Background and Aims

The prognosis for metastatic tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic modalities is critical. The cell-surface glycoprotein B7H3 is expressed on a range of solid tumors with 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.

Methods

We conducted a phase I trial of intraventricular ¹³¹I-omburtamab (clinicaltrials.gov NCT00089245) 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 followed by therapeutic ¹³¹I-omburtamab dose-escalated from 370-2960 MBq. Toxicity was graded using CTCv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and 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

38 patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n=16) and other B7H3-expressing solid tumors (n=22). 35 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 1850MBq/injection. Median radiation dose to the CSF and blood was 1.01 and 0.04 mGy/MBq respectively, iindicating a high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing anti-drug antibodies (38%), 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.

Background and Aims

Long term survival in HRNB patients remains a challenge with relapse as the primary cause of mortality. DFMO has been evaluated as a maintenance therapy in a single arm study designed to compare EFS outcomes with rates from the Phase 3 Children’s Oncology Group ch14.18 immunotherapy trial, ANBL0032.

Methods

A DFMO phase 2 trial enrolled a total of 140 HRNB patients at the completion of disease treatment from 2012 to 2016. Patients received 2 years of DFMO and were followed for 7 years. ANBL0032 enrolled a total of 1328 HRNB patients from 2001 to 2015 who were assigned to treatment with ch14.18 immunotherapy and followed for 10 years. With FDA input, selection rules were defined to identify like groups of treated and control patients. The Kaplan-Meier method and Cox regression analyses were used to compare EFS and overall survival (OS). Additional analysis utilizing propensity score matching (PSM) was performed to balance cohorts on baseline demographic and disease characteristics, matching each treated patient with the 3 closest scored control patients.

Results

A total of 92 treated patients and 852 control patients met selection criteria. Eighty-seven of the treated group had verified participation in ANBL0032 immediately prior to enrollment in the DFMO trial. EFS from end of immunotherapy was significantly improved in the DFMO group (n = 92) vs. control group (n = 852), with hazard ratio of 0.50 (95% CI: 0.29, 0.84) and p-value of 0.0083. Four-year EFS was 83.7% (95% CI 74.4, 89.8) in the DFMO group versus 71.7% (95% CI 68.5, 74.7) in the control group. OS and PSM analyses demonstrated consistent results.

Conclusions

Patients treated with DFMO after standard upfront therapy had approximately half the risk of relapse compared to control patients. The PSM comparisons support the benefit of DFMO as a maintenance treatment for HRNB.

Background and Aims

The BEACON phase II trial (NCT02308527) addressed multiple questions in children with relapsed/refractory high-risk neuroblastoma (RR-HRNB). We present the dinutuximab beta (dB) randomisation and report progression-free survival (PFS) results for all trial randomisations (bevacizumab, irinotecan, topotecan and dB).

Methods

Following a factorial multi-arm design, patients aged 1-21 years with RR-HRNB were randomised to 8 arms containing temozolomide, irinotecan-temozolomide or topotecan-temozolomide alone or in combination with bevacizumab or dB. Primary outcome measure was best response (complete or partial) during the first 6 courses of treatment, by RECIST or International Neuroblastoma Response Criteria for patients with measurable and evaluable disease respectively. PFS, overall survival (OS) and safety were secondary outcomes.

Results

From 2013 to 2021, 225 patients were randomised as follows: bevacizumab (n=160), irinotecan (n=120), topotecan (n=80) and dB (n=65) randomisations. Baseline characteristics were balanced between arms. For the dB randomisation, the objective response rate was 18% with chemotherapy alone and 35% for patients receiving chemotherapy with dB (risk ratio 1.66, 95% confidence interval (CI) 0.65 to 4.24, 1p=0.19). 1-year PFS was 27% for chemotherapy alone, and 57% for those receiving chemotherapy+dB (HR 0.63, 95% CI 0.32 to 1.25, p=0.19). Nine (41%) patients receiving chemotherapy alone and 13 (30%) receiving chemotherapy+dB had grade ≥3 toxicities (CTCAE v4.0). Neurotoxicities were more common in patients receiving dB compared to chemotherapy alone (Grade 1-2: 67.4% vs 13.6%, Grade 3: 9.3 vs 0%).

Hazard ratios for PFS for all other randomisations were: bevacizumab HR=0.84 (95%CI 0.56-1.27), irinotecan HR=0.58 (95%CI 0.38-0.88) and topotecan HR=0.64 (95%CI 0.38-1.08). Within this phase 2 trial, success criteria for PFS were met by the irinotecan, bevacizumab and dinutuximab beta randomisations.

Conclusions

The BEACON Neuroblastoma trial evaluated three chemotherapy regimens and two novel agents, identifying promising combinations for future trials in relapsed neuroblastoma patients.

Background and Aims

Up to 10% of patients with stage 4 neuroblastoma develop CNS/leptomeningeal metastases (LM); limited curative therapies exist. Omburtamab is a murine monoclonal antibody that targets B7-H3, a transmembrane glycoprotein highly expressed in neuroblastoma and other solid tumors. Omburtamab can be labeled with iodine-131 and administered into the cerebrospinal fluid via an indwelling catheter to achieve a high CSF:blood ratio. We report a planned interim analysis for Trial 101, a phase-2/3 trial of intraventricular ¹³¹I-omburtamab in patients with refractory or relapsed CNS/LM neuroblastoma.

Methods

Trial 101 (NCT03275402) is a single-arm, international study (4 US and 1 Spain) in patients aged 0-18 years with radiographically and/or histologically confirmed CNS/LM neuroblastoma. Treatment consisted of a 2 mCi ¹³¹I-omburtamab dosimetry dose followed one week later with 50 mCi ¹³¹I-omburtamab and 4-week observation period. Up to 2 therapy injections were permitted. The primary endpoint was CNS/LM progression-free survival (PFS) at 6 months with overall survival (OS) at 12 months as a secondary endpoint. Long-term follow-up is ongoing.

Results

As of 1 June 2021, 32 patients were included in the full efficacy and safety analysis, of which 26 received a dosimetry dose. The estimated CNS/LM PFS at 6 months was 77.2% (95% CI 58.0-88.4), and 12-month OS was 73.5% (95% CI 53.8-85.8). There were 19 serious treatment-emergent adverse events in 13 patients mostly related to myelosuppression. One patient suffered a fatal intracranial hemorrhage occurring 7 weeks after ¹³¹I-omburtamab treatment in the setting of grade 4 thrombocytopenia.

Conclusions

Interim results suggest that targeted radioimmunotherapy with intraventricular ¹³¹I-omburtamab may provide a survival benefit for patients with neuroblastoma and CNS/LM metastases.

Background and Aims

SIOPEN data from the INES trial (1999-2004) revealed a 5-year overall survival (OS) between 100% in infants without risk factors and 27% in infants with MYCN amplification. We examined population-based survival of infants (age<1 year) with neuroblastoma in six countries.

Methods

Records of infants registered with neuroblastoma in 2000-2009 in the population-based cancer registries of England, France, Germany, Italy (Piedmont), Spain (selected regions) and Switzerland were complemented from clinical records with detailed information on diagnosis, stage, treatment and outcome. OS with 95% confidence interval (95%CI) was calculated using the life-table method and differences in outcome between the patients’ subgroups assessed by hazard ratio (HR) of death and its 95%CI using Cox models adjusted for country.

Results

Overall, 1683 infants were diagnosed: between 10% (Italy) and 28% (Germany) in the first month of life. Patients (99%) were treated in paediatric oncology units. Mean follow-up of survivors was 9.9 years. OS for N=1665 infants with follow-up was 91.5% (90.1,92.8) and did not differ by country. Girls (N=748, HR=0.7, p=0.03) had better survival than boys (N=917). Prenatal (N=95, HR=0.4, p=0.06) and incidental (N=188, HR=0.5, p=0.006) diagnosis was associated with a better prognosis than postnatal (N=759) or symptomatic (N=661) diagnosis, respectively. Infants with metastatic disease (N=406 of 941) had a poor prognosis (HR=7.02, p<0.0001). OS was 98.9% (97.6, 99.5) with stage 1 and 2 (localised, N=599), 95.9% (92.8, 97.6) with stage 3 (N=291), 87.4% (83.6, 90.4) with stage 4S (N=369) and 75.0% (69.3, 79.9) with stage 4 (N=261). Localised tumours represented between 21% (Switzerland) and 49% (Italy). MYCN was amplified in 12.5% (96 of 771 studied) patients, whose OS was 48.6% (38.2,58.2) and HR=12.1 (8.0,18.4).

Conclusions

Principal predictors of survival were MYCN amplification and stage at diagnosis. Enriching registry data with clinical records is a labour intensive, but a feasible method to evaluate prognosis of rare diseases.

Background and Aims

Neuroblastoma (NB) has a high incidence of treatment failure and relapse. Early detection, and monitoring of recurrent disease through monitoring of disease status through blood borne biomarkers could enable more specific and sensitive monitoring, whilst minimising invasive tests. We hypothesised that circulating nucleosomal DNA attached to histone H3.1 could serve as a marker of cancer burden suitable for diagnostic and longitudinal monitoring.

Methods

We have collected serial plasma samples at diagnosis and through treatment from a total of 66 children with solid tumours. Using a novel antibody based immunoassay (Volition nucleosome assay), we measure cell-free DNA associated with histone H3.1 and expressed results as normalised nucleosome concentration. Cell free DNA was also evaluated for tumour-specific mutations using panel and low coverage whole genome sequencing.

Results

There is a significant reduction in plasma nucleosome concentration between diagnosis and treatment, and between on treatment and end of treatment groups (2way ANOVA: Diagnosis vs Treatment =P=<0.0001, Diagnosis vs EOT = P=0.0001).

For six neuroblastoma patients, we have correlated disease burden assessed at different time points by using MIBG scores with nucleosome values, and demonstrated close correlation in all patients. Phenomenologically we identify rises in nucleosome values that suggest subsequent relapse as determined by MIBG scan.

Conclusions

The levels of ctDNA determined by the Volition chromatin assay correlate well with disease appearance, response to treatment and could possibly predict relapse. Moreover, this is an accessible test as ELISAs are already installed in clinical laboratories and therefore could readily be translated to standard of care. Data on the same samples assessed by whole genome sequencing and panel sequencing are needed to determine relative sensitivity and specificity of nucleosome assessments with the sequencing-based technology. Nucleosome assessment could prove a high throughput and economically viable method for early detection of neuroblastoma diagnosis and relapse.