Neoplasms

All Conditions

Rare Diseases

Neuroendocrine Tumors

Pheochromocytoma

Paraganglioma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Paragangliomas 1

Neuroepithelioma

All Drugs and Chemicals

Micronutrients

Anti-Infective Agents

Amino Acids

Endothelial Growth Factors

Mitogens

Iodine

Cadexomer iodine

Tyrosine

Vandetanib (100, 200 or 300 mg once daily) in combination with 131I-mIBG radiation therapy (activity to be prescribed to deliver whole body absorbed dose of 0.5 Gy) on day 1 of each 12-weekly cycle.

Patients will receive up to 4 cycles of vandetanib in combination with 131I-mIBG.

100 mg, 200 mg or 300 mg taken once a day during each 12-weekly cycle

Vandetanib

Activity will be prescribed to deliver whole body absorbed dose of 0.5 Gy (+/-10%)

131I-mIBG

Christina Thirlwell

The phase I trial aims to determine the recommended phase II dose (RP2D) of vandetanib in combination with standard radiation therapy, 131I-mIBG, in patients with advanced phaeochromocytoma (phaeo) and paraganglioma (PG) by assessing the safety and tolerability of the combination treatment.

VIBRaNT is a registered phase I trial in patients with locally advanced or metastatic phaeochromocytoma or paraganglioma, not amenable to surgical resection.

Patients will receive vandetanib (an inhibitor of VEGF, EGFR and RET tyrosine kinase) in combination with standard radiation therapy Iodine-131 labelled Meta-iodobenzylguanidine (131I-mIBG).

Vandetanib and 131I-mIBG will be given in 12-weekly cycles: 131I-miBG will be given on day 1 of each cycle and vandetanib will started on day 1 of each cycle and continue to be taken once every day. The phase I trial aims to determine with recommended phase II dose of vandetanib (either 100, 200 or 300 mg once daily) - the dose of vandetanib that patients will receive will depend on the dose under investigation at the time of patient registration.

The vandetanib dose will be determined by the Modified Continual Reassessment Method (mCRM) - a toxicity model which described the probability of a toxicity occurring at each dose level, which is based on clinical judgement and any available toxicity data.

Phase I Trial of Vandetanib Combined With 131I-mIBG to Treat Patients With Advanced Phaeochromocytoma and Paraganglioma

A Phase I Trial of Vandetanib Combined With 131I-mIBG Radiotherapy in Patients With Neuroendocrine Tumours, Advanced Phaeochromocytoma and Paraganglioma

Detailed adverse event monitoring will be conducted according to CTCAE v4.03. Dose Limiting Toxicity (DLT) is defined as any adverse event or laboratory abnormality detailed in the trial protocol, that is considered to be highly probable or probable trial treatment related and commencing anytime during the DLT evaluation period (from start of cycle 1 to cycle 1 week 12). Adverse Events include: Haematological, Clinical Chemistry, Cardiovascular, Gastrointestinal, Skin.

Response will be assessed according to RECIST v1.1. Confirmation of complete or partial response is not required. Stable disease will be considered the best response only is a second assessment has been carried out which confirmed stable disease at least 4 weeks after trial entry. Assessment will be determined using CT scans and 123I-mIBG scans performed at baseline, then every 3 months after start of treatment until disease progression (up to 3 years from registration)

Will include all grade 1-5 adverse events.

Progression-free survival will be calculated from the date of trial entry to the date of documented disease progression, or death from any cause. Where progression is suspected and subsequently confirmed by scans, the date of documented suspected progression will be used.

Cancer Research UK

AstraZeneca

University College, London

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Pharmaceutical Solutions

Antineoplastic Agents

3-Iodobenzylguanidine

Enzyme Inhibitors

Radiopharmaceuticals

All subjects received 123I-mIBG injection over at least 1 to 2 minutes through a cannula (or indwelling catheter in the vein). After the injection of 123I-mIBG was complete, the cannula was flushed with at least 5 mL of 0.9% sodium chloride solution over a maximum of 10 seconds.

All subjects ≥18 years of age and children with a weight of ≥70 kg were to receive an intravenous injection of 370 ±10% MBq (333 to 407 MBq \[9.0 to 11 mCi\] of 123I-mIBG). Doses of 123I-mIBG for children \<18 years of age (with a weight of 8-70 kg) were to be calculated on the basis of a reference activity for an adult scaled to body weight according to the schedule proposed by the European Association of Nuclear Medicine (EANM) Paediatric Task Group; for children \<8 kg, a scaled activity or a fixed minimum activity of 80 ±10% MBq (72 to 88 MBq \[1.9 to 2.2 mCi\]) was permissible.

123I-mIBG (meta-iodobenzylguanidine)

Diane McCaul

The study is designed to study the effectiveness of 123I-mIBG as a diagnostic imaging agent in evaluating patients with known or suspected neuroblastoma or phaeochromocytoma.

Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma

An Open-Label, Multicentre, Phase 3 Scintigraphy Study Assessing 123I-mIBG Uptake in Subjects Being Evaluated for Phaeochromocytoma or Neuroblastoma

GE Healthcare

Symptoms and General Pathology

Neoplasm Metastasis

Head and Neck Neoplasms

Genetic Predisposition to Disease

Disease Susceptibility

Disease Attributes

Neoplastic Processes

Ulla Feldt-Rasmussen, Professor

Ailsa Maria Main, MD

Ulla Feldt-Rasmussen, Prof., Dr. med.

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system, some which can become metastatic. It is a very rare disease and the tumours are often detected late. Approximately 50 % of the tumours are caused by germline genetic variants screening programmes are recommended for patients and their family members; however, they are not yet well-targeted with respect to individual prognosis. In this study the investigatorscaim to characterize the genotype-phenotype associations in all Danish patients (n=400) diagnosed with PPGLs who have been followed in tertiary centres using medical records and national registries. To this end novel immunohistochemical, genetic, and epigenetic biomarkers in tumour tissues samples from biobank material (blood samples and tumour tissue) will be investigated to develop a comprehensive predictive algorithm for disease prognosis. The study will provide a clinical tool for an improved targeted screening program and subsequently prevention of disease development.

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system, respectively, that often secrete catecholamines(1). The tumours are derived from the neural crest and approximately 50% are caused by a germline variant. Because of the strong heritability, genetic testing is recommended in all patients with PPGLs (2-5). Most PPGLs are non-malignant (defined as non-metastatic) tumours and respond well to surgical treatment. Approximately 15% of PPGLs are metastatic and incurable by currently available therapies(1). The latest WHO Blue Book classifies all PPGLs as possibly malignant due to their unpredictable behaviour(6).

PPGLs are very heterogeneous tumours predisposed by more than 20 distinct genes(1). In two thirds of the tumours a germline or somatic variant can be identified and thus PPGLs have been divided into distinct biological subgroups on the basis of these variants(1). A consensus statement from 2017 stated the necessity for a targeted gene panel (Next-Generation Sequencing, NGS) in all PPGL patients and testing of tumour DNA if possible to identify potential future targets for drug therapies(2). Furthermore, epigenetic changes in PPGLs and other endocrine tumours have been shown to be associated with the risk of metastatic disease(7-11) and future research should be focused on understanding both epigenetic and genetic changes in PPGLs as this will open opportunities for targeted molecular therapies and personalized medicine(11,12). It has been demonstrated that DNA methylation-based tumour classification is a valuable asset for clinical decision making(13).

Many histopathological predictive risk factors for poor prognosis have been proposed and scoring systems have been developed to identify those PPGLs that have a metastatic potential. The PASS (Pheochromocytoma of the Adrenal Gland Scaled Score) and GAPP (Grading system for Adrenal Phaeochromocytoma and Paraganglioma) scores are the most well-known (1,14-18). In a recent meta-analysis the algorithms were evaluated and it was concluded that both algorithms had a low positive predictive value but a high negative predictive value for PPGLs which indicated that the models were relevant for ruling out metastatic potential for both tumour types rather than identifying cases with an increased risk of disseminated disease. This could most probably be attributed to subjective assessment of criteria involved in these scoring systems. The authors concluded that the inclusion of NGS data and an overall molecular approach is needed to accurately pinpoint cases at risk for future metastases(19). Furthermore, there is a need for an algorithm based on objective measurements to ensure objectivity in the pathological diagnosis of PPGLs, similar to algorithms for adrenocortical carcinomas like the Helsinki Score and the Reticulin Algorithm(19-21). To this end computer-assisted techniques have shown promising results(11,20).

Correctly identifying PPGLs with a future risk of metastatic disease is a clinical challenge which impacts not only the physicians but also the patients and their family members. Today's clinical guidelines are based on 'rule all in' methods which have a costly impact on the healthcare resources and the quality of life of the patients. An algorithm based on histopathological, genetic, epigenetic, and clinical variables may be helpful in stratifying patients into risk categories with different needs for clinical follow-up.

Pilot Study: Patients followed at Copenhagen University Hospital, Copenhagen have been part of a pilot study on the effect of genetic screening of family members with SDHX variants on the clinical presentation of cases. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. The investigators found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had severe phaenotypes, underlining the necessity for a broad genetic screening of the proband. The study corroborated previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and therefore useful in the decision of clinical follow-up. This study has been presented as master thesis at the University of Copenhagen 2019 (Grade A) and the manuscript has been published(22). The study corroborates the feasibility of the current project.

Process of the study

Part 1: Description of the genotype-phaenotype association in a nation-wide cohort of approximately 400 patients with PPGLs or germ-line genetic variants predisposing to PPGLs using clinical data, biochemical variables, tumour characteristics and imaging results. This national cohort will provide characterization of patients making it possible to identify a metastatic and non-metastatic clinical course, respectively.

Part 2: Identification of novel prognostic biomarkers using formalin-fixed paraffin-embedded tumor tissue samples for genetic testing (NGS for somatic variants), DNA methylation, PASS scoring, and immunohistochemical markers. Twenty patients with a poor prognosis (proof of metastases) and 20 patients with a good prognosis (non-metastatic) will be included from the Capital Region of Denmark. The results will be used to develop a new algorithm for clinical prognosis.

Part 3: Validation of the new algorithm in a second subcohort of patients with tumor tissue specimens selected at random from the national cohort. Tumor specimens will be subjected to investigation of the same novel prognostic biomarkers identified in part 2. Results will be entered into the new algorithm to test whether the clinical course can be accurately predicted.

Dissemination Positive, negative or inconclusive results will be published in peer-reviewed international journals and presented at scientific meetings and in relevant patient fora. The study group members are affiliated to ENDO-ERN (European Reference Network on Rare Endocrine Conditions), a European collaboration of highly specialized centres treating rare endocrine conditions through which results can be disseminated (https://endo-ern.eu/).

To ensure completeness and transparency in the reporting of results the investigators will use the STROBE reporting guidelines relevant to cohort studies.

Patient involvement:

Patients with lived experiences contribute additional expertise and give valuable, novel insights and thus improve the effectiveness of the study. Furthermore, the patient perspective is essential in the presentation of the results. Relevant patients with the disease in question from our outpatient clinic will be invited to participate in the Steering Committee.

Safety and ethical considerations Treatment of personal data: General Data Protection Regulation will be strictly adhered to. Approval by the Ethics Committee for the Capital Region has been granted (H-20065699, 19th of February 2021).

Database: The database will be established under RedCap, which is accessible nation-wide and managed centrally by the data protection unit of The Capital Region.

Statistics: Based on previous studies which have developed similar algorithms (20,21) the investigators will need approximately 200 patients to achieve statistical power in relation to validation of the algorithm in the larger cohort. Study population characteristics will be presented using descriptive statistics. Group differences will be tested primarily using non-parametric tests (Mann-Whitney, Wilcoxon) or t-test. Associations between the genotype and phaenotype will be analysed by ANOVA (analysis of variance) and regression analysis controlling for relevant confounders, i.e. age and sex, where appropriate. The sensitivity and specificity of the algorithm to predict poor or good outcome will be determined using multiple regression analyses, Chi2 and ROC (Receiver Operating Characteristics). The investigators will seek help from professional statisticians at Copenhagen University at Statistical Advisory Service for PhD-students and students at the Faculty of Health Sciences.

Blood samples and tumour tissue samples from existing biobanks.

Development of a Predictive Model for the Risk of Metastatic Disease in PPGLs, a Retrospective Cohort Study

Development of a Comprehensive Predictive Model for Risk of Metastatic Disease in PPGLs Based on a Combination of Clinical, Biochemical, Genetic, and Pathoanatomical Characteristics a Retrospective National Cohort Study

Rigshospitalet, Denmark

Professor Ulla Feldt-Rasmussen

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I Trial of Vandetanib Combined With 131I-mIBG to Treat Patients With Advanced Phaeochromocytoma and Paraganglioma	NCT01941849	Phaeochromocyto... Paraganglioma	Vandetanib 131I-mIBG	18 Years -	University College, London
Phase I Trial of Vandetanib Combined With 131I-mIBG to Treat Patients With Advanced Phaeochromocytoma and Paraganglioma	NCT01941849	Phaeochromocyto... Paraganglioma	Vandetanib 131I-mIBG	18 Years -	University College, London
Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma	NCT00126412	Pheochromocytom... Neuroblastoma	123I-mIBG (meta...	-	GE Healthcare
Development of a Predictive Model for the Risk of Metastatic Disease in PPGLs, a Retrospective Cohort Study	NCT04788927	Paraganglioma Pheochromocytom... Genetic Predisp... Pathology Somatic Mutatio... Head and Neck C... Neuroendocrine ...		0 Years - 120 Years	Rigshospitalet, Denmark

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