European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors

NCT02813135 | Recruiting Phase 1 DMC

• 3 other identifiers: 2016-000133-402016/23962024-514791-40-00
• Study Type: interventional
• Target: 472
• Locations: 6 countries
• Sites: 21

Brief Summary

This proof-of-concept platform trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe (Geoerger 2017; Geoerger 2019). The aims of the trial are:

1. 1.To determine the recommended phase II dose (RP2D) of a specific anticancer agent and/or a relevant combination in a pediatric population, to document its tolerability and
2. 2.To explore first signals of activity in a molecularly enriched study population.

Conditions

Pediatric Cancer

Keywords

Children; Adolescents; Young adults; Recurrent malignancies; Refractory malignancies

Outcome Measures

Primary Outcomes (3)

• Recommended phase II dose (RP2D)

  Defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and/or PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD)

  During the first cycle

• Maximum Tolerated Dose (MTD)

  The MTD will be defined as the dose associated with or closest to 25% of Dose Limiting Toxicities (DLTs)

  During the first cycle

• Objective Response Rate (ORR)

  Defined as the proportion of participants who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators. In patients with leukemia, ORR is defined as the percentage of patients attaining CR, CRi or CRp.

  During treatment period

Secondary Outcomes (3)

• Pharmacokinetics (PK)

  Depending on the treatment arm

• Progression Free Survival (PFS)

  From treatment initiation until the date of first documented progression or death

• Evaluation of duration of response (DoR)

  Between the first document response and the time of first documented progression

Study Arms (18)

Arm A. Ribociclib + Topotecan and Temozolomide

EXPERIMENTAL

Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Ribociclib capsules or oral solution orally QD from Day 6 to 20 of a 28 day cycle.

Drug: Ribociclib; Drug: Topotecan; Drug: Temozolomide

Arm B. Ribociclib + Everolimus

EXPERIMENTAL

Ribociclib capsules or oral solution orally QD for 21 days of each 28 day cycle; Everolimus orodispersible tablets orally QD for 28 days.

Drug: Ribociclib; Drug: Everolimus

ARM C. Adavosertib + Carboplatin

EXPERIMENTAL

Adavosertib capsules orally BID 3 days on / 4 days off in week 1; Carboplatin iv QD AUC 5 on Day 1 of a 21 day cycle.

Drug: Adavosertib; Drug: Carboplatin

Arm D. Olaparib + Irinotecan

EXPERIMENTAL

Olaparib tablets orally BID on Day 1-10 of a 21 day cycle Irinotecan iv QD on Day 4-8 of a 21 day cycle.

Drug: Olaparib; Drug: Irinotecan

Arm E. Vistusertib single agent

EXPERIMENTAL

Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle.

Drug: Vistusertib

Arm F. Vistusertib + Topotecan and Temozolomide

EXPERIMENTAL

Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Vistusertib tablets orally BID 3 days on/4 days off per week of a 28 day cycle.

Drug: Topotecan; Drug: Temozolomide; Drug: Vistusertib

Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy

EXPERIMENTAL

Nivolumab iv QD every 2 weeks of a 28 day cycle (Days 1 and 15); Cyclophosphamide tablets or oral solution orally BID, 1 week on/1 week off; Palliative irradiation/radiofrequency/cryotherapy starting 2 weeks after the first nivolumab injection.

Drug: Nivolumab; Drug: Cyclophosphamide

Arm H. Selumetinib + Vistusertib

EXPERIMENTAL

Selumetinib capsules twice daily on a continous administration. Vistusertib orally twice daily on an intermittent schedule : 2 days on / 5 days off per week of a 28 day cycle.

Drug: Vistusertib; Drug: Selumetinib

Arm I. Enasidenib

EXPERIMENTAL

Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle.

Drug: Enasidenib

Arm J. Lirilumab + Nivolumab

EXPERIMENTAL

Nivolumab iv QD on Day 1 and 15 of a 28 day cycle; Lirilumab iv QD on Day 1 of a 28 day cycle

Drug: Nivolumab; Drug: Lirilumab

Arm K. Fadraciclib (CYC065) + Temozolomide

EXPERIMENTAL

Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Temozolomide capsules orally QD on Day 1-5 of a 28 day cycle

Drug: Temozolomide; Drug: Fadraciclib

Arm L. Fadraciclib (CYC065) + Cytarabine

EXPERIMENTAL

Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Cytarabine iv or sc on Day 2-5 and Day 8-11 of a 28 day cycle

Drug: Fadraciclib; Drug: Cytarabine

Arm M. Ribociclib + Everolimus +/- Dexamethasone

EXPERIMENTAL

Ribociclib capsules or tablets orally QD on Day 1-21 of a 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle. For patients with leukemia and lymphoma: Dexamethasone orally or iv on Day 1-7 of each 28 day cycle. For patients with ALL, AML and Non-Hodgkin Lymphoma (NHL), Intrathecal chemotherapy will be administered additionally as per standard practice depending on CNS status.

Drug: Ribociclib; Drug: Everolimus; Drug: Dexamethasone

Arm N. Ceralasertib (AZD6738) + Olaparib

EXPERIMENTAL

Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle

Drug: Olaparib; Drug: Ceralasertib

Arm O. Futibatinib (TAS-120)

EXPERIMENTAL

Futibatinib tablets orally on a continuous dosing QD per 28 day cycle

Drug: Futibatinib

Arm P. Capmatinib (INC280) + Everolimus

EXPERIMENTAL

Capmatinib tablets orally on a continuous dosing BID per 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle.

Drug: Everolimus; Drug: Capmatinib

Arm Q. Peposertib + Avelumab and Metronomic Temozolomide

EXPERIMENTAL

Peposertib tablets orally on a continuous dosing BID per 28 day cycle Avelumab IV QD on Day 1 and Day 15 of a 28 day cycle Temozolomide capsules orally QD 5 days/week of a 28 day cycle

Drug: Temozolomide; Drug: Avelumab; Drug: Peposertib

Arm R. Capivasertib + metronomic Vinorelbine

EXPERIMENTAL

Capivasertib tablets orally BID on Day 1-4/week (4 days on/3 days off, every week) of a 28 day cycle. Vinorelbine soft capsules orally once daily on Day 1, 3 and 5/week of a 28 day cycle.

Drug: Capivasertib; Drug: Vinorelbine

Interventions

Ribociclib DRUG

Also known as: Kisqali, LEE011

Arm A. Ribociclib + Topotecan and Temozolomide; Arm B. Ribociclib + Everolimus; Arm M. Ribociclib + Everolimus +/- Dexamethasone

Topotecan DRUG

Also known as: Hycamtin

Arm A. Ribociclib + Topotecan and Temozolomide; Arm F. Vistusertib + Topotecan and Temozolomide

Temozolomide DRUG

Also known as: Temodar

Arm A. Ribociclib + Topotecan and Temozolomide; Arm F. Vistusertib + Topotecan and Temozolomide; Arm K. Fadraciclib (CYC065) + Temozolomide; Arm Q. Peposertib + Avelumab and Metronomic Temozolomide

Everolimus DRUG

Also known as: Afinitor, votubia

Arm B. Ribociclib + Everolimus; Arm M. Ribociclib + Everolimus +/- Dexamethasone; Arm P. Capmatinib (INC280) + Everolimus

Adavosertib DRUG

Also known as: AZD1775

ARM C. Adavosertib + Carboplatin

Carboplatin DRUG

Also known as: Paraplatin

ARM C. Adavosertib + Carboplatin

Olaparib DRUG

Also known as: Lynparza

Arm D. Olaparib + Irinotecan; Arm N. Ceralasertib (AZD6738) + Olaparib

Irinotecan DRUG

Also known as: Camptosar, CPT-11

Arm D. Olaparib + Irinotecan

Vistusertib DRUG

Also known as: AZD2014

Arm E. Vistusertib single agent; Arm F. Vistusertib + Topotecan and Temozolomide; Arm H. Selumetinib + Vistusertib

Nivolumab DRUG

Also known as: Opdivo

Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy; Arm J. Lirilumab + Nivolumab

Cyclophosphamide DRUG

Also known as: Cytoxan

Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy

Selumetinib DRUG

Also known as: Koselugo

Arm H. Selumetinib + Vistusertib

Enasidenib DRUG

Also known as: Idhifa

Arm I. Enasidenib

Lirilumab DRUG

Also known as: BMS-986015

Arm J. Lirilumab + Nivolumab

Fadraciclib DRUG

Also known as: CYC065

Arm K. Fadraciclib (CYC065) + Temozolomide; Arm L. Fadraciclib (CYC065) + Cytarabine

Cytarabine DRUG

Also known as: Arabinosylcytosine, Cytosar-U

Arm L. Fadraciclib (CYC065) + Cytarabine

Dexamethasone DRUG

Also known as: Decadron, Dexasone, Diodex, Hexadrol, Maxidex

Arm M. Ribociclib + Everolimus +/- Dexamethasone

Ceralasertib DRUG

Also known as: AZD6738

Arm N. Ceralasertib (AZD6738) + Olaparib

Futibatinib DRUG

Also known as: Tas-120

Arm O. Futibatinib (TAS-120)

Capmatinib DRUG

Also known as: Tabrecta, INC280

Arm P. Capmatinib (INC280) + Everolimus

Avelumab DRUG

Also known as: BAVENCIO

Arm Q. Peposertib + Avelumab and Metronomic Temozolomide

Peposertib DRUG

Arm Q. Peposertib + Avelumab and Metronomic Temozolomide

Capivasertib DRUG

Also known as: TRUQAP, AZD5363

Arm R. Capivasertib + metronomic Vinorelbine

Vinorelbine DRUG

Also known as: Navelbine

Arm R. Capivasertib + metronomic Vinorelbine

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients must be diagnosed with a haematologic or solid tumor malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists.
• Patient must have had advanced molecular profiling (i.e. WES/WGS +/- RNAseq) of their recurrent or refractory tumor i.e. at the time of disease progression/relapse; exceptionally patients with advanced molecular profiling at diagnosis may be allowed.
• Evaluable or measurable disease as defined by standard imaging criteria for the patient's tumor type (RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, Leukemia criteria, etc.).
• Patients with relapsed or refractory leukemia are eligible for this study.
• Performance status: Karnofsky performance status (for patients \>12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Life expectancy ≥ 3 months
• Adequate organ function:
• Hematologic criteria (Leukemia patients are excluded from hematological criteria):
• Peripheral absolute neutrophil count (ANC) ≥ 1000/μL(unsupported)
• Platelet count ≥ 100,000/μL (unsupported)
• Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)
• Cardiac function:
• Shortening fraction (SF) \>29% (\>35% for children \< 3 years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy).
• Absence of QTc prolongation (QTc \> 450 msec on baseline ECG, using the Fridericia correction \[QTcF formula\]) or other clinically significant ventricular or atrial arrhythmia.
• Renal and hepatic function:

You may not qualify if:

• Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease. Patients on stable doses of corticosteroids for at least 7 days prior to receiving study drug may be included.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
• Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable ischemia,congestive heart failure within 12 months of screening)
• Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
• Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less.
• Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose
• Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
• Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
• Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
• Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8).
• Currently taking medications that are mainly metabolized by CYP3A4/5, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 and have a low therapeutic index that cannot be discontinued at least 7 days or 5 x reported elimination half-life prior to start of treatment with any of the investigational drugs and for the duration of the study (Refer to Appendix 9).
• Known hypersensitivity to any study drug or component of the formulation.
• Pregnant or nursing (lactating) females.
• Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

Sponsors & Collaborators

• National Cancer Institute, France: collaborator
• Fight Kids Cancer: collaborator
• Fondation ARC: collaborator
• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (21)

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Gustave Roussy

Villejuif, Val De Marne, 94805, France

RECRUITING

CHU Angers

Angers, 49933, France

RECRUITING

CHU Pellegrin

Bordeaux, 33076, France

RECRUITING

Centre Oscar Lambret

Lille, 59020, France

RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Hôpital de La Timone

Marseille, 13385, France

RECRUITING

CHU Nantes

Nantes, 44093, France

RECRUITING

Institut Curie

Paris, 75005, France

RECRUITING

Hôpital Armand Trousseau

Paris, 75012, France

RECRUITING

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

RECRUITING

Ospedale Infantile Regina Margherita

Torino, 10126, Italy

NOT YET RECRUITING

Prinses Maxima Centrum

Utrecht, 3584 EA, Netherlands

ACTIVE NOT RECRUITING

Vall d'Hebron

Barcelona, 08035, Spain

RECRUITING

Hospital del Nino Jesus

Madrid, 28009, Spain

RECRUITING

Hospital Universitario La Fe

Valencia, 46026, Spain

RECRUITING

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

RECRUITING

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

RECRUITING

Royal Manchester Children's Hospital

Manchester, M13 9WL, United Kingdom

RECRUITING

Royal Victoria Infirmary

Newcastle, NE1 4LP, United Kingdom

RECRUITING

Pediatric and Adolescent Oncology The Royal Marsden Hospital

Sutton, United Kingdom

RECRUITING

Related Publications (6)

• Rubio-San-Simon A, Marshall LV, Karamouza E, Andre N, Abbou S, Rubino J, Nebchi S, Aerts I, Thebaud E, Brisset C, Ducassou S, Le Teuff G, Geoerger B. Phase I/II Study of the CDK2/9 Inhibitor Fadraciclib in Combination with Chemotherapy in Children with Advanced Malignancies: Arm K of the AcSe-ESMART Trial. Target Oncol. 2026 Mar 16. doi: 10.1007/s11523-026-01208-1. Online ahead of print.

  PMID: 41838385 DERIVED

• Berlanga P, Pierron G, Lacroix L, Chicard M, Adam de Beaumais T, Marchais A, Harttrampf AC, Iddir Y, Larive A, Soriano Fernandez A, Hezam I, Chevassus C, Bernard V, Cotteret S, Scoazec JY, Gauthier A, Abbou S, Corradini N, Andre N, Aerts I, Thebaud E, Casanova M, Owens C, Hladun-Alvaro 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 Discov. 2022 May 2;12(5):1266-1281. doi: 10.1158/2159-8290.CD-21-1136.

  PMID: 35292802 DERIVED

• Morscher RJ, Brard C, Berlanga P, Marshall LV, Andre N, Rubino J, Aerts I, De Carli E, Corradini N, Nebchi S, Paoletti X, Mortimer P, Lacroix L, Pierron G, Schleiermacher G, Vassal G, Geoerger B. First-in-child phase I/II study of the dual mTORC1/2 inhibitor vistusertib (AZD2014) as monotherapy and in combination with topotecan-temozolomide in children with advanced malignancies: arms E and F of the AcSe-ESMART trial. Eur J Cancer. 2021 Nov;157:268-277. doi: 10.1016/j.ejca.2021.08.010. Epub 2021 Sep 17.

  PMID: 34543871 DERIVED

• Bautista F, Paoletti X, Rubino J, Brard C, Rezai K, Nebchi S, Andre N, Aerts I, De Carli E, van Eijkelenburg N, Thebaud E, Corradini N, Defachelles AS, Ducassou S, Morscher RJ, Vassal G, Geoerger B. Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSe-ESMART Trial. J Clin Oncol. 2021 Nov 10;39(32):3546-3560. doi: 10.1200/JCO.21.01152. Epub 2021 Aug 4.

  PMID: 34347542 DERIVED

• Pasqualini C, Rubino J, Brard C, Cassard L, Andre N, Rondof W, Scoazec JY, Marchais A, Nebchi S, Boselli L, Grivel J, Aerts I, Thebaud E, Paoletti X, Minard-Colin V, Vassal G, Geoerger B. Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSe-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium. Eur J Cancer. 2021 Jun;150:53-62. doi: 10.1016/j.ejca.2021.03.032. Epub 2021 Apr 20.

  PMID: 33892407 DERIVED

• Rossoni C, Bardet A, Geoerger B, Paoletti X. Sequential or combined designs for Phase I/II clinical trials? A simulation study. Clin Trials. 2019 Dec;16(6):635-644. doi: 10.1177/1740774519872702. Epub 2019 Sep 20.

  PMID: 31538815 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

ribociclib; Topotecan; Temozolomide; Everolimus; adavosertib; Carboplatin; olaparib; Irinotecan; vistusertib; Nivolumab; Cyclophosphamide; AZD 6244; enasidenib; lirilumab; CYC065; Cytarabine; Dexamethasone; Calcium Dobesilate; ceralasertib; futibatinib; capmatinib; avelumab; peposertib; capivasertib; Vinorelbine

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Sirolimus; Macrolides; Lactones; Coordination Complexes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Birgit Geoerger, MD

  Gustave Roussy, Cancer Campus, Grand Paris

  STUDY CHAIR

Central Study Contacts

Birgit Geoerger, MD

CONTACT

+33 (0)1 42 11 46 61; birgit.geoerger@gustaveroussy.fr

Estelle Jullemier, MS

CONTACT

+33 (0)1 42 11 55 51; Estelle.JULLEMIER@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2016
• First Posted: June 24, 2016
• Study Start: August 3, 2016
• Primary Completion (Estimated): February 1, 2031
• Study Completion (Estimated): February 1, 2031
• Last Updated: January 16, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (5); NL (1); ES (3); FR (9); DK (1); IT (2)