Malignant Melanoma
Conditions
Keywords
Cutaneous Melanoma
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.
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).
Interventions
DRUGPeginterferon alfa-2b
Given either IV or SQ. Therapeutic drug class: interferon.
DRUGTemozolomide
Given PO. Therapeutic drug class: antineoplastic agent.
DRUGRecombinant interferon alfa-2b
Given IV. Therapeutic drug classes: antineoplastic agent, immunomodulatory agent, interferon
Sponsors
St. Jude Children's Research Hospital
Schering-Plough
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) |
| 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) |
| 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAlberto Pappo, MD
St. Jude Children's Research Hospital
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.
Participants by arm
| Arm | Count |
|---|---|
| Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b 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. | 23 |
| Temozolomide/Peginterferon ɑ-2b With Measureable Disease 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. | 2 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease 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. | 4 |
| Total | 29 |
Baseline characteristics
| Characteristic | Peginterferon ɑ-2b/Non-pegylated Interferon ɑ-2b | Temozolomide/Peginterferon ɑ-2b With Measureable Disease | Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Total |
|---|---|---|---|---|
| Age, Continuous | 10.3 years FULL_RANGE 2.4 | 11.9 years FULL_RANGE 3.96 | 18.4 years FULL_RANGE 3.6 | 10.77 years FULL_RANGE 2.4 |
| Sex: Female, Male Female | 15 Participants | 0 Participants | 1 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 2 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| other Total, other adverse events | 23 / 23 | 2 / 2 | 4 / 4 |
| serious Total, serious adverse events | 3 / 23 | 0 / 2 | 0 / 4 |
Outcome results
Primary
Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Strata B1 and B2
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Stratum B1 | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Strata B1 and B2 | 0 participants |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Strata B1 and B2 | 0 participants |
Primary
Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum B1 | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients | Grade 4 non-hem toxicity | 2 participants |
| Stratum B1 | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients | Grade 4 non-hem/NOT constitutional | 0 participants |
| Stratum B1 | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients | Grade 4 cardiopulmonary toxicity | 0 participants |
| Stratum B1 | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients | Grade 4 mood alteration | 1 participants |
| Stratum B1 | Number of Patients Who Experience Toxicity at or Above the Target Toxicity for Stratum A Patients | Grade 3 elevations in creatinine or BUN | 0 participants |
Primary
Probability of Event-free Survival (EFS) of Stratum A Participants
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum B1 | Probability of Event-free Survival (EFS) of Stratum A Participants | 0.913 probability |
Primary
Tumor Response Rate
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum B1 | Tumor Response Rate | Progressive Disease | 2 participants |
| Stratum B1 | Tumor Response Rate | Clinical Remission | 0 participants |
Other Pre-specified
Apparent Clearance (CL) of Pegylated Interferon ɑ-2B
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Apparent Clearance (CL) of Pegylated Interferon ɑ-2B | 19.8 ml/hr/kg |
Other Pre-specified
Area Under the Curve (AUC) of Interferon ɑ-2b
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Area Under the Curve (AUC) of Interferon ɑ-2b | 5026 pcg * hr/ml |
Other Pre-specified
Area Under the Curve (AUC) of Pegylated Interferon ɑ-2B
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Area Under the Curve (AUC) of Pegylated Interferon ɑ-2B | 50556 pcg * hr/ml |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Area Under the Curve (AUC) of Pegylated Interferon ɑ-2B | 48480 pcg * hr/ml |
Other Pre-specified
BASC-2 Psychological Assessment (Stratum A)
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
Population: This QOL analysis included patients only within Stratum A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum B1 | BASC-2 Psychological Assessment (Stratum A) | 44.9 T score | Standard Deviation 8.1 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | BASC-2 Psychological Assessment (Stratum A) | 45.9 T score | Standard Deviation 8.3 |
| Week 4 | BASC-2 Psychological Assessment (Stratum A) | 44.2 T score | Standard Deviation 6.9 |
| Week 8 | BASC-2 Psychological Assessment (Stratum A) | 47.2 T score | Standard Deviation 11.1 |
| Week 12 | BASC-2 Psychological Assessment (Stratum A) | 42.3 T score | Standard Deviation 7.2 |
Other Pre-specified
BASC-2 Psychological Assessment (Stratum B)
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
Population: Only one patient had evaluable data in Stratum B, but scores were not available for this instrument due to the age of the patient.
Other Pre-specified
BRIEF Psychological Assessment (Stratum A)
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
Population: This QOL analysis included patients only within Stratum A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum B1 | BRIEF Psychological Assessment (Stratum A) | 47.9 T score | Standard Deviation 12.8 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | BRIEF Psychological Assessment (Stratum A) | 50.8 T score | Standard Deviation 11.9 |
| Week 4 | BRIEF Psychological Assessment (Stratum A) | 48.6 T score | Standard Deviation 12.4 |
| Week 8 | BRIEF Psychological Assessment (Stratum A) | 47.6 T score | Standard Deviation 12.6 |
| Week 12 | BRIEF Psychological Assessment (Stratum A) | 42.6 T score | Standard Deviation 8.1 |
Other Pre-specified
BRIEF Psychological Assessment (Stratum B)
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
Population: Only one patient had evaluable data in Stratum B, but scores were not available for this instrument due to the age of the patient.
Other Pre-specified
Half-Life of Interferon ɑ-2b
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stratum B1 | Half-Life of Interferon ɑ-2b | ɑ half-life | 0.7 hours |
| Stratum B1 | Half-Life of Interferon ɑ-2b | ß half-life | 14.7 hours |
Other Pre-specified
ɑ Half Life of Pegylated Interferon ɑ-2B
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | ɑ Half Life of Pegylated Interferon ɑ-2B | 24.8 hours |
Other Pre-specified
Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A)
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
Population: PedsQL v3.0 was not completed pretherapy. This QOL analysis included patients only within Stratum A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum B1 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 71.1 units on a scale | Standard Deviation 17.2 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 76.1 units on a scale | Standard Deviation 15.4 |
| Week 4 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 79.2 units on a scale | Standard Deviation 19.2 |
| Week 8 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 78.5 units on a scale | Standard Deviation 14.7 |
| Week 12 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 77.1 units on a scale | Standard Deviation 16 |
| Week 24 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 77.0 units on a scale | Standard Deviation 16.5 |
| End of Therapy | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 83.7 units on a scale | Standard Deviation 18 |
| 6 Months After End of Therapy | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum A) | 85.4 units on a scale | Standard Deviation 8.9 |
Other Pre-specified
Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Stratum B1 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B) | 92.8 units on a scale |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B) | 90.1 units on a scale |
| Week 4 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B) | 93.2 units on a scale |
| Week 8 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B) | 79.6 units on a scale |
| Week 24 | Mean Total PedsQL 3.0 Scores for Child Cancer Quality of Life (QoL) Assessments (Stratum B) | 67.4 units on a scale |
Other Pre-specified
Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A)
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
Population: PedsQL v3.0 was not completed pretherapy. This QOL analysis included patients only within Stratum A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum B1 | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 73.2 units on a scale | Standard Deviation 13.9 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 75.1 units on a scale | Standard Deviation 15.2 |
| Week 4 | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 81.4 units on a scale | Standard Deviation 11.6 |
| Week 8 | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 78.7 units on a scale | Standard Deviation 17.7 |
| Week 12 | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 81.6 units on a scale | Standard Deviation 17.1 |
| Week 24 | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 85.6 units on a scale | Standard Deviation 13.8 |
| End of Therapy | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 85.0 units on a scale | Standard Deviation 11.5 |
| 6 Months After End of Therapy | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum A) | 89.1 units on a scale | Standard Deviation 11.6 |
Other Pre-specified
Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum B)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Stratum B1 | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum B) | 67.7 units on a scale |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 3.0 Scores for Parent Cancer Quality of Life (QoL) Assessments (Stratum B) | 71.4 units on a scale |
Other Pre-specified
Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A)
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
Population: This QOL analysis included patients only within Stratum A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum B1 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 75.5 units on a scale | Standard Deviation 18.4 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 71.6 units on a scale | Standard Deviation 18.7 |
| Week 4 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 77.2 units on a scale | Standard Deviation 16.3 |
| Week 8 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 79.3 units on a scale | Standard Deviation 17.4 |
| Week 12 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 77.8 units on a scale | Standard Deviation 20.6 |
| Week 24 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 80.6 units on a scale | Standard Deviation 15.6 |
| End of Therapy | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 80.4 units on a scale | Standard Deviation 16.1 |
| 6 Months After End of Therapy | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 87.5 units on a scale | Standard Deviation 12.5 |
| 12 Months After End of Therapy | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum A) | 91.0 units on a scale | Standard Deviation 7.1 |
Other Pre-specified
Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Stratum B1 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) | 90.3 units on a scale |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) | 93.1 units on a scale |
| Week 4 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) | 72.8 units on a scale |
| Week 8 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) | 79.2 units on a scale |
| Week 12 | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) | 68.1 units on a scale |
| End of Therapy | Mean Total PedsQL 4.0 Scores for Child Quality of Life (QoL) Assessments (Stratum B) | 65.6 units on a scale |
Other Pre-specified
Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A)
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
Population: This QOL analysis included patients only within Stratum A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stratum B1 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 70.3 units on a scale | Standard Deviation 19.1 |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 71.8 units on a scale | Standard Deviation 16.4 |
| Week 4 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 74.4 units on a scale | Standard Deviation 17.9 |
| Week 8 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 79.1 units on a scale | Standard Deviation 16.6 |
| Week 12 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 79.0 units on a scale | Standard Deviation 19 |
| Week 24 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 82.2 units on a scale | Standard Deviation 14.5 |
| End of Therapy | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 87.5 units on a scale | Standard Deviation 15.3 |
| 6 Months After End of Therapy | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 86.0 units on a scale | Standard Deviation 17.6 |
| 12 Months After End of Therapy | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum A) | 87.3 units on a scale | Standard Deviation 17.5 |
Other Pre-specified
Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum B)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Stratum B1 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum B) | 77.6 units on a scale |
| Temozolomide/Peginterferon ɑ-2b Without Measureable Disease | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum B) | 72.2 units on a scale |
| Week 4 | Mean Total PedsQL 4.0 Scores for Parent Quality of Life Assessments (Stratum B) | 89.1 units on a scale |
Other Pre-specified
Median Steady State Trough Concentration of Pegylated Interferon ɑ-2B
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Median Steady State Trough Concentration of Pegylated Interferon ɑ-2B | 52.8 pcg/ml |
Other Pre-specified
Systemic Clearance (CL) of Interferon ɑ-2B
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Systemic Clearance (CL) of Interferon ɑ-2B | 15.3 l/hr/m^2 |
Other Pre-specified
Volume of Central Compartment (Vc) of Interferon ɑ-2b
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Volume of Central Compartment (Vc) of Interferon ɑ-2b | 25.1 l/m^2 |
Other Pre-specified
Volume of Central Compartment (Vc) of Pegylated Interferon ɑ-2B
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum B1 | Volume of Central Compartment (Vc) of Pegylated Interferon ɑ-2B | 772 ml/kg |