Neuroblastic Disorder

The LuDO-N Trial is a multi-centre phase II clinical trial on 177Lu-DOTATATE treatment of recurrent or relapsed high-risk neuroblastoma in children. The LuDO-N Trial builds on the experience from the previous LuDO Trial and utilises an intensified dosing schedule to deliver 2 doses over a 2-week period, in order to achieve a maximal effect on the often rapidly progressing disease. This strategy requires a readiness for autologous stem cell transplantation in all patients, but is not anticipated to increase the risk of long-term sequelae, since the cumulative radiation dose remains unchanged. The primary aim of the study is to assess the response to 177Lu-DOTATATE treatment at 1 and 4 months after ende of treatment. Secondary aims are to assess survival and treatment-related toxicity. Additional aim are to correlate tumour dosimetry with response, correlate SSTR-2 expression with 68Ga-DOTATATE uptake and to correlate the uptake with the treatment response.

BACKGROUND AND RATIONALE 6-\[18F\]fluoro-dihydroxyphenylalanine (18F-DOPA) is a large neutral amino acid that resembles natural L-3.4-dihydroxyphenylalanine (L-DOPA) biochemically. L-DOPA is a precursor for dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline), collectively known as catecholamines. 18F-DOPA enters the biochemical pathway of L-DOPA both in the brain and peripherally, and can be imaged with a positron emission tomography / computed tomography (PET/CT) scanner. 18F-DOPA can therefore allow imaging of the L-DOPA metabolic pathway with a high target-to-background ratio providing valuable information for a number of diseases. While 18F-DOPA is an established diagnostic tracer at a number of different institutions globally, given the short half-life of 18F (110 minutes) this tracer cannot be imported for local use. The Edmonton PET Centre has recently developed a production method for this tracer allowing local access. An initial study at the University of Alberta (Pro00055342) has demonstrated this tracer to have an acceptable safety profile, an expected biodistribution (both physiologic and disease-related), and has established clinical efficacy of the tracer. In March, 2020 the University of Alberta Hospital (UAH) installed a new PET/CT scanner (GE Discovery MI) with a digital detector system and new iterative image reconstruction algorithms that represent a substantial technological improvement compared to the previously installed scanner. It is expected that this new system will reduce artifact and will increase the sensitivity for the detection of smaller lesions. Our initial study demonstrated rapid urinary excretion with intense collection of activity within the urinary bladder. While this physiology was expected, it did result in diminished image quality in the evaluation of the pelvis in some patients. Improved image reconstruction algorithms available on the new GE Discovery MI PET/CT system may improve imaged quality related to this problem. Based on our experience with 18F-fluorodeoxyglucose (FDG) PET/CT scans, the administration of intravenous furosemide prior to imaging can also substantially improve the image quality in the pelvis. These potential improvements have not yet been established with 18F-DOPA. A second observation from our initial study was that many participants demonstrated intense early activity at the gallbladder fundus. While biliary and gallbladder activity are described in the normal biodistribution of 18F-DOPA, the observed distribution suggests that the gallbladder fundus activity reflects primary uptake rather than reflux of activity within bile into the gallbladder. The rationale for this study is to explore the efficacy of these optimization parameters (new digital PET/CT camera system and use of intravenous furosemide) in the context of 18F-DOPA PET/CT imaging for patients with clinical indications for the scan. Imaging data from this study will be compared with data from the prior study (Pro00055342) to determine if the new digital detector PET/CT technology and preparatory furosemide administration improves image quality for these patients. A subgroup will also be scanned dynamically at the abdomen to better assess the pattern of gallbladder activity over time. This will include a mixture of clinical indications listed within the inclusion criteria. All patients will be screened for a history of previous gallbladder disease at the time of the scan by questionnaire. The intention of this sub-study is to better determine 18F-DOPA activity patterns associated with the gallbladder and to explore if there is a correlation between dopaminergic degeneration in the brain and the gallbladder. PURPOSE AND STUDY OBJECTIVE: Trial Type: Phase III non-randomized, non-blinded prospective cohort clinical trial of patients with a clinical indication for 18F-DOPA PET/CT imaging. The primary purpose of this study is to assess optimization parameters for 18F-DOPA PET CT imaging at UAH including the impact of new digital detector PET/CT technology as well as the impact of preparatory intravenous furosemide administration on image quality within the pelvis. A secondary purpose of this study is to better delineate the pattern of 18F-DOPA activity associated with the gallbladder and to explore if there is a relationship between dopaminergic denervation in the gallbladder and the brain. Only patient populations for which there are established clinical indications for the use of 18F-DOPA will be included in this study. Participation in this study will allow access to this tracer for patients in Alberta as there is no Health Canada approved similar tracer currently available. 18F-DOPA is an established clinical tracer at multiple institutions globally and has been approved for clinical use at multiple European centres for many (10+) years. Established clinical indications in the literature include: 1. Pediatric patients (less than 18 years old) with congenital hyperinsulinism. The 18F-DOPA scan is used to plan required surgical intervention for these patients. 2. Pediatric patients (less than 18 years old) with neuroblastoma. The 18F-DOPA scan is indicated for pre-operative assessment of a mass suspected to be a neuroblastoma, staging, re-staging, and assessment of recurrence in this patient group. 3. Pediatric (less than 18 years old) or Adult patients (18 or older) with known or clinically suspected neuroendocrine tumor. These include patients with carcinoid tumor, pheochromocytoma, paraganglioma, and medullary thyroid cancer. 18F-DOPA is indicated for metabolic assessment of a mass suspected to represent one of these tumor-types, for staging of a known tumor, for re-staging, and for assessment of recurrence in this patient group. 4. Adult patients (18 or older) with a clinical suspicion of Parkinson's disease or Lewy body dementia. 18F-DOPA is indicated to differentiate benign essential tremor from Parkinson's disease in this patient group \[22-26\]. 18F-DOPA may also be used to differentiate Lewy body dementia from other dementia types. 5. Pediatric (less than 18 years old) or Adult patients (18 or older) with brain tumors (primary or metastatic). 18F-DOPA is indicated for biopsy planning, radiation therapy planning, and post-therapy assessment to differentiate residual viable tumor from post-therapy necrosis in this patient population. When requested for patients falling into one of these diagnostic groups, an 18F-DOPA PET/CT scan will be performed and interpreted clinically with the results conveyed to the referring physician. Image optimization (the primary study objective) will be evaluated based on the following: * For patients with abnormal activity, the smallest 3 lesions will be recorded in terms of size (mm) and activity (SUVmax). For PET-avid lesions, the size measurement will be based on measuring the maximum dimension of the corresponding lesion on the CT scan component if possible. If not possible, a size measurement based on the PET images will be used. The minimum lesion size and average (3 smallest lesions) will be compared with a cohort of scans acquired on the previous non-digital PET/CT scanner (retrospective cohort of 50 positive patients, Pro00055342). * The SUVmax, SUVmean, and SUV standard deviation of urinary bladder activity will be measured and compared to a retrospective cohort of 50 patients from a previous study (Pro00055342) * A subjective score will be applied to the pelvis with respect to image artifact related to bladder activity (0 = no artifact, 1 = mild artifact, 2 = severe artifact). This will be compared to scoring of the previous study (retrospective cohort of 50 patients, Pro00055342) retrospectively. Gallbladder activity pattern (the secondary objective) will be evaluated based on the following: * SUVmax measurements of the gallbladder fundus, gallbladder neck, common bile duct, right and left main intrahepatic ducts, and liver parenchyma (right and left lobes, 3 cm diameter VOI) will be measured at 5 minute increments. These will be analyzed in total, and subgroups will be compared (32 PD vs. 32 non-PD participants). * All participants will be screened by questionnaire at the time of the scan as to whether there is a history of previous gallbladder disease. The positive response rate will be compared between three groups: non-PD patients, PD patients with objective evidence of dopaminergic denervation (positive FDOPA scan), PD patients without objective evidence of dopaminergic denervation (negative FDOPA scan). PATIENT POPULATION: A total of 800 patients who meet the inclusion criteria will be identified based on referrals from physicians who deem the imaging studies potentially useful for clinical care. It is anticipated that complete enrollment will take 5 years (approximately 160 scans per year). Sample size calculation is based on the following. There will typically be 5 participants total scanned per day. Dynamic imaging will be restricted to one patient per scanning day due to time constraints related to the scanner, as this requires the participant to lie quietly in the PET/CT scanner for up to one hour. Allowing for this restriction, it is estimated that the overall participation rate for dynamic scanning will be 10%. Based on a minimum total sample size of 64 participants for the secondary objective analysis, a total minimum study population of 640 is required. Allowing for some potential buffer for recruitment, a total of 800 participants is planned. The minimum sample size of 64 participants is based on the following estimations: gallbladder fundus SUVmax mean 10.9, SUVmax DS 4.6 (measured from cohort of 10 patients from the previous study), α = 0.05, and power = 0.80. Two groups of 32 participants (64 total) should allow for detection of a minimum 30% difference in SUVmax involving the gallbladder fundus between the two groups.

This is a prospective study designed to assess the use of 18F-mFBG PET imaging compared to 123I-mIBG scintigraphy in subjects with known or presumed neuroblastoma. Eligible participants will have either histopathologically established diagnosis of neuroblastoma or a presumed diagnosis based on signs, symptoms, physical examination, imaging findings, and laboratory and genetic test results. Subjects will only be administered 18F-mFBG if they have undergone or are scheduled to undergo a 123I-mIBG within +/- 7 days of the date of the 18F-mFBG scan. Subjects should not have received any chemotherapy, immunotherapy or radiotherapy between the clinical and 18F-mFBG imaging studies. 18F-mFBG PET studies will be evaluated by 2 independent teams of blinded readers: a nuclear medicine physician and a radiologist, both specialized in pediatric nuclear medicine co-reading side-by side. The clinical 123I-mIBG is also evaluated by 2 independent teams of blinded readers: a nuclear medicine physician and a radiologist, both specialized in pediatric nuclear medicine co-reading side-by side. Blinded readers will record whether findings on 18F-mFBG and 123I-mIBG scans are consistent with neuroblastoma. Subject-level diagnostic performance will be assessed on the basis of differencies in lesion-counting between the blinded 18F-mFBG scan interpretation and the 123I-mIBG scan. In case of discrepancy, independently assessed by an Expert Panel.

Neuroblastoma highly expresses norepinephrine transporter (NET) which is targeted by function alanalogue of norepinephrine, 123/131I-MlBG. However, low spatial resolution of 123/131I-MlBG and inaccurate attenuation correction of single photon emission tomography (SPECT/CT) will affect the image quality of MlBG SPECT and lead to poor diagnosis of small lesions. In addition, 123l-MlBG imaging is usually performed at 24h after injection, while 131I-MlBG is performed at 48h or even 72h after injection. The procedure is complicated and takes a long time, which limits clinical application. 18F-labeled MFBG is an ideal tracer to show the expression of NET. Preliminary data show that 18F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. Patients can undergo PET 0.5 hours after injection without special preparation. Our study will assess the safety profile, image quality and evaluate the diagnostic performance and tumor burden of 18F-MFBG. Patients with suspected or histologically confirmed neuroblastoma will be enrolled in this study.

Pheochromocytoma and paraganglioma (PPGL) and neuroblastoma (NB) highly express norepinephrine transporter (NET) which is targeted by functional analogue of norepinephrine, 131I/123I-MIBG. However, low spatial resolution of 123/131I-MIBG and inaccurate attenuation correction of single photon emission tomography (SPECT/CT) will affect the image quality of MIBG SPECT and lead to poor diagnosis of small lesions. In addition, 123I-MIBG imaging is usually performed at 24 h after injection, while 131I-MIBG is performed at 48 h or even 72 h after injection. The procedure is complicated and takes a long time, which limits clinical application. 18F-labeled MFBG is an ideal tracer to show the expression of NET. Preliminary data show that 18F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. Patients can undergo PET 0.5 hours after injection without special preparation. Our study will assess the safety profile, image quality and evaluate the diagnostic performance and tumor burden of 18F-MFBG on nural crest tumors including PPGL and NB. Patients with histologically confirmed or clinically suspected neural crest tumor will be prospectively recruited in this study.

Background: Neuroblastoma is the most frequent extracranial childhood tumor, with an annual incidence of approximately 10.2 per million children. Initial staging of the disease and monitoring of the treatment response can be performed with different imaging modalities that include contrast-enhanced computed tomography (ceCT), ultrasound, magnetic resonance imaging (MRI), bone scintigraphy and 123I-MIBG scintigraphy. Another potential target for neuroblastoma imaging is the somatostatin receptor (SSTR) that is present in many neuroendocrine tumours (NET). The superior PET imaging technology used with new radiotracers (such as 68Ga-DOTATATE) enables imaging at advantageous resolutions well below what is possible by current clinical SPECT systems that are used for 123I-MIBG. Design: Prospective single-arm non-randomized clinical trial (phase II) - pilot Objective: 1) Assess the feasibility and safety of 68Ga-DOTATATE PET/CT imaging in patients with neuroblastoma or suspected of having neuroblastoma. 2) Compare lesion-by-lesion the uptake of 68Ga-DOTATATE and 123I-MIBG in the same participant. Study population: Children and adults with biopsy-proven or suspected neuroblastoma Procedure and Follow-up: Few days after 123I-MIBG scan, participants will undergo a 68Ga-DOTA-cTATE PET/CT scan (duration 2 hours). Clinical data will be collected from this imaging and from the participant's medical record (demographic, treatment, medication, pathology, lab test results) for a 2-year follow-up period.

Background: A lot of children with cancer suffer from emotional distress, fatigue and relational difficulties. Their parents are also impacted by the disease: their responsibilities increase and they can feel more distressed and tired. Different psychological interventions designed for ill children and their parents seem to be efficient to improve their social functioning, coping strategies and well-being. However, more research is needed in this field. Hypnosis is often used in paediatric oncology, mostly to decrease procedure-related pain and distress. It has been used efficiently to improve the well-being of adults with cancer. This paper describes a pilot study designed to assess the feasibility and interest of a group intervention combining self-care and hypnosis for children with cancer and their parents, and a quasi-experimental protocol aimed at assessing the efficacy of this group intervention to improve the quality of life of children and their parents. Methods: Our pilot study showed that our intervention was feasible and positive for the participants. To test the efficacy of the intervention, two groups will be set up: one with children with cancer and their interested siblings, and one with their parents. Data will be collected for each group before and after the intervention by questionnaires and a semi-structured interview. Discussion: There is a growing interest in hypnosis in oncology settings. The results of this study should improve knowledge about the efficacy of a group intervention combining self-care and hypnosis to improve quality of life of children with cancer and their family.

To evaluate safety and efficacy of CBA-1205 in the following five parts in a stepwise manner: Part 1 * In Part 1, safety and tolerability in patients with Solid Tumor where no standard treatment is available, or who are intolerable or non-responder to the standard treatment will be evaluated. Initial dose for Part 2 will be determined. Part 2 * In Part 2, safety and tolerability in patients with advanced and/or recurrent Hepatocellular Carcinoma which are unresectable, or who are intolerable or non-responder to the standard treatment will be evaluated. Recommended dose in this population will be determined. Part 3 * In Part 3, safety and efficacy at the recommended dose in patients with advanced and/or recurrent Hepatocellular Carcinoma which are unresectable, or who are intolerable or non-responder to the standard treatment will be evaluated. Part 4 * In Part 4, safety and efficacy in patients with Malignant Melanoma who are refractory or intolerant to standard therapy. Part 5 * In Part 5, safety, tolerability and the recommended dose of the study drug in patients with Pediatric Cancer where no standard treatment is available, or who are intolerable or non-responder to the standard treatment will be evaluated. PK analysis

Rationale and Background: Neuroblastoma, is the most common extra-cranial solid tumour in children. Most patients with neuroblastoma are diagnosed under the age of 5 years and most present with metastatic disease and/or high-risk features. Despite the introduction of novel treatment strategies, including high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), the outcome of these patients remains poor. Dinutuximab beta is a chimeric monoclonal immunoglobulin G 1 (IgG1) antibody that is specifically directed against the carbohydrate moiety of disialoganglioside antigen (GD2), which is overexpressed on neuroblastoma cells. By binding to neuroblastoma cells, dinutuximab beta can induce both complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC). The efficacy of dinutuximab beta has been evaluated in a randomised controlled trial comparing the administration of dinutuximab beta with or without interleukin 2 (IL-2) in the first-line treatment of patients with high-risk neuroblastoma and in two singlearm studies in the relapsed/refractory setting. The efficacy and safety of dinutuximab beta will further be evaluated in this registry that will provide information on survival, pain severity and incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events, hypersensitivity reactions and long-term safety. Study Design: This is a non-interventional, multi-national, observational, prospective patient registry of patients with high-risk neuroblastoma being treated with the monoclonal antibody dinutuximab beta. The efficacy and safety of dinutuximab beta will further be evaluated in this registry that will provide information on survival, pain severity and incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events, hypersensitivity reactions and long-term safety. Research Questions and Objectives: Primary objectives: * To assess pain severity and use of analgesics during the period of first dose of dinutuximab beta to end of last 35 day course of the 5th cycle of treatment * To assess the incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions * To assess the long term safety profile Secondary objectives: * Progression free survival (PFS) in patients treated with dinutuximab beta. * Event Free Survival (EFS) in patients treated with dinutuximab beta * Overall survival (OS) in patients treated with dinutuximab beta Population: Patients diagnosed with high-risk neuroblastoma who are starting treatment with dinutuximab beta in the standard clinical practice setting or participating in a clinical trial where dinutuximab beta is provided according to the indication as per the country/regional marketing authorisation, provide consent/assent and are willing to be followed up for up to 10 years. Study Size: It is planned to enroll a sufficient number of patients (estimated at 125) such that 100 patients will have completed all five treatment courses of dinutuximab beta. It is anticipated that this will result in 40-50 patients who are progression free at 10 years. Data Sources: Data will be collected from physicians using an electronic data capture (EDC) system. The electronic case report forms (eCRFs) will be designed to gather data from the medical records at baseline, during treatment and at normal clinical practice follow up visits. Data Analysis: The safety analysis set, containing all patients treated with at least one dose of dinutuximab beta will be considered for safety and efficacy analyses. All baseline, treatment period and follow up characteristics will be summarized using descriptive statistics. Endpoints addressing primary and secondary analysis will include 95% confidence intervals (CIs) including the Clopper Pearson method for binomial, log-log transform for survival. OS, PFS and EFS will be analysed using Kaplan-Meier methods. Variables: Baseline (prior to start of treatment): Demographics, clinical trial participation, neuroblastoma disease history, and presence or absence of neurotoxicity, visual impairment, and cardiovascular abnormality. Treatment period (up to end of last 35 day course of 5th cycle of treatment): Dosing regimen, total cumulative amount of dinutuximab beta per course, concomitant medications during course (IL-2, retinoic acid and/or antihistamines), daily analgesics (opioids, gabapentin/ pregabalin and/or non-opioid analgesics and other neuropathic pain treatments), daily pain assessment during infusion of dinutuximab beta, occurrence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events, and hypersensitivity reactions, adverse events (AEs)/serious adverse events (SAEs) treatment interruptions and discontinuations, progression of disease, date and cause of death, reason for study withdrawal (if applicable) Follow up (from end of last 35 day course of 5th cycle of treatment): Status of neurotoxicity, visual impairment, cardiovascular events, (resolved, not resolved), SAEs and adverse drug reaction (ADRs), progression of disease, date and cause of death, reason for study withdrawal (if applicable).

The purpose is to explore the efficacy and safety of the SYSUCC-RMS regimen for pediatric RMS patients and to explore the impact of concurrent radiotherapy and chemotherapy on the survival rate of low-risk, medium risk, high-risk, and extremely high-risk patients in children.