Principal Investigator:

Lucas Moreno, MD, PhD & Raquel Hladun, MD

Research Team:

- Carlota Aguilera, Senior Study Coordinator

- Elena Andretta, Senior Study Coordinator

- Raquel Andreu, Data Manager

- Raquel Anta, Data Manager

- Marina Bonfill, Psycho-Oncologist

- Cristina Diaz de Heredia, Pediatric Oncologist

- Verónica Fernández, Study Nurse

- Paula Pérez Albert, Pediatric Oncologist

- Laura Romero, Study Nurse

- Lorena Valero, Pediatric Oncologist

- Pablo Velasco, Pediatric Oncologist

Clinical Associated Researchers:

- Luis Gros, MD: Pediatric Oncologist

- Anna Llort, MD, PhD: Pediatric Oncologist

- Constantino Sábado, MD: Pediatric Oncologist

- Luz Uría, MD: Pediatric Oncologist

- Maribel Benitez, MD: Pediatric Oncologist

- Laura Alonso, MD: Pediatric Oncologist

- Thais Murciano, MD: Pediatric Oncologist

- Laura Murillo, MD: Pediatric Oncologist

- Blanca Espinosa, MD: Pediatric Oncologist

- Anna Collado, MD: Pediatric Oncologist

- María Perez-Torres, MD: Pediatric Oncologist

- Ángela Menárguez, MD: Pediatric Oncologist

- Melissa Panesso, MD: Pediatric Oncologist

Collaborators:

- Marina Ortiz, MD: Pediatric Oncologist

- Josefa Elida Vázquez & Pediatric Radiology team

- Santiago Aguadé, Cristina Gámez & Nuclear Medicine team

- Nieves Martin & Pediatric Ophtalmology team

- Ferran Roses & Pediatric Cardiology team

BACKGROUND

Childhood cancer is the first cause of death due to disease in children. New drugs are needed to increase cure rates and reduce long-term sequelae of survivors. More than half of children with high-risk tumors, such as metastatic neuroblastoma, sarcomas or leukemias, or those with refractory or relapsed disease will not achieve a long-term cure.

Similarly, great advances have occurred in the development of novel drugs for non-malignant hematological conditions, leading to improved quality of life and avoidance of toxic therapies; our team focuses in the fields of hemolytic anemias such as sickle cell disease and pyruvate Kinase deficiency and bone marrow failure syndromes such as Fanconi anemia.

We have a wide clinical trial portfolio through our participation in the international ITCC consortium, with more than 50 clinical trials open at each given timepoint. Of those, more than 30 are early phase (phase 1 and phase 2), and many are first-in-child.

Our team receives patient consultations for participation in clinical trials from all regions of Spain and second opinion consultations are available through contact with the clinical team. If interested in participating in one of our clinical trials, please ask your primary physician to contact our team.

Over the past five years, we have developed and participated in multiple breakthrough academic and industry-driven clinical trials, such as the first-in-child, first-in-human trial of gene therapy for Fanconi anemia (reference Nat Med . 2019 Sep;25(9):1396-1401), the first-in-child trial of the ALK inhibitor ceritinib (Fischer/Moreno ref) and trials with oncolytic virus (EudraCT TVEC and AloCelyvir), CAR-T cells (BIANCA EudraCT 2017-005019-15) and cell therapies (ALVR-105 EudraCT 2021-003450-22) and larotrectinib for NTRK-positive tumours [SCOUT] (Neuro Oncol. 2022 Jun 1;24(6):997-1007).

The team has also participated and led practice-changing randomized trials, together with academic international consortia; such as the SCT Forum trial (Use of total body irradiation for SCT in childhood ALL), the EpSSG RMS 2005 trial (use of vinorelbine-cyclophosphamide as maintenance therapy in childhood rhabdomyosarcoma). The BEACON-Neuroblastoma trial, led by Dr. Lucas Moreno, evaluated the addition of bevacizumab and dinutuximab beta to chemotherapy in relapsed and refractory neuroblastoma. European sequencing project MAPPYACTS facilitate matching targeted therapies (Cancer Discov. 2022 May 2;12(5):1266-1281.).

RESEARCH STRATEGY AND SCOPE

Our clinical trials program aims to provide access to innovative medicines for children and adolescents with cancer and hematologic conditions; and facilitate the clinical development of these from phase 1 to phase 3 and into clinical use.

Our group has a clear focus to develop targeted, immunotherapy and advanced therapy medicines (gene and cell therapy). Where needed, our group thrives to develop and contribute to academic clinical trials bringing novel therapies.

Clinical trials for patients with solid tumors and lymphoma

Leukemia clinical trials for children and adolescents with relapsed and refractory B and T acute lymphoblastic leukemia and acute myeloblstic leukemia.

Non-malignant Hematology clinical trials for the treatment of patients with hemolytic anemias such as sickle cell disease, piruvate kinase deficiency and PNH, bone marrow failure syndromes such as Fanconi anemia and for ultra-rare diseases such as atransferrinemia.

Clinical trials for hematopoietic stem cell transplantation (HSCT) conditioning and post HSCT complications such as acute and chronic graft versus host disease, thrombotic microangiopathy and infections.

CAR-T cell therapies for patients with acute lymphoblastic leukemia and lymphoma,

Advanced therapies for the treatment of post hematopoietic cell transplantation viral infections

In the field of non-oncological hematology, we have open trials to reduce the most frequent symptoms of sickie cell anemia with targeted therapies, as well as new therapies for pyruvate kinase deficiency or paroxysmal hemoglobinuria in children.

For pediatric patients affected by oncological diseases of the blood, we have new molecules for patients with acute lymphoblastic leukemia (including Ph+ALL) acute myeloblastic leukemia and chronic myeloid leukemia in a situation of refractoriness or relapse.

ONGOING COMPETITIVE PROJECTS:

• ETNA

• BEACON2

• ARI CAR-T trial (CDdH)

• ALADDIN

SELECTED PUBLICATIONS:

• Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study. J Clin Oncol. 2022 Jun 16:JCO2102981. doi: 10.1200/JCO.21.02981.

• Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. doi: 10.1200/JCO.20.02529. Epub 2020 Dec 17.

• Opportunities and Challenges in Drug Development for Pediatric Cancers. Cancer Discov. 2021 Mar;11(3):545-559. doi: 10.1158/2159-8290.CD-20-0779. Epub 2020 Dec 4.

• Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1566-1575. doi: 10.1016/S1470-2045(19)30617-5. Epub 2019 Sep 24.

• A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2021 Mar 25;137(12):1582-1590. doi: 10.1182/blood.2020007848.

• Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. Lancet Haematol. 2018 Oct;5(10):e450-e461. doi: 10.1016/S2352-3026(18)30153-4.

• Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer. Eur J Cancer. 2018 Sep;100:27-34. doi: 10.1016/j.ejca.2018.05.002. Epub 2018 Jun 21.

• Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat Med . 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 9.

PAST MEMBERS:

The success of our clinical trials unit has been possible thanks to the pioneering work by Soledad Gallego, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR and Josep Sanchez de Toledo, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR.

Principal Investigator:

Aroa Soriano, PhD & Lucas Moreno, MD, PhD

Research Team:

- Raquel Hladun, MD: PhD researcher and Pediatric Oncologist

- Gabriela Guillén, MD: PhD researcher and Pediatric Surgeon

- Ainara Magdaleno: Laboratory Technician

- Lorena Valero, MD: Pediatric Oncologist

- Andrea Vilaplana: Biologist

- Alba Fernández, MD: Pediatric Oncologist

Collaborators or Associated Researchers or Clinical Associated Researchers:

- Luís Gros, MD: Pediatric Oncologist

- Anna Llort, MD, PhD: Pediatric Oncologist

- Constantino Sábado, MD, PhD: Pediatric Oncologist

- Maria Paula Pérez, MD: Pediatric Oncologist

- Marta Sesé, PhD: Biologist

- Javier Hernández, PhD: Biologist

- Elena Martínez, MD, PhD: Pathologist

- Marta Garrido, MD: Pathologist

- Alexandra Navarro, MD: Pathologist

- Jessica Camacho, MD, PhD: Pathologist

- Josep Roma, PhD: Sarcoma Lab PI

- Miguel Segura, PhD: Neural Tumors PI

- José Andrés Molino, MD: Pediatric Surgeon

- Sergio López, MD: Pediatric Surgeon

- Mª Antonia Poca: Pediatric Neurosurgeon

- Katiuska Rosas: Pediatric Neurosurgeon

- Diego Fernando Lopez: Pediatric Neurosurgeon

- Josefa Elida Vázquez: Radiologists

- Luis Riera: Radiologists

- Ana Coma: Radiologists

- Joan Albert Prat: Radiologists

- Angel Sánchez-Montañez: Radiologists

- José Miguel Escudero: Radiologists

- Lucia Riaza: Radiologists

- Ignacio Delgado: Radiologists

BACKGROUND

Revolution of Personalized Medicine in cancer care: The recent advances of anticancer precision medicine drugs have changed the paradigm of cancer treatment, particularly in tumors with single driving genetic alteration or oncogene addiction. Some of the most prominent examples of targeted drugs in pediatric cancers include NTRK, BRAF or ALK inhibitors. These novel drugs have completely changed frontline treatment practice for small subgroups of patients across tumor types, which need to be identified upfront.

Deep molecular profiling helps to improve diagnosis, and molecular diagnostics is already included in many childhood cancer entities in the WHO classification. Moreover, it refines prognostic stratification by identifying poor/good prognosis subgroups which need different treatments. In addition, it allows the identification of cancer predisposition syndromes which have major implications in management and surveillance, not only for the patients but also for their families.

The main goal of our Personalized Medicine Program is to build, implement and consolidate a strong personalized medicine program based on molecular profiling approaches to improve diagnosis accuracy, prognosis, treatment and identification of cancer predisposition syndromes for all children and adolescents with cancer in Spain. Our final aim is to offer every child with cancer the best possible chance of survival.

The personalised medicine program consists of a true multidisciplinary team formed by pediatric oncologists, surgeons, pathologists, radiologists, geneticists, molecular translational researchers and bioinformaticians who are committed to their work.

Our group also works in several Data Science projects, particularly focused in neuroblastoma. The genomic data generated in sequencing programs (COMIK, MAPPYACTS among others) together with clinical data generated within clinical trials (such as BEACON) and through the INRG collaboration (www.inrgdb.org) is further analysed and combined to identify novel biomarkers and targets that can be implemented in the clinic; also in collaboration with international data sharing initiatives.

RESEARCH STRATEGY AND SCOPE

The Pediatric Oncology Personalized Medicine Program is composed of:

COMIK (Cancer OMIcs for Kids) Program

• COMIK is the personalised medicine program of Vall d’Hebron Hospital for children, adolescents and young adults with relapsed/refractory solid tumours. COMIK includes patients from all the autonomous communities. Within COMIK programme we perform whole exome sequencing (WES) and RNA sequencing to obtain the complete profile of molecular alterations of the patients’ tumors to improve the access of children and adolescents with cancer to innovative therapies and targeted therapies within basket clinical trials. Our pre-screening platform is the only one in Spain based on WES and RNAseq molecular profiling.

• Functional Screening: Clinical pediatric precision oncology platforms have already identified actionable molecular targets in approximately 60% of pediatric cancers by applying next generation sequencing technologies. Despite the immense knowledge generated through sequencing efforts the remaining 40% of the children and adolescents lack actionable alterations indicating significant currently unmet needs in precision medicine programs. New targets and combinations must be identified combining profiling with functional data. We want to integrate the results of deep molecular profiling with novel functional screening tools, to increase and improve the therapeutic options available for pediatric patients.

• PDOX (Patient-derived orthotopic xenografts): COMIK program includes the generation of PDOX. Currently, we have established 50 orthotopic PDX models of pediatric solid tumors in collaboration with Dr. Alberto Villanueva from ICO/IDIBELL. Primary tumors and metastases from different locations were surgically grafted in their original locations in immunocompromised mice, maintaining their three-dimensional tissue structure. PDOX are unique valuable tools for

pediatric drug development, the discovery of molecular mechanisms for drug efficacies and combinations and in personalized medicine programs.

SEHOP-PENCIL (Personalised Medicine for Cancer in Children in Spain) Program

While France, the UK or Germany have now implemented routine next generation sequencing (NGS) panels and WES and RNAseq for all childhood cancer patients at diagnosis and relapse, sequencing has not yet been widely incorporated by the Spanish health care system for pediatric cancer patients. SEHOP-PENCIL is the Precision Medicine Strategy of our national scientific society (SEHOP-Sociedad Española de Hematología y Oncología Pediátrica) to create a network of eight hubs, all of which will be accessible to all hospitals treating pediatric cancer patients across our territory.

We want to implement molecular profiling approaches to improve diagnosis accuracy, treatment and identification of cancer predisposition syndromes for all children and adolescents with cancer in Spain. Moreover, we want to evaluate the efficacy and cost-effectiveness of these personalized medicine approaches and facilitate the regulatory and administrative pathway for their introduction in clinical care in the Spanish national healthcare system, ensuring equity and excellence in care for Spanish children and adolescents with cancer.

MAPPYACTS (MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification)

We have also collaborated in a European study of personalised medicine in paediatric cancer called MAPPYACTS. MAPPYACTS is a world-leading personalised medicine program that has changed the model of care for children with cancer in France. Vall d’Hebron was the only hub outside France accredited for genomic analyses of Spanish patients within this trial. Our participation in MAPPYACTS2 will start during 2022.

ONGOING COMPETITIVE PROJECTS:

• PI21/01661 (AES-ISCIII)- PI: Lucas Moreno & Aroa Soriano. COMIK 2.0: Integration of a genomic and functional screening platform for pediatric precision oncology. From 2022 to 2024. Amount granted: 214.170 €.

Our group started the personalized medicine program COMIK in 2016-2017, which has conducted WES in more than 100 pediatric patients to date. The program included patients with high-risk, refractory and relapsed solid tumours in the Paediatric Haematology & Oncology Unit of the Vall d'Hebron Hospital. COMIK2.0 is to enlarge the COMIK project including functional testing in addition to WES & RNASeq and facilitating referrals from all centres in Spain.

Nowadays, molecular screening is mandatory for 14 early phase trials in Spain and 4 of them require deep genomic screening with WES/WGS/RNAseq (i.e AcSe-ESMART [EudraCT 2016-000133-40]) Our main goal in this project is the development of a pre-screening platform for pediatric basket trials for relapsed & refractory childhood and adolescent cancers to maximize chances of antitumor efficacy and increase access of the pediatric patients to innovative therapies.

We also propose to integrate molecular analyses with a functional screening assay to improve the ability to predict clinical benefit of therapeutic options for pediatric patients. Functional screening assays perfectly complement molecular analysis in personalized medicine platforms when actionable alterations are not found or when we identify multiple genetic alterations. Our goal is to develop more accurate predictive pre-screening methods to offer the best therapeutic option for pediatric patients with relapsed and refractory tumors.

• PMP21/00073 (AES-ISCIII)-PI: Lucas Moreno. SEHOP-PENCIL Study: Personalised Medicine for Cancer in Children in Spain. From 2022 to 2025. Total amount: 1.890.703 €. VHIR coordinating group: 1.025.179,10

Incorporating high level personalized medicine programs in standard treatment of childhood cancer offers a unique opportunity to improve survival and reduce morbidities for all children.

The PENCIL project by the Spanish Society of Paediatric Haematology and Oncology has four major objectives: 1) To implement a nation-wide sequencing program offering access to next generation sequencing (NGS) panels at the time of diagnosis for high-risk cancers, whole exome/whole-genome sequencing (WES/WGS) and RNASeq at relapse, germline NGS panel or WGS to identify cancer predisposition syndromes and DNA methylation profiling for CNS tumours and sarcomas. 2) To develop tools to facilitate access to PerMed to all patients across Spain, by creating a network of clinicians and genomic hubs and molecular tumour boards. 3) To evaluate the implementation of PerMed into routine care for childhood cancer including cost-effectiveness and clinical outcomes. 4) To develop novel technologies that will overcome current limitations of diagnostic and surveillance approaches, such as liquid biopsy. The incorporation of PerMed into routine care will lead to improved diagnostic and prognostic information at diagnosis, increased access to novel targeted therapies at relapse and early identification and intervention on cancer predisposition syndromes for patients in all autonomous regions of Spain, resulting in major benefits for our society.

BEACON-BIO (Fights Kids Cancer)-IP: Lucas Moreno. Total amount:104.500 € VHIR coordinating group: 499.776 €

The BEACON trial (EudraCT 2012-000072-42) is a collaborative trial between the European consortia for early clinical trials and neuroblastoma research (ITCC and SIOPEN respectively)

for RRNB that started in 2013 that is now completed (n=225). In the first 160 patients, it evaluated three regimens (temozolomide, irinotecan-temozolomide and topotecantemozolomide) and bevacizumab (an anti-VEGF monoclonal antibody) showing improvements in response rates and survival, meeting trial pre-defined success criteria for progression-free survival (PFS). The Bevacizumab-Irinotecan-Temozolomide (BIT) combination may be more effective than irinotecan or bevacizumab separately: 2-year PFS was 49% for this arm. The trial was then amended to evaluate the addition of dinutuximab beta to topotecan-temozolomide chemotherapy following results from US trials with chemo-immunotherapy. 65 patients have been recruited and results will be available during Q4 2021 (Gray, Moreno & Wheatley). Currently, relapsed and refractory patients show different clinical phenotype and outcomes, but they are commonly grouped together in clinical trials. A crucial objective of this project will be to fully characterise these two populations.

SELECTED PUBLICATIONS (Top 10):

1. Berlanga P, Pierron G, Lacroix L, Chicard M, Adam de Beaumais T, Marchais A, Harttrampf AC, Iddir Y, Larive A, Soriano A, Hezam I, Chevassus C, Bernard V, Cotteret S, Scoazec JY, Gauthier A, Abbou S, Corradini N, André N, Aerts I, Thebaud E, Casanova M, Owens C, Hladun R, Michiels S, Delattre O, Vassal G, Schleiermacher G, Geoerger B. The European MAPPYACTS trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies. Cancer Discovery 2022.

2. Gargallo P, Bautista F, Juan-Ribelles A, Izquierdo E, Soriano A, de Rojas T, Escudero A, Lavarino C, Solano P, Hladun R, Rubio-San-Simón A, Martínez-Romera I, Calabria I, Olaciregui NG, Castañeda-Heredia A, de Álava E, Pérez-Martínez A, Astigarraga I, Patiño-García A, Alonso J, Fernández-Teijeiro A, Cañete A & Moreno L. Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP). Clinical and Translational Oncology. 2022 Feb. PMID: 35152364. DOI: 10.1007/s12094-021-02759-7.

3. Segura MF, Soriano A, Roma J, Piskareva O, Jiménez C, Boloix A, Fletcher JI, Haber M, Gray JC, Cerdá-Alberich L, Martínez de Las Heras B, Cañete A, Gallego S, Moreno L. Methodological advances in the discovery of novel neuroblastoma therapeutics. Expert Opin Drug Discov. 2022 Feb;17(2):167-179. doi: 10.1080/17460441.2022.2002297. Epub 2021 Nov 22. PMID: 34807782.

4. Masanas M, Masiá N, Suárez-Cabrera L, Olivan M, Soriano A, Majem B, Devis-Jauregui L, Burgos-Panadero R, Jiménez C, Rodriguez-Sodupe P, Boloix A, Toledano I, Guillén G, Navarro A, Llobet-Navas D, Villanueva A, Sánchez de Toledo J, Roma J, Noguera R, Moreno L, Krauss R, Gallego S, Santamaria A*, Segura MF*. The oral KIF11 inhibitor 4SC-205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic

neuroblastoma models. Clin Transl Med. 2021 Oct;11(10):e533. doi: 10.1002/ctm2.533. PMID: 34709738; PMCID: PMC8516339. (*corresponding authors).

5. Alcon C, Manzano-Muñoz A, Prada E, Mora J, Soriano A, Guillén G, Gallego S, Roma J, Samitier J, Villanueva A, Montero J. Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance. Cell Death Dis. 2020 Aug 15;11(8):634. PMID: 32801295. DOI: 10.1038/s41419-020-02887-y.

6. Carrillo-Reixach J, Torrens L, Simon-Coma M, Royo L, Domingo-Sàbat M, Abril-Fornaguera J, Akers N, Sala M, Ragull S, Arnal M, Villalmanzo M, Cairo S, Villanueva A, Kappler R, Garrido M, Guerra L, Sábado C, Guillén G, Mallo M, Piñeyro D, Vázquez-Vitali M, Kuchuk O, Mateos ME, Ramírez G, López Santamaría M, Mozo Y, Soriano A, Grotzer M, Branchereau S, García de Andoin N, López-Ibor B, López-Almaraz R, Salinas JA, Torres B, Hernández F, Uriz JJ, Fabre M, Blanco J, Paris C, Bajciová V, Laureys G, Masnou H, Clos A, Belendez C, Guettier C, Sumoy L, Planas R, Jordà M, Nonell L, Czauderna P, Morland B, Sia D, Losic B, Annick Buendia M, Sarrias MR, Llovet JM, Armengol C. Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol. 2020 Aug;73(2):328-341. doi: 10.1016/j.jhep.2020.03.025. Epub 2020 Mar 30. PMID: 32240714.

7. Zarzosa P, Navarro N, Giralt I, Molist C, Almazán-Moga A, Vidal I, Soriano A, Segura MF, Hladun R, Villanueva A, Gallego S, Roma J. Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments. Clin Transl Oncol. 2017 Jan;19(1):44-50. doi: 10.1007/s12094-016-1557-2. Epub 2016 Oct 7. PMID: 27718156

PAST MEMBERS:

The success of our clinical trials unit has been possible thanks to the pioneering work by Soledad Gallego, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR.

Josep Sanchez de Toledo, MD, PhD. Former Division Head of Pediatric Hematology and Oncology of Vall d’Hebron Hospital and Chair of the Cancer in Childhood and Adolescence Group of VHIR.