Relapsed High-risk Neuroblastoma Research Articles

Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study

BackgroundShort-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.MethodsIn this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.ResultsOf the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108–290). Three-year progression-free and overall survival rates were 31% (95% CI 17–47) and 66% (95% CI 47–79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.ConclusionLong-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.Clinical trial registrationThe study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy. Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded. Responses were evaluated using the International Neuroblastoma Response Criteria. One hundred forty-six patients were included. Tumors were MYCN-amplified in 50 of 134 (37%). Seventy-one patients (49%) had an objective response to I/T/DIN/GM-CSF (objective response; 29% complete response, 14% partial response [PR], 5% minor response [MR], 21% stable disease [SD], and 30% progressive disease). Of patients with SD or better at first post-I/T/DIN/GM-CSF disease evaluation, 22% had an improved response per International Neuroblastoma Response Criteria on subsequent evaluation (13% of patients with initial SD, 33% with MR, and 41% with PR). Patients received a median of 4.5 (range, 1-31) cycles. The median progression-free survival (PFS) was 13.1 months, and the 1-year PFS and 2-year PFS were 50% and 28%, respectively. The median duration of response was 15.9 months; the median PFS off all anticancer therapy was 10.4 months after discontinuation of I/T/DIN/GM-CSF. Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.

A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N.

BackgroundHalf the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. “A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N” (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule.MethodsThe LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022.ResultsThe pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3–5 years.DiscussionIn this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.

Abstract 2045: Characterization of inpatient opioid use among pediatric neuroblastoma patients during dinutuximab therapy

Abstract Background: Dinutuximab is a chimeric anti-GD-2 (disialoganglioside) antibody approved for use in post-consolidation care of patients with high-risk neuroblastoma. GD-2 receptors are also expressed in cerebellar neurons, melanocytes, and peripheral sensory nerve fibers in normal human tissue. Given this pattern of expression, pain is a common and often infusion rate-limiting adverse effect, with greater than 50% of patients experiencing severe (Grade 3 or above) pain. Standard pain management for dinutuximab infusions at our center includes initiation of continuous infusion of opioid patient-controlled analgesia along with demand, loading, and boluses doses. Little to no data exist in the literature to describe opioid use in pediatric patients with acute, episodic pain. Therefore, this study aims to characterize opioid use in this setting. Methods: Data were collected retrospectively from the electronic medical record under a study protocol approved by the Institutional Review Board at the University of Michigan, C.S. Mott Children's Hospital. Patients were included in the study if they had a clinical diagnosis of metastatic or relapsed high-risk neuroblastoma, received at least one dinutuximab cycle, and were aged 2-14 at the time of admission. Daily amount of opioids, calculated as the oral morphine equivalent daily dose (MEDD), acetaminophen, and gabapentin administered were calculated. Repeated measures ANOVA was used to evaluate within-subjects changes. Results: The average age of patients was 5.7 years [range 2-14 years]. Four of eleven (36.4%) were female and 7/11 (63.6%) were male. All patients received four days of dinutuximab infusions for an average length of 11.8 hours (SD=2.0) per day. All patients received gabapentin prophylactic treatment and an average of 3387 mg (SD=1275.5). Average total MEDD across all patients was 184.7 mg (SD=137.6) during the inpatient hospitalization. Females (p=0.003) and older patients (p=0.04) had significantly increased daily MEDD as compared to their day 1 intake. All patients experienced a fever spike and received acetaminophen (2915 mg, SD=1737.8) Older patients received higher doses of acetaminophen (p=0.007) Only 1 patient met definition of a chronic opioid user and was discharged with an outpatient opioid prescription. The remaining opioid-naïve patients were discontinued on opioid treatment at the time of discharge. Conclusions: Pediatric patients on dinutuximab therapy received a high MEDD parenteral opioids dose alongside adjunctive analgesics. Future studies are needed to determine opioid requirement trends across gender, age, and cycles in a larger cohort of patients, as well as to determine the risk of chronic opioid use in this patient population. Citation Format: Jola Mehmeti, Jae Eun Choi, Ian Wolfe, Juan Cata, Rajen Mody. Characterization of inpatient opioid use among pediatric neuroblastoma patients during dinutuximab therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2045.

High-dose 131I-metaiodobenzylguanidine therapy in patients with high-risk neuroblastoma in Japan.

The aim of the study was to investigate the outcomes and prognostic factors of high-dose 131I-metaiodobenzylguanidine (131I-MIBG) therapy in patients with refractory or relapsed neuroblastoma (NBL) in Japan. We retrospectively analyzed 20 patients with refractory or relapsed high-risk NBL who underwent 131I-MIBG therapy with an administration dose ranging from 444 to 666MBq/kg at Kanazawa University Hospital, Japan, between September 2008 and September 2013. We focused on measurements regarding their initial responses, prognostic factors, survivals, and toxicities following 131I-MIBG therapy using our hospital data and questionnaires from the hospitals that these patients were initially referred from. Furthermore, we performed Kaplan-Meier survival analysis to evaluate event-free survival (EFS) and overall survival (OS). In 19 patients with complete follow-up data, the median age at first 131I-MIBG treatment was 7.9years (range 2.5-17.7years). Following 131I-MIBG therapy, 17 of the 19 patients underwent stem-cell transplantations, and their treatment response was either complete (CR) or partial (PR) in three and two cases, respectively. The EFS and OS rates at 1year following 131I-MIBG therapy were 42% and 58%, respectively, and those at 5years following 131I-MIBG therapy were 16% and 42%, respectively. Using the two-sample log-rank test, the OS time following 131I-MIBG therapy was significantly longer for < 3-year time interval between the initial diagnosis and 131I-MIBG therapy (p = 0.017), Curie score < 16 just before 131I-MIBG therapy (p = 0.002), without pain (p = 0.002), without both vanillylmandelic acid (VMA) and homovanillic acid (HVA) elevation (p = 0.037) at 131I-MIBG therapy, and with CR or PR following 131I-MIBG therapy (p = 0.015). Although severe hematological toxicities were identified in all 19 patients, severe nonhematological toxicity was not recorded in any patient, except for one patient with grade 3 anorexia and nausea. High-dose 131I-MIBG therapy in patients with refractory or relapsed high-risk NBL can provide a favorable prognosis without severe nonhematological toxicities. Better prognosis may be anticipated in patients with the initial good response, no pain at 131I-MIBG therapy, no VMA and HVA elevation at 131I-MIBG therapy, low Curie score (< 16) just before 131I-MIBG therapy, and short time interval (< 3years) between the initial diagnosis and 131I-MIBG therapy.

STEM-01NEURAL STEM CELL-MEDIATED ENZYME/PRODRUG THERAPY FOR NEUROBLASTOMA: TRANSLATION TO THE CLINIC

Neuroblastoma (NB), a neuroendocrine tumor, is the most common extracranial solid tumor of childhood. 45% of these patients are diagnosed with metastatic high-risk tumors, for which treatment options are limited. Neural stem cells (NSCs), engineered to secrete a modified carboxylesterase (CE) can home to metastatic neuroblastoma tumor foci in multiple organs, and convert the prodrug CPT-11 (Irinotecan; IRN) to the 1000 fold more potent topoisomerase-1 inhibitor SN-38. The goal of our current efficacy and safety/toxicity IND-enabling studies is to identify the optimal dose and schedule of IV administered NSCs adenovirally transduced to secrete a modified human CE (hCE1m6-NSCs), followed by human equivalent doses of IRN. This would ideally provide a tumor selective, more effective and less toxic treatment for children with high-risk NB. We have determined the in vitro IC50 values of 4 human derived neuroblastoma lines to SN-38, IRN only and IRN + hCE1m6-NSC conditioned media. All NB lines were 500-2000 fold more sensitive to hCE1m6-NSC conditioned media + IRN as compared to IRN alone. In vivo clearance of hCE1m6-NSCs through peripheral organs and circulation in naive non-tumor bearing Es1e/SCID mice was within 24h, as detected using PCR analysis. In subcutaneous models of human NB we have quantified NSC tumor distribution and performed pharmacokinetic studies demonstrating tumor-specific conversion of IRN to SN-38. In our metastatic NB mouse models, preliminary results showed that hCE1m6-NSCs in combination with 3 days of IRN (15 mg/kg) had a significant decrease in bioluminescent signal as an indicator of tumor burden, as compared to the IRN only group. Treatment with hCE1m6-NSCs and IRN increased long-term survival of mice bearing CHLA-136 NB tumors. If ongoing IND-enabling studies are successful, we plan to be in phase I studies in pediatric patients with refractory or relapsed high-risk NB by 2018.

634. Translation of a Neural Stem Cell-Mediated Enzyme/Prodrug Gene Therapy for Metastatic Neuroblastoma

Neuroblastoma (NB), a neuroendocrine tumor, is the most common extracranial solid tumor of childhood. Forty-five percent of these patients are diagnosed with metastatic high-risk tumors, for which treatment options are limited both in anti-tumor efficacy and patient tolerance. We have previously shown that neural stem cells (NSCs), engineered to secrete a modified rabbit carboxylesterase (CE), can home to metastatic NB tumor foci, and convert the prodrug CPT-11 (Irinotecan; IRN) to the 1000-fold more potent anti-cancer agent SN-38, resulting in significant therapeutic efficacy. The goal of our current biodistribution, efficacy and safety/toxicity IND-enabling studies is to identify the optimal dose and schedule of intravenously administered clinically relevant NSCs secreting a modified human CE (hCE1m6), followed by human equivalent doses of irinotecan. This would ideally provide a tumor selective, more effective and less toxic treatment for children with high-risk NB.In vitro cytotoxicity studies demonstrated IC50 values for four human NB tumors were significantly more sensitive to CPT-11 in the presence of hCE1m6 (similar to treatment with SN-38) compared to IRN alone. The sensitivity of NB tumor cells to CPT-11 was enhanced ≈6000-fold by hCE1m6 for KCNR tumor, while the sensitivity of SKNAS cells was enhanced ≈1200-fold for SKNAS, and approximately 150 to 600-fold decrease in IC50s of IRN for CHLA-136 and CHLA-255 NB cells. In vivo qPCR and MRI studies demonstrate NSC clearance through normal circulation and organs (lung, liver, brain) in naive non-tumor bearing Es1e/SCID mice is 24h following intravenous adminstration. In subcutaneous models of human NB we have quantified NSC tumor distribution and performed pharmacokinetics studies demonstrating a significant increase in tumor specific conversion of IRN to SN-38 with the CE-NSCs. Therapeutic efficacy studies are ongoing. If successful, we plan to be in Phase I studies in pediatric patients with refractory or relapsed high-risk neuroblastoma. This would be a first-in-human use of NSC-mediated enzyme/prodrug therapy in metastatic cancer patients.

177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

This study tested the principle that (68)Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with (177)Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with (68)Ga-DOTATATE PET/CT. The criterion of eligibility for (177)Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Of the 8 children imaged, 6 had abnormally high uptake on the (68)Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of (177)Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. (68)Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with (177)Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with (177)Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I-II clinical trial.

18F-FDG PET/CT and 123I-Metaiodobenzylguanidine Imaging in High-Risk Neuroblastoma: Diagnostic Comparison and Survival Analysis

The aim of our study was to evaluate prospectively the diagnostic performance and prognostic significance of (18)F-FDG PET/CT in comparison with (123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging in patients with high-risk neuroblastoma. Twenty-eight patients with refractory or relapsed high-risk neuroblastoma (16 male and 12 female patients; age range, 2-45 y; median age, 7.5 y) were simultaneously evaluated with (18)F-FDG PET/CT and (123)I-MIBG imaging before treatment with high-dose (131)I-MIBG. We compared the 2 methods in mapping tumor load, according to the extent of disease and intensity of positive lesions identified in each patient. Separate comparisons were performed for the soft-tissue and bone-bone marrow components of tumor burden. Survival analysis was performed to assess the prognostic significance of (18)F-FDG and (123)I-MIBG imaging parameters. (18)F-FDG PET/CT results were positive in 24 of 28 (86%) patients, whereas (123)I-MIBG imaging results were positive in all patients. (18)F-FDG was superior in mapping tumor load in 4 of 28 (14%) patients, whereas (123)I-MIBG was better in 12 of 28 (43%) patients. In the remaining 12 (43%) patients, no major differences were noted between the 2 modalities. (18)F-FDG PET/CT missed 5 cases of bone-bone marrow disease, 4 cases of soft-tissue disease, and 6 cases of skull involvement that were positive on (123)I-MIBG scans. Cox regression and Kaplan-Meier survival curves showed that the group of patients (4/28) in whom (18)F-FDG was superior to (123)I-MIBG had a significantly lower survival rate than the others. Tumoral avidity for (18)F-FDG (maximum standardized uptake value) and extent of (18)F-FDG-avid bone-bone marrow disease were identified as adverse prognostic factors. (123)I-MIBG imaging is superior to (18)F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, (18)F-FDG PET/CT has significant prognostic implications in these patients.

Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma

To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma. One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG. Those without hematopoietic stem cells (n = 16) received 12 mCi/kg. Patients were stratified according to prior myeloablative therapy and whether they had measurable soft tissue involvement or only bone and/or bone marrow disease. Hematologic toxicity was common, with 33% of patients receiving autologous hematopoietic stem cell support. Nonhematologic grade 3 or 4 toxicity was rare, with 5% of patients experiencing hepatic, 3.6% pulmonary, 10.9% infectious toxicity, and 9.7% with febrile neutropenia. The overall complete plus partial response rate was 36%. The response rate was significantly higher for patients with disease limited either to bone and bone marrow, or to soft tissue (compared with patients with both) for patients with fewer than three prior treatment regimens and for patients older than 12 years. The event-free survival (EFS) and overall survival (OS) times were significantly longer for patients achieving response, for those older than 12 years and with fewer than three prior treatment regimens. The OS was 49% at 1 year and 29% at 2 years; EFS was 18% at 1 year. The high response rate and low nonhematologic toxicity with 131I-MIBG suggest incorporation of this agent into initial multimodal therapy of neuroblastoma.

Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2/d x 5 days every 28 days) was undertaken in children with refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine (MIBG) score. Activity was defined by a reduction in lesion size or isotope uptake at anytime. Methodology included a two-step design using Fleming's method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort. All data was centrally reviewed by a panel. Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy. Twenty-three patients had metastatic NB either refractory (n = 9) or in relapse (n = 14). Grade 3 or 4 thrombocytopenia was the most frequent toxicity (16% of cycles). Myelosuppression resulted in treatment delays and dose reductions (24% and 21% of cycles, respectively). Response (complete response, very good partial response, or partial response) was observed in five patients (RR = 20% +/- 8%) with a median duration of 6 months and an objective or mixed response in five additional patients. Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

Temozolomide phase II study in children with relapsing refractory high-risk neuroblastoma

9012 Background: To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. Methods: A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2 on 5 consecutive days and repeated every 28 days) was undertaken in children with a refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Evidence of activity was defined by radiologic or MIBG scan evidence of sustained reduction in lesion size or activity whenever it occurs. Methodology included a two-step study using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if 2 to 4 responses had been observed in the first cohort. All data were centrally reviewed by a panel. Results: Among 34 registered patients over a 14 month period in 14 centres, twenty five are finally evaluable and received 94 cycles of chemotherapy. Disease status was metastatic NB (n=23) either refractory (n=9) or in relapse (n=14). Grade ¾ thrombocytopenia was the most frequent toxic event (16% of the cycles). Myelosuppression resulted in significant treatment delays and dose reductions (24% and 21% of cycles respectively). Out of 25 patients, response (CR, VGPR or PR) was observed in 5 (RR=20 ± 8%) with a median duration of 6 months. Furthermore a mixed response or an objective effect was observed in respectively 2 and 3 additional patients. Conclusions: Temozolomide is effective in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug No significant financial relationships to disclose.