ch14.18 Pharmacokinetic Study in High-risk Neuroblastoma

• ClinicalTrials.gov Identifier: NCT01592045
• Recruitment Status: Completed
• First Posted: May 4, 2012
• Results First Posted: September 23, 2015
• Last Update Posted: September 23, 2015
• Sponsor: United Therapeutics
• Information provided by (Responsible Party): United Therapeutics

Tracking Information

• First Submitted Date: April 30, 2012
• First Posted Date: May 4, 2012
• Results First Submitted Date: June 3, 2015
• Results First Posted Date: September 23, 2015
• Last Update Posted Date: September 23, 2015
• Study Start Date: August 2012
• Actual Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 20, 2015)

• Area Under the Plasma Concentration Curve (AUC) [ Time Frame: 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 ]
  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
• Peak Plasma Concentration (Cmax) [ Time Frame: 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 ]
  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

Original Primary Outcome Measures (submitted: May 2, 2012)

Area under the plasma concentration curve (AUC) [ Time Frame: 6 months ]

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

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: May 2, 2012)

Number of Participants with Adverse Events as a Measure of Safety and Tolerability. [ Time Frame: Six months ]

Adverse events measured throughout study.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ch14.18 Pharmacokinetic Study in High-risk Neuroblastoma
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neuroblastoma

Intervention

• Biological: ch14.18 -NCI
  25 mg/m^2/day IV for four consecutive days
• Biological: ch14.18-UTC
  17.5 mg/m^2/day IV for four consecutive days
• Biological: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
  GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5.
• Biological: Aldesleukin (IL-2)
  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.
• Drug: Isotretinoin

  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).

  Other Name: 13-cis-retinoic acid

Study Arms

• Experimental: Sequence 1
  UTC ch14.18 for two courses and NCI ch14.18 for three courses
  Interventions:

  • Biological: ch14.18 -NCI
  • Biological: ch14.18-UTC
  • Biological: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
  • Biological: Aldesleukin (IL-2)
  • Drug: Isotretinoin
• Experimental: Sequence 2
  NCI ch14.18 for two courses and UTC ch14.18 for three courses
  Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 2, 2012): 28
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 2014
• Actual Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 8 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01592045
• Other Study ID Numbers: DIV-NB-201
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: United Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: United Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Araz Marachelian, MD; Children's Hospital Los Angeles

• PRS Account: United Therapeutics
• Verification Date: August 2015