Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes.

PURPOSE: We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.

The impact of gross total resection on local control and survival in high-risk neuroblastoma.

BACKGROUND/PURPOSE: Gross total resection of the primary tumor in treatment of high-risk neuroblastoma remains controversial. Furthermore, there are few reports of the effect of primary tumor resection on local control as opposed to overall survival. The authors reviewed their institutional experience to assess the effect of primary tumor resection on local control and overall survival. METHODS: A total of 141 patients were treated on protocol between November 1, 1979 and June 25, 2002 and are the subject of this report. Gross total resection was assessed by review of operative notes, postoperative computerized axial tomograms, and postoperative meta-iodobenzyl guanidine (MIBG)1 scans when available. RESULTS: The median age was 3.3 years, and all patients were International Neuroblastoma Staging System (INSS) stage 4 with 79% having metastases to cortical bone. The primary site was the adrenal gland in 74%, the central abdominal compartment in 13%, the posterior mediastinum in 7%, and other sites in 6%. Gross total resection was accomplished in 103 (73%) but was more than 90% for the last 3 protocols. Five kidneys were lost overall. The probability of local progression was 50% in unresected patients compared with 10% in patients undergoing gross total resection (P <.01). Overall survival rate in resected patients was 50% compared with 11% in unresected patients (P <.01). CONCLUSIONS: Our data indicate that local control and overall survival rate are correlated with gross total resection of the primary tumor in high-risk neuroblastoma. Gross total resection should be part of the management of stage 4 neuroblastoma in patients greater than 1 year of age.

Neuroblastoma in adolescents and adults: the Memorial Sloan-Kettering experience.

BACKGROUND: We reviewed the utility of different treatment modalities in a large series of adolescents/adults with neuroblastoma (NB). PROCEDURE: The 30 adolescents/adults (median age, 19 years) had stage 2B (n = 1), 3 (n = 2), or 4 (n = 27) NB. Treatments included conventional and myeloablative therapy; local radiotherapy (RT); immunotherapy with anti-G(D2) 3F8 monoclonal antibody +/- granulocyte-macrophage colony-stimulating factor (GM-CSF); and 3F8 alternating with low-dose oral etoposide. RESULTS: Seven patients are in first (n = 4) or second (n = 3) complete/very good partial remission (CR/VGPR) at 9+ to 181+ (median, 45+) months. Among 13 newly diagnosed or minimally prior-treated patients, no major responses were seen in 4/4 treated with N4/N5 chemotherapy, but 6/9 treated with the higher dose N6/N7 regimens and surgery had major responses, and immunotherapy produced CR in BM in three patients. Among 17 patients referred because of resistant NB, favorable responses occurred in 6/12 treated with high-dose cyclophosphamide-based salvage therapy, including one patient who is in CR 170+ months after myeloablative consolidation and five patients who achieved CR/VGPR after 3F8/GM-CSF (n = 4) or 3F8/oral etoposide (n = 1). With a median follow-up of 32+ months post-RT, no local relapses occurred in 10/10 patients who received hyperfractionated 21 Gy RT to prevent regrowth of soft tissue masses that had been resected. CONCLUSIONS: High-dose chemotherapy and surgery can achieve a minimal disease state in >50% of newly diagnosed older NB patients. In that setting, local RT, and the use of agents with recently confirmed anti-NB activity, including anti-G(D2) antibodies, and cis-retinoic acid, may improve the poor prognosis of these patients reported to date.

Quantitation of GD2 synthase mRNA by real-time reverse transcriptase polymerase chain reaction: clinical utility in evaluating adjuvant therapy in neuroblastoma.

PURPOSE: Minimal residual disease (MRD) is one of the final hurdles to cancer cure. Because therapy (myeloablation, immunotherapy, or differentiation) for MRD is applied at the time of clinical remission, objective surrogate markers are needed to gauge treatment efficacy. PATIENTS AND METHODS: Using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) of GD2 synthase (beta1,4-N-acetylgalactosaminyltransferase, EC 2.4.1.92) mRNA, we evaluated MRD response to anti-GD2 monoclonal antibody 3F8 adjuvant therapy, namely, one cycle of radioimmunotherapy using iodine-131 ((131)I)-3F8 plus one cycle of unlabeled 3F8 in 45 stage 4 neuroblastoma patients (newly diagnosed or without prior relapse) on the N7 protocol at Memorial Sloan-Kettering Cancer Center. The prognostic effect of MRD in their bone marrows before and after this phase of adjuvant therapy on progression-free survival (PFS) and overall survival (OS) was also analyzed. RESULTS: Before 3F8 treatment, 24 of 45 patients were in complete remission (CR), 12 were in very good partial remission (VGPR), and nine were in partial remission (PR), according to criteria from International Neuroblastoma Staging System plus (131)I-3F8 scan; 71% had detectable tumor cells in marrow by real-time RT-PCR. Of the 32 positive patients, 20 became negative after therapy, with a 63% efficacy. When patients were stratified by CR/VGPR versus PR, GD2 synthase positivity was prognostic when detected before 3F8-targeted therapy (PFS, P =.045 and OS, P =.010). Persistent marker positivity was also predictive of PFS (P =.035) and OS (P =.027). Patients who succumbed to the disease had transcript levels four times higher than those who remain alive. CONCLUSION: GD2 synthase mRNA is a useful surrogate marker for evaluating adjuvant treatment efficacy in neuroblastoma with prognostic potential.

Chronic neuroblastoma.

BACKGROUND: An indolent course is associated with neuroblastoma (NB) in adolescents and adults. In the current study, the authors analyzed this phenomenon in a large series of children with metastatic NB. METHODS: The authors studied 38 patients who were diagnosed with NB in the first decade of life and had metastatic disease 5 years or more from diagnosis. RESULTS: The median age at diagnosis was 3 years 10 months. MYCN was amplified in 2 of 28 patients tested. Of 30 patients with classic Stage 4 NB, 9 had a late first recurrence of disease (4.3-13 years from diagnosis). Of eight patients who had atypical cases at diagnosis (one isolated mandibular lesion, two Stage 4-N, five non-Stage 4), six had a late first distant recurrence of disease (4 years 11 months-38 years 8 months). Nineteen patients were off therapy continuously for 3 years or more before disease recurred a first or second time. Myeloablative therapy was used to consolidate a first or second response in 27 patients. High-dose conventional therapy helped to achieve a second remission of disease in 9 of 20 patients assessable for response of first recurrence but achieved no major responses of second or third relapse in 10 of 11 patients. The combination of anti-G(D2) immunotherapy and/or cis-retinoic acid, targeted radiotherapy, and multiple cycles of chemotherapy with modest toxicity helped prolong survival. Twelve patients survive at 5 years 6 months+ to 19 years 4 months+ from diagnosis (median, 6 years 10 months+), including four with complete remission of disease; 10 received anti-G(D2) immunotherapy after recurrence. The other 26 patients died of disease (n = 22) or toxicity (n = 4) at 5 years-41 years 5 months from diagnosis (median, 6 years 5 months). CONCLUSIONS: The concept of indolent or smoldering NB should not be limited to adolescents/adults. The expanding repertoire of anti-NB treatments, including biologic therapies and chemotherapy regimens of modest toxicity, can convert childhood NB into a chronic disease with prolonged survival after recurrence.