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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Peginterferon alfa-2b; Drug: Temozolomide; Drug: Recombinant interferon alfa-2b

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 Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • The Children's Cancer Hospital at UT M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	8 weeks
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)	52 weeks
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)	52 weeks
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.	3 years from diagnosis

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28
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.	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28
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.	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28
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.	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28
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.	Before first dose, and 24, 96 and 168 hours after dose during weeks 5 and 28
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.	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion
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.	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion
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.	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion
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.	Before first dose, and 1, 2, 4, 6, 8, 12, and 24 hours postinfusion
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.	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Pretherapy; Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Weeks 2, 4, 8, 12, and 24; and End of therapy at 6 months and 12 months post
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.	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy
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.	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy
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.	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy
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.	Pretherapy, Week 4, Week 24, End of Therapy, and 6 Months Post End of Therapy

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Schering-Plough
• Investigators: Principal Investigator: Alberto Pappo, MD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2008
• Primary Completion (Actual): June 1, 2015
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: October 2, 2007
• First Submitted That Met QC Criteria: October 3, 2007
• First Posted (Estimated): October 4, 2007

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Cutaneous Melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Interferons; Interferon-alpha; Temozolomide; Interferon alpha-2; Peginterferon alfa-2b
• Other Study ID Numbers: MEL06; NCI-2011-01192 (Registry Identifier: NCI Clinical Trials Registration Program ID)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No