviation) [T score]	47.9 (12.8)	50.8 (11.9)	48.6 (12.4)	47.6 (12.6)	42.6 (8.1)

25. Other Pre-specified Outcome

Title	BRIEF Psychological Assessment (Stratum B)
Description	The Behavioral Rating Inventory of Executive Function (BRIEF) was administered to parents, assessing for any effects on behavior or mood in children undergoing study therapy. The global executive composite (GEC) T-score (range 0-100) is reported for the BRIEF assessment. Higher scores reflect poorer executive function.
Time Frame	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy

Outcome Measure Data

Analysis Population Description

Only one patient had evaluable data in Stratum B, but scores were not available for this instrument due to the age of the patient.

Arm/Group Title	Pretherapy	Week 4	Week 24	End of Therapy	6 Months After End of Therapy
Arm/Group Description	Psychological assessment completed before start of therapy.	Psychological assessment completed at Week 4	Psychological assessment completed at Week 24	QoL assessment completed at end of therapy.	QoL assessment completed 6 months after end of therapy.
Measure Participants	0	0	0	0	0

Adverse Events

Time Frame	Adverse events are reported from the start of treatment for the first patient in May 2008 through April 2016.
Arm/Group Title	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b		Temozolomide/Peginterferon ɑ-2b With Measureable Disease		Temozolomide/Peginterferon ɑ-2b Without Measureable Disease
Arm/Group Description	Stratum A: American Joint Committee on Cancer (AJCC) resected Stages IIC, IIIA, and IIIB Participants received recombinant interferon ɑ-2b 20 million units/m^2/day intravenously 5 consecutive days per week for 4 weeks followed by peginterferon ɑ-2b 1 mcg/kg subcutaneously once a week for 48 weeks.		Stratum B1: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants with measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks.		Stratum B2: American Joint Committee on Cancer (AJCC) resected Stage IIIC, unresectable Stage III, Stage IV, and recurrent participants without measurable disease Participants received 8 weekly doses of peginterferon ɑ-2b 0.5 mcg/kg/dose subcutaneously in combination with temozolomide 75 mg/m^2/dose by mouth daily for 6 weeks followed by 2 week break. The duration of each treatment course was 8 weeks. Stratum B2 (no measurable disease) proceeded with 7 courses as outlined.
All Cause Mortality
	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b		Temozolomide/Peginterferon ɑ-2b With Measureable Disease		Temozolomide/Peginterferon ɑ-2b Without Measureable Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b		Temozolomide/Peginterferon ɑ-2b With Measureable Disease		Temozolomide/Peginterferon ɑ-2b Without Measureable Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/23 (13%)		0/2 (0%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Joint effusion	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Joint function	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Nervous system disorders
Confusion	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Extrapyramidal/involuntary movement/restlessness	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Mood alteration, agitation	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Psychosis (hallucinations/delusions)	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Seizure	1/23 (4.3%)	1	0/2 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b		Temozolomide/Peginterferon ɑ-2b With Measureable Disease		Temozolomide/Peginterferon ɑ-2b Without Measureable Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/23 (100%)		2/2 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Hemoglobin	13/23 (56.5%)	29	2/2 (100%)	2	2/4 (50%)	11
Leukocytes) total WBC)	22/23 (95.7%)	116	2/2 (100%)	4	4/4 (100%)	16
Neutrophils/granulocytes (ANC/AGC)	23/23 (100%)	142	0/2 (0%)	0	4/4 (100%)	16
Platelets	15/23 (65.2%)	28	0/2 (0%)	0	3/4 (75%)	18
Edema: head and neck	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	1
Edema: limb	2/23 (8.7%)	5	0/2 (0%)	0	1/4 (25%)	1
Edema: trunk/genital	3/23 (13%)	3	0/2 (0%)	0	0/4 (0%)	0
Lymphatics - other	1/23 (4.3%)	1	0/2 (0%)	0	1/4 (25%)	2
Cardiac disorders
Supraventricular and nodal arrhythmia, sinus bradycardia	8/23 (34.8%)	20	0/2 (0%)	0	1/4 (25%)	3
Supraventricular and nodal arrhythmia, sinus tachycardia	9/23 (39.1%)	22	2/2 (100%)	4	1/4 (25%)	3
Hypertension	6/23 (26.1%)	21	0/2 (0%)	0	2/4 (50%)	2
Endocrine disorders
Hot flashes/flushes	3/23 (13%)	3	0/2 (0%)	0	0/4 (0%)	0
Thyroid function, low (hypothyroidism)	3/23 (13%)	5	0/2 (0%)	0	0/4 (0%)	0
Eye disorders
Ocular surface disease	2/23 (8.7%)	3	0/2 (0%)	0	0/4 (0%)	0
Ocular/visual - other	2/23 (8.7%)	3	0/2 (0%)	0	0/4 (0%)	0
Vision-blurred vision	1/23 (4.3%)	1	0/2 (0%)	0	1/4 (25%)	1
Gastrointestinal disorders
Anorexia	18/23 (78.3%)	42	2/2 (100%)	2	2/4 (50%)	3
Constipation	9/23 (39.1%)	18	0/2 (0%)	0	0/4 (0%)	0
Dehydration	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Diarrhea	13/23 (56.5%)	32	1/2 (50%)	1	4/4 (100%)	9
Flatulence	1/23 (4.3%)	1	1/2 (50%)	1	0/4 (0%)	0
Heartburn/dyspepsia	2/23 (8.7%)	3	0/2 (0%)	0	1/4 (25%)	1
Mucositis/stomatitis (clinical exam), oral cavity	3/23 (13%)	3	0/2 (0%)	0	0/4 (0%)	0
Nausea	17/23 (73.9%)	38	0/2 (0%)	0	4/4 (100%)	9
Taste alteration (dysgeusia)	2/23 (8.7%)	3	0/2 (0%)	0	0/4 (0%)	0
Vomiting	12/23 (52.2%)	30	0/2 (0%)	0	3/4 (75%)	17
General disorders
Fatigue (asthenia, lethargy, malaise)	20/23 (87%)	100	0/2 (0%)	0	3/4 (75%)	4
Fever (in the absence of neutropenia, where neutropenia is defined as ANC<1.0 x 10e9/L)	16/23 (69.6%)	39	1/2 (50%)	1	2/4 (50%)	3
Rigors/chills	10/23 (43.5%)	19	0/2 (0%)	0	0/4 (0%)	0
Sweating (diaphoresis)	2/23 (8.7%)	5	0/2 (0%)	0	0/4 (0%)	0
Weight gain	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Weight loss	4/23 (17.4%)	9	1/2 (50%)	2	1/4 (25%)	1
Pain, abdomen NOS	8/23 (34.8%)	16	1/2 (50%)	2	2/4 (50%)	5
Pain, back	3/23 (13%)	22	1/2 (50%)	1	2/4 (50%)	2
Pain, chest wall	2/23 (8.7%)	2	0/2 (0%)	0	1/4 (25%)	4
Pain, chest/thorax NOS	3/23 (13%)	5	0/2 (0%)	0	2/4 (50%)	3
Pain, dental/teeth/peridontal	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Pain, external ear	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Pain, extremity-limb	12/23 (52.2%)	27	1/2 (50%)	1	0/4 (0%)	0
Pain, head/headache	18/23 (78.3%)	257	1/2 (50%)	2	2/4 (50%)	6
Pain, joint	3/23 (13%)	4	0/2 (0%)	0	0/4 (0%)	0
Pain, muscle	6/23 (26.1%)	12	0/2 (0%)	0	1/4 (25%)	1
Pain, neck	3/23 (13%)	3	0/2 (0%)	0	0/4 (0%)	0
Pain, pain NOS	8/23 (34.8%)	43	0/2 (0%)	0	0/4 (0%)	0
Pain, stomach	3/23 (13%)	3	0/2 (0%)	0	0/4 (0%)	0
Pain, throat/pharynx/larynx	7/23 (30.4%)	9	0/2 (0%)	0	0/4 (0%)	0
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	11/23 (47.8%)	19	0/2 (0%)	0	2/4 (50%)	2
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils, lip/perioral	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils, middle ear (otitis media)	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, nerve-peripheral	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, sinus	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, upper airway NOS	3/23 (13%)	4	0/2 (0%)	0	1/4 (25%)	1
Infection with unknown ANC, sinus	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, Lung (pnemonia)	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum gluatmic pyruvic transaminase)	22/23 (95.7%)	90	0/2 (0%)	0	2/4 (50%)	10
AST, SGOT (serum glutamic oxaloacetic transaminase)	23/23 (100%)	73	1/2 (50%)	1	1/4 (25%)	3
Albumin, serum-low (hypoalbuminemia)	6/23 (26.1%)	6	1/2 (50%)	1	1/4 (25%)	1
Alkaline phosphatase	4/23 (17.4%)	6	0/2 (0%)	0	0/4 (0%)	0
Amylase	8/23 (34.8%)	14	0/2 (0%)	0	1/4 (25%)	4
Calcium, serum-high (hypercalcemia)	0/23 (0%)	0	1/2 (50%)	2	0/4 (0%)	0
Calcium, serum-low (hypocalcemia	3/23 (13%)	5	0/2 (0%)	0	0/4 (0%)	0
Glucose, serum-high (hyperglycemia)	12/23 (52.2%)	23	1/2 (50%)	1	2/4 (50%)	5
Glucose, serum-low (hypoglycemia)	10/23 (43.5%)	14	0/2 (0%)	0	1/4 (25%)	3
Lipase	3/23 (13%)	4	0/2 (0%)	0	2/4 (50%)	5
Magnesium, serum-high (hypermagnesemia)	6/23 (26.1%)	9	0/2 (0%)	0	0/4 (0%)	0
Magnesium, serum-low (hypomagnesemia)	3/23 (13%)	8	0/2 (0%)	0	0/4 (0%)	0
Metabolic/laboratory - other	7/23 (30.4%)	23	0/2 (0%)	0	0/4 (0%)	0
Potassium, serum-high (hyperkalemia	5/23 (21.7%)	9	0/2 (0%)	0	2/4 (50%)	8
Potassium, serum-low (hypokalemia)	4/23 (17.4%)	4	0/2 (0%)	0	2/4 (50%)	2
Proteinuria	1/23 (4.3%)	1	0/2 (0%)	0	1/4 (25%)	1
Sodium, serum-high (hypernatremia)	9/23 (39.1%)	17	0/2 (0%)	0	2/4 (50%)	2
Triglyceride, serum-high (hypertriglyceridemia)	11/23 (47.8%)	17	0/2 (0%)	0	1/4 (25%)	1
Uric acid, serum-high (hyperuricemia)	7/23 (30.4%)	7	0/2 (0%)	0	3/4 (75%)	9
Bilirubin (hyperbilirubinemia)	2/23 (8.7%)	6	0/2 (0%)	0	0/4 (0%)	0
Nervous system disorders
Dizziness	3/23 (13%)	5	0/2 (0%)	0	0/4 (0%)	0
Mood alteration, agitation	9/23 (39.1%)	23	0/2 (0%)	0	0/4 (0%)	0
Mood alteration, anxiety	3/23 (13%)	3	0/2 (0%)	0	1/4 (25%)	1
Mood alteration, depression	3/23 (13%)	4	0/2 (0%)	0	0/4 (0%)	0
Neuropathy: sensory	5/23 (21.7%)	8	0/2 (0%)	0	0/4 (0%)	0
Personality/behavioral	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Incontinence, urinary	1/23 (4.3%)	1	0/2 (0%)	0	1/4 (25%)	2
Urinary frequency/urgency	1/23 (4.3%)	1	0/2 (0%)	0	1/4 (25%)	2
Reproductive system and breast disorders
Irregular menses (change from baseline)	2/23 (8.7%)	3	0/2 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	6
Cough	6/23 (26.1%)	8	0/2 (0%)	0	1/4 (25%)	1
Dyspnea (shortness of breath)	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	4/23 (17.4%)	9	0/2 (0%)	0	0/4 (0%)	0
Dermatology/skin - other	4/23 (17.4%)	7	0/2 (0%)	0	0/4 (0%)	0
Dry skin	6/23 (26.1%)	6	0/2 (0%)	0	0/4 (0%)	0
Flushing	3/23 (13%)	7	0/2 (0%)	0	1/4 (25%)	1
Hair loss/alopecia (scalp or body)	7/23 (30.4%)	8	0/2 (0%)	0	1/4 (25%)	1
Photosensitivity	1/23 (4.3%)	1	0/2 (0%)	0	1/4 (25%)	1
Pruritus/itching	5/23 (21.7%)	5	1/2 (50%)	1	1/4 (25%)	1
Rash/desquamation	20/23 (87%)	83	1/2 (50%)	2	3/4 (75%)	5
Urticaria (hives, welts, wheals)	0/23 (0%)	0	1/2 (50%)	1	0/4 (0%)	0
Vascular disorders
Hemorrhage, GI, lower GI NOS	3/23 (13%)	4	0/2 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, oral cavity	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, rectum	2/23 (8.7%)	2	0/2 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, upper GI NOS	0/23 (0%)	0	0/2 (0%)	0	1/4 (25%)	2
Hemorrhage, pulmonary/upper respiratory, nose	3/23 (13%)	7	0/2 (0%)	0	0/4 (0%)	0
Hemorrhage/bleeding - other	2/23 (8.7%)	3	0/2 (0%)	0	0/4 (0%)	0

Limitations/Caveats

The study closed early due to poor accrual to stratum B1.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.