ch14.18 Pharmacokinetic Study in High-risk Neuroblastoma

Study Overview
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Brief Summary
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The purpose of this study is to compare the pharmacokinetics (blood levels) and safety of chimeric (ch) 14.18 manufactured by two independent drug makers (United Therapeutics [UTC] or the National Cancer Institute [NCI]).

Detailed Description
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This is a multi-center, randomized, open-label, two-sequence, cross-over study for eligible subjects with high-risk neuroblastoma to assess the comparability of ch14.18 manufactured with UTC drug product and ch14.18 manufactured with NCI drug product. Subjects will be randomly allocated to receive ch14.18 manufactured by UTC or NCI during Courses 1 and 2 followed by ch14.18 manufactured by other manufacturer (UTC or NCI) during Courses 3, 4, and 5.

Official Title
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A Comparative Pharmacokinetic and Safety Study of Chimeric Monoclonal Antibody ch14.18 With Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interleukin-2 (IL-2) and Isotretinoin in High Risk Neuroblastoma Patients Following Myeloablative Therapy

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: ch14.18 -NCI
* Biological: ch14.18-UTC
* Biological: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
* Biological: Aldesleukin (IL-2)
* Drug: Isotretinoin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of high-risk neuroblastoma 8 years of age or younger at diagnosis of high-risk neuroblastoma Patients must have completed therapy including intensive induction followed by autologous stem cell transplantation (ASCT) and radiotherapy * Radiotherapy may be waived for patients who either have small adrenal masses which are completely resected up front, or who never have an identifiable primary tumor Must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases, and bone metastases AND must also meet the protocol specified criteria for bone marrow response as follows: * No more than 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy Patient who have no tumor seen on the prior bone marrow, and then have ≤ 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible No more than 12 months from starting the first induction chemotherapy after diagnosis to the date of ASCT * For patients who became high-risk neuroblastoma after initial non-high risk disease, the 12 months period should start from the date of induction therapy for high-risk neuroblastoma to the date of ASCT No progressive disease at time of registration except for protocol-specified bone marrow response Adequate hematological, renal, hepatic, pulmonary and cardiac function CNS toxicity < Grade 2 Exclusion Criteria: Prior anti-GD2 antibody therapy Prior vaccine therapy for neuroblastoma Concurrent anti-cancer or immunosuppressive therapy

Ages Eligible for Study
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Maximum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1<br>UTC ch14.18 for two courses and NCI ch14.18 for three courses | Biological: ch14.18 -NCI<br>* 25 mg/m^2/day IV for four consecutive days<br>Biological: ch14.18-UTC<br>* 17.5 mg/m^2/day IV for four consecutive days<br>Biological: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)<br>* GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5.<br>Biological: Aldesleukin (IL-2)<br>* Aldesleukin (IL-2) will be administered IV at a dose of 3 MIU/m^2/day for the first week and at a dose of 4.5 MIU/m^2/day for the second week during Courses 2 and 4.<br>Drug: Isotretinoin<br>* Isotretinoin (13-cis-retinoic acid; ISOT) will be administered by mouth over six courses as follows: If weight > 12 kg: 80 mg/m^2/dose twice daily (total daily dose is 160 mg/m^2/day, divided twice daily). If weight ≤ 12 kg: 2.67 mg/kg/dose twice daily (total daily dose is 5.33 mg/kg/day, divided twice daily).<br>* Other names: 13-cis-retinoic acid;|
| Experimental: Sequence 2<br>NCI ch14.18 for two courses and UTC ch14.18 for three courses | Biological: ch14.18 -NCI<br>* 25 mg/m^2/day IV for four consecutive days<br>Biological: ch14.18-UTC<br>* 17.5 mg/m^2/day IV for four consecutive days<br>Biological: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)<br>* GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5.<br>Biological: Aldesleukin (IL-2)<br>* Aldesleukin (IL-2) will be administered IV at a dose of 3 MIU/m^2/day for the first week and at a dose of 4.5 MIU/m^2/day for the second week during Courses 2 and 4.<br>Drug: Isotretinoin<br>* Isotretinoin (13-cis-retinoic acid; ISOT) will be administered by mouth over six courses as follows: If weight > 12 kg: 80 mg/m^2/dose twice daily (total daily dose is 160 mg/m^2/day, divided twice daily). If weight ≤ 12 kg: 2.67 mg/kg/dose twice daily (total daily dose is 5.33 mg/kg/day, divided twice daily).<br>* Other names: 13-cis-retinoic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Curve (AUC) | Twenty-two PK samples will be obtained at the following timepoints: Courses 1 and 3: Day: 0 Days: 3, 4, 5 and 6: post ch14.18 Days 7:10 to 14 hours post ch14.18 Days 9 to 11: Single sample Days 14 to 17: Single sample Courses 2 and 4: Day 0: Pre-IL-2 Day 7: Pre-ch14.18 Day 10 (Course 4 only): Post ch14.18 End of Treatment: Within 2 weeks post isotretinoin | PK samples obtained during Courses 1 and 3: Days 0, 3, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, 17; PK samples obtained during Courses 2 and 4: Days 0, 7, 10; End of Treatment | 
| Peak Plasma Concentration (Cmax) | Twenty-two PK samples will be obtained at the following timepoints: Courses 1 and 3: Day: 0 Days: 3, 4, 5 and 6: post ch14.18 Days 7:10 to 14 hours post ch14.18 Days 9 to 11: Single sample Days 14 to 17: Single sample Courses 2 and 4: Day 0: Pre-IL-2 Day 7: Pre-ch14.18 Day 10 (Course 4 only): Post ch14.18 End of Treatment: Within 2 weeks post isotretinoin | PK samples obtained during Courses 1 and 3: Days 0, 3, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, 17; PK samples obtained during Courses 2 and 4: Days 0, 7, 10; End of Treatment |