ANBL0032: Phase III Randomized Study of Chimeric Antibody 14.18 (Ch 14.18) in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue
Please note: As of amendment 9, accrual to regimen A (isotretinoin alone), is closed and all newly enrolled eligible patients will receive treatment per regimen B only (ch14.18 + cytokines in addition to isotretinoin). In the first cohort of randomized ANBL0032 patients, Regimen B has been proven to be effective, based on superior EFS and OS as compared to those patients randomized to regimen A.
Eligibility requirement for cross-over patients impacted by Amendment 9:
ANBL0032 Patients who were previously randomized to regimen A (isotretinoin alone) have the option of crossing over to regimen B (ch14.18 + cytokines in addition to isotretinoin) provided that:
1) The patient has not experienced disease progression since enrollment onto ANBL0032
2) The patient has NOT received any further anti-neuroblastoma therapy following completion of cis-RA therapy.
3) The patient meets all eligibility requirements noted in Sections 4.7 through 4.11.
A new informed consent was required to be signed by all existing patients, prior to initiation of further therapy after amendment #9 activation.
Patients will be stratified by pre-ASCT CR versus VGPR versus PR and by purging vs. non-purging of the stem cells for ASCT. All patients will receive isotretinoin (13-cis-retinoic acid, or RA) at 80 mg/m2/dose twice a day for 14 days every 28 days, for 6 courses. In addition, patients will receive 5 courses of ch14.18 + cytokines, with ch14.18 + GM-CSF administered in Courses 1, 3, and 5, and ch14.18 + aldesleukin (IL-2) given in Courses 2 and 4. The intervals between antibody administrations are 28 days for all courses.
Patients with persistent active disease documented by biopsy after the post ASCT / radiotherapy evaluation are eligible to enroll onto study under stratum 07. Biopsy is suggested but not required for persistent soft tissue density by CT, MRI, bone scan, or MIBG scan. Findings of MIBG scan can be used to guide biopsy but not as a criterion for proven active disease. Those who do not undergo biopsy will be enrolled and stratified based upon INRC disease response. The criteria for active disease in the bone marrow is based on morphological examination, regardless of the results of immunocytology and PCR analysis, since one of the study objectives of this protocol is to assess the value of the latter two parameters in detecting MRD.
Crossover patients are already enrolled on ANBL0032. Hence, re-enrollment of crossover patients is unnecessary and should NOT be attempted. A new Case Report Form (CRF) has been added which should be completed for crossover patients.
Patients enrolled after amendment #9 activation will NOT be allowed registration beyond Day 100 after ASCT.
This treatment regimen (ch14.18 plus GM-CSF/IL2 plus isotretinoin) has been proven to be effective in the context of starting therapy within the first 110 days following stem cell infusion (within 10 days of study enrollment). In addition, this regimen has significant toxicities which can be potentially life threatening and may be worsened at later times following ASCT (greater immune reconstitution may predispose to more stimulatory activation of immune mediated toxicity). Thus, since there is no evidence that this regimen is effective if initiated later than 110 days after ASCT, and it has significant associated toxicities, possibly worse with time, eligible patients (considered after amendment # 9 activation) must be able to enter this study within 100 days of ASCT.
All patients must be diagnosed with neuroblastoma and categorized as high risk at the time of diagnosis and must be ≤ 30.99 years of age. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible. Radiotherapy may be waived for patients who either had a small adrenal mass which was completely resected upfront, or who never had an identifiable primary tumor. No more than 12 months from the date of starting the first induction chemotherapy after diagnosis to the date of autologous stem cell transplantation (ASCT). The exception would be for the rare occasion regarding those subjects who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma, the 12 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT. For tandem ASCT patients, this will be the date of the FIRST stem cell infusion. At pre-ASCT evaluation patients must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases and bone metastases. Patients who meet those criteria must also meet the protocol specified criteria for bone marrow response: ≤10 % tumor seen on any specimen from a bilateral bone marrow aspirate/biopsy; patient who have no tumor seem 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. Prior to starting therapy on this study, a determination of mandatory disease staging must be performed prior to enrollment. This disease assessment is required for eligibility adn should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before enrollment. Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must be no later than ten calendar days after the date of study enrollment. Patients should be enrolled preferably between day 56 and day 85 after PBSC infusion. Patients must be enrolled no later than Day 100 after PBSC infusion. Enrollment must occur after completion of radiotherapy, and after completion of tumor assessment post-ASCT and radiotherapy. All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated in Section 4.9 below. Patients must not have received prior anti-GD2 antibody therapy. Patients must have a Lansky or Karnofsky Performance Scale score of ≥ 50% (see Appendix II) and patients must have a life expectancy of >2 months. Patients must have adequate organ functions at the time of registration as defined in the protocol. Written informed consent in accordance with institutional and FDA guidelines must be obtained from parent or legal guardian. Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding. Spanish-speaking patients will be eligible to participate in this study.