Ear, Nose, and Throat Diseases

Nervous System Diseases

Symptoms and General Pathology

All Conditions

Substance Related Disorders

Wounds and Injuries

Hearing Loss

Deafness

Ototoxicity

Hearing Disorders

Ear Diseases

Otorhinolaryngologic Diseases

Sensation Disorders

Neurologic Manifestations

study of mutations of metabolic enzymes and membrane transport genes, which will be performed by sequencing.

Genetic study

study of mutations of the mitochondrial gene MT-RN1, which will be performed by sequencing.

Genetic study MT-RN1

A limited number of relatively contradictory studies have suggested that the development of serious ototoxicity in children treated with cisplatin or, more rarely, carboplatin could be partly related to genetic risk factors affecting detoxification enzymes and membrane transporters of platinum derivatives. The objective of this study is therefore to identify genetic variants associated with the development of platinum ototoxicity in patients treated with cisplatin or carboplatin (minimum follow-up of 3 years) for one of the following diseases: neuroblastoma, hepatoblastoma, retinoblastoma, malignant germ cell tumour, osteosarcoma, high-risk or recurrent Wilms' tumour, non-parameningealrhabdomyosarcoma. A total of 180 patients, corresponding to 60 cases with grade 3 or 4 ototoxicity and 120 controls with no signs of ototoxicity (separate complete audiograms for each ear) will be included. A saliva sample will be used to obtain DNA for pharmacogenetic studies. The value of this study will be to define a population at high risk of developing ototoxicity in order to adapt treatment, or even develop preventive treatment of ototoxicity based on antioxidant medications

* Platinum derivatives and their toxicity Cisplatin, carboplatin, and oxaliplatin are major cytotoxic agents used in the treatment of many types of cancer. They exert their cytotoxic action by forming DNA adducts. However, their structural differences confer different pharmacokinetic and pharmacodynamic properties, and especially different toxicity profiles. Cisplatin induces a risk of nephrotoxicity at all ages, peripheral neuropathy of the extremities in young adults and a risk of ototoxicity in children. Carboplatin is essentially haematotoxic and sometimes ototoxic (especially at high doses), while oxaliplatin is essentially neurotoxic. Ototoxicity is measured by pure-tone audiometry and is scored from grade 0 to grade 4, where grades 3 and 4 correspond to severe ototoxicity, according to the Brock grading system, the reference system for measuring ototoxicity at the time of treatment of these children and up until the present time (Brock et al., 1991) (Peters et al., 2000). Ototoxicity limits the cumulative dose of platinum derivatives in children. Cisplatin remains a major drug in paediatric oncology (osteosarcoma, high-risk neuroblastoma, malignant germ cell tumours, hepatoblastoma, medulloblastoma, other brain tumours). Cisplatin ototoxicity is fairly frequent and can be very severe (more than 50% of grade 1 or higher ototoxicity; 15% of grade 3 or 4 ototoxicity) (Bertolini et al., 2004). Carboplatin, an important component of the treatment of many embryonal tumours (neuroblastoma, medulloblastoma, retinoblastoma) is less frequently responsible for ototoxicity (between 1 and 5% of grade 1 or higher ototoxicity), but can nevertheless occasionally cause serious ototoxicity (1% of grade 4) (Jehanne et al., 2009). Ototoxicity can also appear and deteriorate for several years after treatment (median time to discovery of carboplatin ototoxicity: 3.7 years), while no cases of recovery of high-grade hearing loss have been reported (Bertolini et al., 2004; Jehanne et al., 2009). These ototoxicity phenomena can have very harmful consequences for the child's social development and schooling. Oxaliplatin will be excluded from this study, as few children are currently treated with this molecule, which is generally not ototoxic.
* Detoxification of platinum derivatives The glutathione (GSH) conjugation pathway is involved in detoxification of platinum derivatives and decreases their cytotoxicity by inhibiting the formation of DNA adducts. Conjugation to GSH is ensured by glutathione-S-transferases (GSTs), which constitute a multigenic family of enzymes involved in phase II metabolism that inactivate electrophilic molecules by conjugating them to glutathione, thereby promoting their elimination. GSTP1 is particularly involved in the conjugation of platinum derivatives. Elimination of glutathione conjugates then involves membrane transporters. These conjugates can be expelled from target tumour cells and then eliminated, essentially in the urine, by efflux membrane transporters, particularly MRP2 (Sun et al., 2009). Two other enzymes, thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase, have been reported to be associated with increased toxicity of cisplatin when their activity is decreased (Ross et al., 2009).
* Genetic factors predisposing to or protecting against the toxicity of platinum derivatives Several GST isoenzymes present polymorphisms modifying their activity. This is the case for the GSTM1 and GSTT1 isoenzymes, which can undergo deletions responsible for loss of activity of the enzyme, and GSTM3, for which the GSTM3\*B allele has been associated with induction of enzyme activity by cisplatin (Peters et al., 2000). An A/G polymorphism situated in the substrate binding domain of the GSTP1 isoenzyme in position +313 of exon 5 (A313G) induces substitution of a isoleucine by a valine (Ile105Val). This polymorphism is relatively frequent (about 10% of homozygous mutants in Caucasian populations). It influences the activity of the enzyme and has been associated with better survival of patients receiving platinum-based chemotherapy (Goekkurt et al., 2006; Stoehlmacher et al., 2002; Sun et al., 2009). This polymorphism has also been shown to influence the toxicity of platinum-based treatments. For example, one study showed that the neurotoxicity of oxaliplatin was more frequent in subjects homozygous for GSTP1 105Ile allele than in heterozygous subjects or subjects homozygous for the GSTP1 105Val allele (odds ratio = 5.75). (Lecomte et al., 2006). This protective effect of the mutant allele has also been demonstrated for docetaxel peripheral neuropathies (odds ratio = 6.11) and cisplatin ototoxicity in testicular cancers in young men (Mir et al., 2009; Oldenburg et al., 2007).

A study conducted in children demonstrated an association between GSTM1 and GSTT1 polymorphisms (presence of at least one null genotype) and the development of grade 3 or higher toxicity related to treatment of medulloblastoma. However, this study, based on a small sample of children (42 children, 19 of whom experienced severe ototoxicity) and comprising patients receiving very different treatments, was unable to determine the proportion of toxicity specifically related to platinum derivatives, as some patients also received brain irradiation. Furthermore, this association between GST polymorphisms and toxicity was not observed when the analysis was specifically confined to grade 3 or higher ototoxicity. Finally, the role of GSTP1 Ile105Val polymorphism has not been evaluated in children (Barahmani et al., 2009). To our knowledge, only one study has specifically evaluated the potential impact of GST polymorphism on cisplatin ototoxicity in children. This study showed a protective effect of the GSTM3\*B variant, but did not observe a protective effect of the GSTP1 105Val allele with respect to ototoxicity, as demonstrated in adults for neurotoxicity. However, these findings were based on small sample sizes (20 patients with ototoxicity versus 19 patients without ototoxicity) and the ototoxicity experienced by these patients was grade 2 (8 patients) or 3 (12 patients) with no cases of grade 4 ototoxicity (Peters et al., 2000). The results of this study therefore need to be confirmed by a study comprising a greater number of patients, cases and controls, including patients with more severe ototoxicity. Ross et al., studying drug metabolism enzymes, demonstrated a highly significant association between cisplatin ototoxicity in children and genetic variants of TPMT (rs12201199, p = 0.00022, OR = 17.0) and COMT (rs9332377, p = 0.00018, OR = 5.5). However, as the role of these enzymes in detoxification of platinum derivatives has not been previously reported, these results need to be confirmed by other studies with, in particular, matching for age, exclusion of cases of grade 2 ototoxicity from the group of severe ototoxicity, and a greater number of control patients (Ross et al., 2009). Finally, no study has investigated the genetic factors involved in carboplatin ototoxicity in children. One study concerning membrane transporters showed that a common polymorphism situated in the promoter region of the MRP2 (-24C\>T) transporter gene was associated with a better response to platinum-based chemotherapy (allelic frequency: 18% of Caucasian) (Cascorbi, 2006; Sun et al., 2009). It would be interesting to determine whether polymorphisms affecting this gene can also modulate the toxicity of these treatments. A polymorphism of the gene coding for the influx transporter OCT2 (c.808G\>T; p.270Ala\>Ser) has also been shown to be associated in vivo and in vitro in mice with a protective effect in relation to cisplatin nephrotoxicity and ototoxicity (Ciarimboli et al.; Filipski et al., 2009), but the potential influence of this polymorphism on platinum ototoxicity has never been demonstrated in man. It therefore appears very interesting to study the potential impact of this polymorphism in the context of our study.

In summary, all of these studies clearly confirm the hypothesis that genetic factors are involved in the predisposition of some children to experience harmful ototoxic effects of platinum derivatives, particularly cisplatin and carboplatin. These studies also suggest the existence of good candidate gene variants likely to be associated with the development of this ototoxicity. However, the results of most these studies have either not been reproduced or remain controversial, indicating the need for confirmation studies based on larger sample sizes and more homogeneous patient groups in terms of treatment, as in the Otoplat study.

Cancer and Hearing Loss Related in Children

Cancer and Deafness Associated With the Use of Platinum Derivatives in Children

Assistance Publique - Hôpitaux de Paris

interventions of Cancéropôle Nord-Ouest during 1 year after an observational period of 2 years.

interventions of Cancéropôle Nord-Ouest during 2 years after an observational period of 1 year.

During the time defined by the randomization, the Cancéropôle Nord-Ouest offers to help to develop a clinical research activities in the centers. The various aids are : Structuring clinical research at the local level, Support (strategy, logistics, technical, Data management, methodology), a portfolio of "straightforward" studies ( French National Cancer Institute, cooperative groups conducting cancer clinical research, New Project), Good Clinical Practice training, Clinical research technician, Others,.....

interventions of the Cancéropôle Nord-Ouest

Jean-Claude BARBARE, MD

This study evaluates the interventions of the Cancéropôle Nord-Ouest in the development of clinical research in non-academic health institution. The randomization, in open label,determines the duration of the interventions. Half of participants will receive the interventions during 2 years, while the other half during 1 year.

French National recommendations ask to increase the accessibility of patients to clinical trials. But this accessibility is far from the optimal care in non-university healthcare institutions (public and private hospital). These non-academic healthcare facilities support at national level about 60% of chemotherapy and 70% of radiotherapy, but only 17% of the inclusions in trials.

A dissociation exist between a care package guaranteed on quality criteria (criteria to obtain the capacity to treat the cancers in healthcare institution) distributed all over the country, and the research, mainly concentrated in few referral centers (University hospital and French Comprehensive Cancer Centers).

Clinical trials allow patients to have early access to new treatments, optimal and formalized information, and supported by physicians in connection with a strict protocol for patients included.

Several studies have shown the existence of geographical and socio-economic determinants for access to reference centers and for the duration of survival of cancer patients. In France, it was found that for patients with gastrointestinal cancer, the remoteness of the place of residence compared to the nearest referral center and a higher level of deprivation decreased the probability of being supported in a reference center.

The hypothesis of the ERNU study is that aid from the Cancéropole Nord-Ouest facilitates clinical research activity resulting in a significant development of inclusions in non-university centers of the french north-west inter-region with an influence on the social and geographical inequalities recruitment.

Study Evaluating Intervention in the Development of Clinical Research in Non-Academic Health Institution (ERNU)

Randomized Trial Evaluating Intervention of the Cancéropôle Nord-Ouest in the Development of Clinical Research in Non-Academic Health Institutions (ERNU)

Measure the increase in inclusions in clinical trials of patients attending a Hospital or a private clinic "authorized to treat cancer" associated with a support provided by the Cancéropôle Nord-Ouest

assessment of the average of the reduction of social inequalities recruitment in clinical trial before and after the intervention of the Cancéropöle Nord-Ouest in each centers and in global. the social inequalities are calculated with the social and demographic tool developped by the french national institute of statistic and economic studies

Centre de traitement des données du Cancéropôle Nord-Ouest, Centre F. BACLESSE, Caen, France

Institut National de la Santé et de la Recherche Médical (INSERM) 1086 (Pr Guy LAUNOY) Centre F. BACLESSE, Caen, France

Centre Hospitalier Universitaire, Amiens

Immune System Diseases

Neoplasms

Rare Diseases

Multiple Sclerosis

Multiple Sclerosis, Chronic Progressive

Sclerosis

Autoimmune Diseases

Neoplasm Metastasis

Demyelinating Autoimmune Diseases, CNS

Autoimmune Diseases of the Nervous System

Demyelinating Diseases

Neoplastic Processes

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

All Drugs and Chemicals

Siponimod

Patients with secondary progressive multiple sclerosis (SPMS) randomized to receive BAF312 (siponimod). Refer to ClinicalTrials.gov record NCT01665144 for more information.

Patients with secondary progressive multiple sclerosis (SPMS) randomized to receive placebo. Refer to ClinicalTrials.gov record NCT01665144 for more information.

Blood draws (65 mLs \[\~4 tablespoons\] per blood draw) at 4 time points: Prior to study medication initiation, and at +6, +12 and+24 months post treatment initiation.

Blood Draw

For participants who volunteer to donate CSF samples: up to 25 mLs (\<2 tablespoons): prior to study medication initiation, and at month 24 post treatment initiation.

CSF collection by lumbar puncture (Optional)

Yang Mao-Draayer, MD, PhD

David Fox, MD

The primary goal of this study is to evaluate the effects of BAF312 (siponimod) on select immune and neuronal (nerve) cells by examining laboratory specimens (blood and/or spinal fluid) at multiple time points, prior to, and following the initiation of BAF312 or placebo treatment, in patients with Secondary Progressive Multiple Sclerosis (SPMS) who are enrolled in a clinical trial (NCT01665144) to evaluate the effectiveness and safety of BAF312.

This study is complementary to a multi-center, randomized, double-blind,parallel-group, placebo-controlled, variable treatment duration study comparing the efficacy and safety of BAF312 to placebo in patients with SPMS (NCT01665144). Investigators will explore both immunological and neuroprotective mechanisms of BAF312 (siponimod), a novel agent in the setting of a SPMS clinical trial.

This study is part of a multi-center study, with the University of Michigan serving as the central site.

Mechanistic Studies of Phase III Trial With BAF312 in Secondary Progressive Multiple Sclerosis

Mechanistic Studies of Phase III Trial With BAF312 in Secondary Progressive Multiple Sclerosis (AMS04)

Evaluation (BAF312 versus placebo) of dominant cytokines produced by myelin basic protein (MBP)-stimulated peripheral blood mononuclear cells (PBMCs), measured by ELISpot.

Compare BAF312 and Placebo (Control) Groups

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cancer and Hearing Loss Related in Children	NCT02425397	Cancer in Child... Hearing Loss	Genetic study Genetic study M...	4 Years -	Assistance Publique - Hôpitaux de Paris
Study Evaluating Intervention in the Development of Clinical Research in Non-Academic Health Institution (ERNU)	NCT02765451	Clinical Resear... Cancer	interventions o...	-	Centre Hospitalier Universitaire, Amiens
Mechanistic Studies of Phase III Trial With BAF312 in Secondary Progressive Multiple Sclerosis	NCT02330965	Secondary Progr...	Blood Draw CSF collection ...	18 Years - 60 Years	National Institute of Allergy and Infectious Diseases (NIAID)

Spots Global Cancer Trial Database for clinical research