Background and Aims

BEACON is a randomized phase 2 trial assessing whether bevacizumab adds to chemotherapy and evaluating chemotherapy regimens for RR-HRNB.

Methods

Patients with RR-HRNB underwent randomizations, in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were already reported. Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B randomizations are reported here (To rand continued). The B randomization used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I randomization was Bayesian. Cox model hazard ratios (HR) <1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat.

Results

From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with median follow-up 15.4 months. B randomization: HR (95%CI) for PFS and OS were 0.85(0.59-1.23) and 0.84(0.56-1.24) respectively. I randomization: HR (95%CI) for PFS and OS were 0.66(0.43-1.00) and 0.63(0.41-0.99). I improved PFS and OS (98% probability that true HR<1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19).There was some, but not conclusive, evidence of a positive interaction between B and I for both PFS (HT:p=0.06) and OS (HT:p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both (BIT) does.

Conclusions

The BEACON results show that single agent T is suboptimal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are better than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evaluation is needed.

Background and Aims

In preclinical and phase I studies, naxitamab displayed greater G_D2 affinity and enhanced antibody-dependent cellular cytotoxicity (ADCC) compared to other anti-GD2 antibodies; substantial but less complement activation; safe dosing >2.5x higher than dinutuximab and murine-3F8; low immunogenicity; major anti-neuroblastoma activity; and pharmacokinetics supporting 3 doses/cycle administered outpatient (JAMA Oncol 2018;4:1729). GM-CSF is well-tolerated, exerts dose-response ADCC (Blood 1989;73:1936), and significantly improves outcome with murine-3F8 (JCO 2012;30:426).

Methods

In this phase II study (NCT01757626) for disease restricted to bones and/or marrow, patients with primary refractory neuroblastoma (persistent but no prior progressive disease [PD]) (Group 1) or secondary refractory disease (persistent disease post-treatment for PD) (Group 2) received naxitamab 9mg/kg/cycle (~270mg/m²/cycle) divided into 3 doses infused (0.5-1.5hrs) Mon-Wed-Fri. GM-CSF started 5 days pre-naxitamab at 250µg/m²/day, then stepped-up to 500µg/m²/day with naxitamab. Initial cycles were monthly. International criteria (JCO 2017;35:2580) defined responses. This study is being supplanted by an international trial (NCT02502786) opened for pursuing FDA approval of naxitamab (already accorded Breakthrough Therapy Designation).

Results

We report on 80 of 120 planned patients enrolled 2016-2019. Group 1 patients (n=29) were 2.0-to-12.1 (median 4.6) years old at enrollment and 4.9-to-19 (median 6.5) months post-diagnosis. Seven previously received chemo-immunotherapy. Four were inevaluable for response (prior radiotherapy to the only positive sites or only ganglioneuroma in marrow). Responses among the other 25 patients were: complete (CR) 11(44%), partial (PR) 10(40%), stable disease (SD) 4(16%). Group 2 patients (n=51) were 2.2-to-32.9 (median 6.9) years old at enrollment, 0.4-to-10.8 (median 2.7) years post-diagnosis, and had 1-to-7 (median 2) prior episodes of PD. Forty-seven previously received >1 anti-G_D2 antibodies. Ten were inevaluable for response (prior radiotherapy). Responses among the other 41 patients were: CR 10(24%), PR 6(15%), SD 15(37%), PD 10(24%). Treatment was outpatient.

Conclusions

Notable efficacy and convenience to patients support further development of naxitamab.

Background and Aims

Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare.

We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a HITS patient restricted use against resistant HR-NB following the phase II study (NCT03189706).

Methods

Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria.

Results

Forty-four (36 evaluable and 8 non-evaluable) heavily prior-treated patients (median age at enrollment: 6 years; median number of prior relapses: 2) have received 210 (median 6; range 1-14) cycles to date. 16 patients had HR-NB refractory to induction chemotherapy while 28 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other >grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 17 (47%) of 36 evaluable patients and were complete (n=11), and partial (n=6); 10 patients had stable disease. Nine (25%) patients progressed before or at cycle 2 evaluation. 1-year progression-free survival is 37.0%, 95% CI (21.8%, 62.9%), median time to progression 9.2 months. 1-year Overall Survival is 55%, CI (39.4%, 76.9%).

Conclusions

High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB.

Background and Aims

A neuroblastoma cancer vaccine consisting of keyhole limpet hemocyanin-conjugated lactonized gangliosides GD2 and GD3 and a saponin adjuvant (OPT-821) given subcutaneously, plus oral beta-glucan elicits anti-GD2 and anti-GD3 antibody titers against neuroblastoma. This vaccine was proven safe in a phase I trial (Clin Can Res 2014;20:1375). Dose-limiting toxicities were not encountered, and phase II OPT-821 dose was established. >250 additional patients have been treated on an ongoing phase II expansion study (NCTNCT00911560). Here we report toxicity data on the first completed stage of the phase II trial in patients in remission after prior progressive disease (PD)

Methods

Toxicities were scored using CTC version 3 for 24 months after starting treatment or until PD, whichever was earlier.

Results

102 patients were evaluated for toxicities (median follow-up 18.9 [range 1.5-24] months). There were no related serious adverse events, >grade 3 toxicities, hospitalizations, neuropathy, neuropathic pain, ophthalmoplegia, or capillary leak syndrome. All patients experienced grade 1 or 2 pain at injection sites. Other related toxicities occurred <1 week post-injection: ALT elevation (22%) (grade 3=1 patient; grade 2=2, grade 1=19), AST elevation (25%) (grade 2=3, grade 1=23), injection-site reactions (83%) (grade 2=44, grade 1=39), fever (50%) (grade 2=32; grade 1=18), grade 1 pruritus (6%) and grade 2 urticaria (2%). Toxicities possibly related to beta-glucan were grade 1 vomiting/nausea (11%), grade 1 diarrhea(3%) and grade 2 urticaria (1%). All clinical toxicities lasted <1 week from onset. Fever was managed with antipyretics for <48 hours. All laboratory abnormalities were self-limited. No long-term toxicities were documented.

Conclusions

Bivalent GD2/GD3 neuroblastoma cancer vaccine was a well-tolerated outpatient treatment. The mild and transient toxicities were similar to those in the phase I trial. Efficacy and biomarker analyses are underway. Results of patients treated in first remission will be reported separately. A randomized study comparing the role of beta-glucan is actively accruing patients.

Background and Aims

We present results of a phase I/II-trial with subsequent immunotherapy with anti-GD2mAb (CH14.18/CHO) after HLA mismatched, haploidentical stem cell transplantation (SCT) in pediatric patients with relapsed metastatic neuroblastomas.

Methods

T- and B-cell depleted stem cells from parental donors were used in combination with Melphalan140mg/m², Thiotepa10mg/kg, Fludarabin160mg/m² and ATG-F. Infusions with CH14.18/CHOmAb were started on day 60-180 posttransplant: 6 cycles with 20mg/m²/day x 5 days; in cycles 4-6, 1x10⁶ U/m² Interleukin 2 (IL2) was given additionally. Disease status was evaluated with MRI, MIBG and BM-aspirates.

Results

68 patients with 1^st to 5^th metastatic relapse were enrolled, relapse treatment comprised induction chemotherapy, surgical intervention and local irradiation if possible.

Stem cell transplantation was well tolerated without TRM. Induction of late onset GvHD (during antibody treatment) was seen in two patients. Frequent side effects of antibody treatment were pain, fever and CRP elevation; rare side effects SIRS, seizures, and accommodation disturbances.

Thirteen of twenty-four patients (54,2%) who achieved CR already prior to antibody treatment, could maintain a complete remission (CR), 20/36 patients (55%) with partial remission prior to antibody treatment achieved CR or could significantly reduce their tumour load after the last cycle of antibody administration. 2/8 patients (25%) with NR (stable disease/mixed resp.) responded only transiently.

Thus, success of treatment, defined as stable disease or improvement after the last treatment cycle, was shown in 58,8%. Overall survival at 2 and 3 years was 68,6% and 58%. Event free survival at 2 and 3 years was 51,2% and 46,9% (median follow up: 2.5 years).

Significant factors of influence on OS and EFS were: remission status prior to SCT and bone marrow (BM) involvement after SCT.

Conclusions

CH14.18/CHO infusions after haploidentical SCT appear to be feasible without increased risk of inducing GvHD. Results suggest an anti-tumour effect of the new, donor-derived immune system.

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Background and Aims

Minimally invasive surgery (MIS) is now considered for resection of neuroblastomas without image-defined risk factors (IDRFs). We present preliminary results of robotic surgery for pediatric neuroblastic tumors (NT) with the Da Vinci Xi surgical system dedicated to a tertiary paediatric surgical centre.

Methods

Retrospective analysis of prospectively collected data from October 2016 to December 2019. Gender, age, diagnosis, image-defined risk factors (IDRFs), surgical indication, operative time, conversion, bleeding, post-operative complications, hospital stay and short-term outcome were assessed prospectively.

Results

71 tumors were resected by three surgeons during 65 procedures (among 296 during the same period : 24%) in 61 children. Seventeen NT (8 neuroblastoma, 6 ganglioneuroma, 3 ganglioneuroblastoma) were operated in 15 children by 2 attending surgeons. The median age was 5.7 years (3.9–13.4); the youngest was 10 month-old. The median weight was 16 kg (12–54) with the smallest weighing 8 kg. Six were adrenal (38%), three thoracic (19%), two presacral (12%), one inter aortico cave, one around the renal pedicle (adrenal healthy), one prerenal, one Zuckerkandl and one paravaginal.

Six patients had 7 IDRFs at the preoperative imaging workup (43%). IDRFs were: contact with (n=5) or encasement (n=1) of the renal pedicle, encasement of the vena cava in the last case, which was converted. No per or post-operative complication occurred. None of the patient presented local recurrence or metastatic relapse (for neuroblastoma or ganglioneuroblastoma cases) at a mean follow up of 1.2 years.

Conclusions

Robotic surgery for NT in children is feasible and safe in highly selected children. In some selected positive IDRFs, such as renal pedicle encasement aorta/cava vein encasement, robotic surgery seems to enhance the security of the dissection when compared to classical MIS. Careful patient selection is crucial and requires high volume centers.