Creatividad y transdisciplinariedad para la formación

PROGRAM HIGHLIGHTS

Thanks to the collaboration with ITCC, the number of clinical trials with innovative drugs was significantly implemented and several phase I – first in children - studies have been opened recently.

In most of the ongoing studies, our Institution plays a pivotal role; it is the only Italian center selected for participation, and in others it acts as coordinating center.

As an example, in 2011 we started the phase I- first in children - of LDE225, an oral, potent and selective inhibitor of Smo, a key positive regulator of Hedgehog signaling ; it was a dose-escalation study to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug in children with recurrent or refractory medulloblastoma, or other tumors potentially dependent on Hedgehog (Hh) signaling pathway. At that time, our institution was the only Italian center open for accrual. The drug went subsequent- ly entered in phase 2 at is now in phase 3 in patients with recurrent/ refractory medulloblastoma. In the phase 3 study, only patients with activated Hh-pathway are included, who are identified on the basis of a 5-gene signature defined during the phase 1/2 study. Our institution is the coordinating center for Italy, which is currently the country with the highest enrollment. The results of the phase 1/2 studies, already presented in several meetings, will be published soon.

Also in the ongoing phase I – first in children – trail on LDK378, a selective inhibitor of ALK, our Institution is the only open center in Italy. Thanks to the positive interaction with the manufacturer, we also received the compound for preclinical evaluation. In vitro and in vivo experiments have been performed and are ongoing.

PROGRAM MEMBERSHIP

Michela Casanova, Responsible New Drug Project and member of the

Clinical Trial Committee of ITCC

Maura Massimino, Director of the SC Pediatria Oncologica Elena Barzanò, Trial Coordinator

Carla Moscheo, Clinical Researcher Carlo Morosi, Senior Radiologist Paola Collini, Senior Pathologist Patrizia Piotti, Senior Cardiologist Gabriella Saibene, Senior Pharmacist Valentina Sinno, Clinical Trial Office

SELECTED RECENT PUBLICATIONS

Di Giannatale A., Dias-Gastellier N., Devos A., Mc Hugh K., Boubaker A., Courbon F., Verschuur A., Ducassoul S., Malekzadeh K., Casanova M., Amoroso L., Chastagner P., Zwaan C.M., Munzer C., Aerts I., Landman-Parker J., Riccardi R., Le Deley MC., Geoerger B., Rubie H.: Phase II study of temozolomide in combination with topotecan in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study. Eur J Cancer 2014; 50(1): 170-177 Zsiros J., Brugieres L., Brock P., Roebuck D., Maibach R., Zimmermann A., Childs M., Pariente D., Laithier V., Otte J.B., Branchereau S., Aronson D., Rangaswami A., Ronghe M., Casanova M., Sullivan M., Morland B., Czauderna P., Perilongo G.; International Childhood Liver Tumours Strategy Group (SIOPEL): Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study. Lancet Oncol 2013; 14: 834-842

Semeraro M., Branchereau S., Maibach R., Zsiros J., Casanova M., Brock P., Domerg C., Aronson D.C., Zimmermann A., Laithier V.,

Childs M., Roebuck D., Perilongo G., Czauderna P., Brugieres L.: Relapses in hepatoblastoma patients: Clinical characteristics and outcome-experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 2013; 49: 915-922 Relapse in synovial sarcoma: What can be done for poor outcomes? Clinical Practice 2013; 10: 389-391

Massimino M., Casanova M., Polastri D., Biassoni V., Modena P., Pecori E., Schiavello E., De Pava M.V., Indini A., Rampini P., Bauer D., Catania S., Podda M., Gandola L.: Relapse in medulloblastoma: What can be done after abandoning high-dose chemotherapy? A mono-institutional experience. Childs Nerv System 2013; 29: 1107-1112

Zsíros J., Brugières L., Brock P., Roebuck D., Maibach R., Child M., Morland B., Casanova M., Pariente D., Paris C., de Camargo B., Ronghe M., Zimmermann A., Plaschkes J., Czauderna P.,

Perilongo G.: Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma - A phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 2012; 48: 3456-3464

ASSOCIATED CLINICAL TRIALS

Phase II open-label, randomized, multi-center comparative study of bevacizumab-based therapy in pediatric patients with newly diagnosed supratentorial high-grade glioma (Herby)

Open-label, multi-center, randomized phase II study evaluating the addition of bevacizumab to chemotherapy for childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and non- rhabdomyosarcoma soft tissue sarcoma (the Bernie study)

International randomized phase II trial of the combination of vincristine and irinotecan with or without temozolomide (VI or VIT) in children and adults with refractory or relapsed rhabdomyosarcoma

An open-label, multicenter, single-arm, phase I dose- escalation with efficacy tail extension study of RO5185426 in pediatric patients with surgically incurable and unresectable stage IIIc or stage IV melanoma harboring BRAFv600 mutations

A phase I/II study of sunitinib in young patients with advanced gastrointestinal stromal tumor (GIST)

A phase III, multi-center, open-label, randomized, controlled study of the efficacy and safety of oral LDE225 versus temozolomide in patients with HH-pathway activated relapsed medulloblastoma

A phase I, open-label, dose escalation study of LDK378 in pediatric patients with malignancies that have a genetic alteration in anaplastic lymphoma kinase (ALK)

A phase I/II, multicenter, open-label, dose-finding study to assess the safety, tolerability, and preliminary efficacy of weekly nab®-paclitaxel in pediatric patients with recurrent or refractory solid tumors

A phase III, randomized, double-blind, active comparator-controlled clinical trial, conducted under in-house blinding conditions, to examine the efficacy and safety of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients.

A phase I/II combined dose ranging and randomized, open-label comparative study of the efficacy and safety of plerixafor in addition to standard regimens for mobilization of hematopoietic stem cells into peripheral blood, and subsequent collection by apheresis, versus standard mobilization regimens alone in pediatric patients, aged 2 to <18 years, with solid tumors eligible for autologous transplants

SELECTED RECENT MAJOR GRANTS Grant from the ROL (Rete Oncologica Lombarda) for the clinical management of the academic trial - International randomized phase II trial of the combination of vincristine and irinotecan with or without temozolomide (VI or VIT) in children and adults with refractory or relapsed rhabdomyosarcoma – as national sponsor and coordinating the activities of Italian centers

Grants by patient Charities (Associazione Bianca Garavaglia) KEYWORDS

PATHWAYS OF RESEARCH/