Neuroblastoma
Conditions
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.
Interventions
BIOLOGICALch14.18 -NCI
25 mg/m\^2/day IV for four consecutive days
BIOLOGICALch14.18-UTC
17.5 mg/m\^2/day IV for four consecutive days
GM-CSF will be administered SC at a dose of 250 mcg/m\^2/day for 14 days during Courses 1, 3, and 5.
BIOLOGICALAldesleukin (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.
DRUGIsotretinoin
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).
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 8 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Curve (AUC) | 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) | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 UTC ch14.18 for two courses followed by NCI ch14.18 for three courses
ch14.18 -NCI: 25 mg/m\^2/day IV for four consecutive days
ch14.18-UTC: 17.5 mg/m\^2/day IV for four consecutive days
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.
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.
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). | 14 |
| Sequence 2 NCI ch14.18 for two courses followed by UTC ch14.18 for three courses
ch14.18 -NCI: 25 mg/m\^2/day IV for four consecutive days
ch14.18-UTC: 17.5 mg/m\^2/day IV for four consecutive days
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.
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.
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). | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Disease Progression | 1 | 1 |
| Overall Study | Moved out of country | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence 2 | Sequence 1 | Total |
|---|---|---|---|
| Age, Continuous | 4 years | 4 years | 4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 10 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Pre-ASCT Response Complete Response (CR) | 3 participants | 5 participants | 8 participants |
| Pre-ASCT Response Partial Response (PR) | 7 participants | 4 participants | 11 participants |
| Pre-ASCT Response Very Good Partial Response (VGPR) | 4 participants | 5 participants | 9 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 12 Participants | 23 Participants |
| Region of Enrollment United States | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 27 | 27 / 27 |
| serious Total, serious adverse events | 17 / 27 | 12 / 27 |
Outcome results
Primary
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
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UTC ch14.18 | Area Under the Plasma Concentration Curve (AUC) | 518 mcg*hr/mL | Standard Deviation 418 |
| NCI ch14.18 | Area Under the Plasma Concentration Curve (AUC) | 470 mcg*hr/mL | Standard Deviation 376 |
Primary
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
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UTC ch14.18 | Peak Plasma Concentration (Cmax) | 6468 ng/mL | Standard Deviation 719 |
| NCI ch14.18 | Peak Plasma Concentration (Cmax) | 6689 ng/mL | Standard Deviation 853 |