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

January 15, 2026 updated by: Gustave Roussy, Cancer Campus, Grand Paris

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. 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. To explore first signals of activity in a molecularly enriched study population.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The first molecular profiling protocols have been launched in Europe (MOSCATO-01 (Geoerger 2014), MAPPYACTS, INFORM, iTHER, SM-PAEDS, etc.) determining multiple actionable alterations in pediatric recurrent cancers. Increasingly, stratified approaches are being implemented to enrich clinical trials of molecularly targeted agents and possibly improve outcomes in specific populations i.e. a molecularly enriched/predictive biomarker-driven approach. The diversity and heterogeneity of the detected molecular alterations and the low number of pediatric patients mandate an adapted, innovative trial design for the attributed treatment options in order to satisfy the current unmet medical need.

This basket trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe.

Study Type

Interventional

Enrollment (Estimated)

472

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
  • France
      • Angers, France, 49933
        • Recruiting
        • CHU Angers
        • Principal Investigator:
          • Isabelle Pellier
      • Bordeaux, France, 33076
        • Recruiting
        • CHU Pellegrin
        • Principal Investigator:
          • Stephane Ducassou
      • Lille, France, 59020
        • Recruiting
        • Centre Oscar Lambret
        • Principal Investigator:
          • Sandra Raimbault
      • Lyon, France, 69373
        • Recruiting
        • Centre léon bérard
        • Principal Investigator:
          • Nadege Corradini
      • Marseille, France, 13385
        • Recruiting
        • Hôpital de la Timone
        • Principal Investigator:
          • Nicolas ANDRE
      • Nantes, France, 44093
        • Recruiting
        • CHU Nantes
        • Principal Investigator:
          • Estelle Thebaud
      • Paris, France, 75005
        • Recruiting
        • Institut Curie
        • Principal Investigator:
          • Isabelle Aerts
      • Paris, France, 75012
        • Recruiting
        • Hôpital Armand Trousseau
        • Principal Investigator:
          • Arnaud Petit
    • Val De Marne
      • Villejuif, Val De Marne, France, 94805
        • Recruiting
        • Gustave Roussy
        • Principal Investigator:
          • Pablo Berlanga, MD
  • Italy
      • Milan, Italy
      • Torino, Italy, 10126
        • Not yet recruiting
        • Ospedale Infantile Regina Margherita
        • Principal Investigator:
          • Fagioli
  • Netherlands
      • Utrecht, Netherlands, 3584 EA
        • Active, not recruiting
        • Prinses Maxima Centrum
  • Spain
      • Barcelona, Spain, 08035
        • Recruiting
        • Vall d'Hebron
        • Principal Investigator:
          • Raquel Hladun
      • Madrid, Spain, 28009
        • Recruiting
        • Hospital del Niño Jesus
        • Principal Investigator:
          • Alba Rubio
      • Valencia, Spain, 46026
        • Recruiting
        • Hospital Universitario la Fe
        • Principal Investigator:
          • Adela Cañete
  • United Kingdom
      • Birmingham, United Kingdom, B4 6NH
        • Recruiting
        • Birmingham Children's Hospital
        • Principal Investigator:
          • Susanne Gatz
      • London, United Kingdom, WC1N 3JH
        • Recruiting
        • Great Ormond Street Hospital
        • Principal Investigator:
          • Giuseppe Barone
      • Manchester, United Kingdom, M13 9WL
        • Recruiting
        • Royal Manchester Children's Hospital
        • Principal Investigator:
          • Guy Makin
      • Newcastle, United Kingdom, NE1 4LP
        • Recruiting
        • Royal Victoria Infirmary
        • Principal Investigator:
          • Quentin Campbell-Hewson
      • Sutton, United Kingdom
        • Recruiting
        • Pediatric and Adolescent Oncology The Royal Marsden Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 14 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. 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.
  2. Age < 18 years at inclusion; patients 18 years and older may be included after discussion with the sponsor if they have a pediatric recurrent/refractory malignancy.
  3. 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.
  4. 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.).
  5. Patients with relapsed or refractory leukemia are eligible for this study.
  6. 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.
  7. Life expectancy ≥ 3 months

  8. 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:

    • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age
    • Total bilirubin ≤ 1.5 x ULN
    • Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 2,5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2,5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN.
  9. Able to comply with scheduled follow-up and with management of toxicity.
  10. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months (7 months for arm J) after the last study treatment administration. Acceptable contraception are defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials"
  11. For all oral medications patients must be able to comfortably swallow capsules (except for those for which an oral solution is available); nasogastric or gastrostomy feeding tube administration is allowed only if indicated.
  12. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
  13. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion Criteria:

  1. 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.
  2. 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).
  3. 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)
  4. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
  5. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
  6. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less.
  7. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose
  8. 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.
  9. 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).
  10. 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.
  11. Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8).
  12. 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).
  13. Known hypersensitivity to any study drug or component of the formulation.
  14. Pregnant or nursing (lactating) females.
  15. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A. Ribociclib + Topotecan and Temozolomide
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: Temozolomide
Other Names:
  • Temodar
Drug: Topotecan
Other Names:
  • Hycamtin
Drug: Ribociclib
Other Names:
  • LEE011
  • Kisqali
Experimental: Arm B. Ribociclib + Everolimus
Ribociclib capsules or oral solution orally QD for 21 days of each 28 day cycle; Everolimus orodispersible tablets orally QD for 28 days.
Drug: Everolimus
Other Names:
  • Afinitor
  • votubia
Drug: Ribociclib
Other Names:
  • LEE011
  • Kisqali
Experimental: ARM C. Adavosertib + Carboplatin
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: Carboplatin
Other Names:
  • Paraplatin
Drug: Adavosertib
Other Names:
  • AZD1775
Experimental: Arm D. Olaparib + Irinotecan
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: Irinotecan
Other Names:
  • Camptosar
  • CPT-11
Drug: Olaparib
Other Names:
  • Lynparza
Experimental: Arm E. Vistusertib single agent
Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle.
Drug: Vistusertib
Other Names:
  • AZD2014
Experimental: Arm F. Vistusertib + Topotecan and Temozolomide
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: Temozolomide
Other Names:
  • Temodar
Drug: Topotecan
Other Names:
  • Hycamtin
Drug: Vistusertib
Other Names:
  • AZD2014
Experimental: Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy
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: Cyclophosphamide
Other Names:
  • Cytoxan
Drug: Nivolumab
Other Names:
  • Opdivo
Experimental: Arm H. Selumetinib + Vistusertib
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: Selumetinib
Other Names:
  • Koselugo
Drug: Vistusertib
Other Names:
  • AZD2014
Experimental: Arm I. Enasidenib
Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle.
Drug: Enasidenib
Other Names:
  • Idhifa
Experimental: Arm J. Lirilumab + Nivolumab
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
Other Names:
  • Opdivo
Drug: Lirilumab
Other Names:
  • BMS-986015
Experimental: Arm K. Fadraciclib (CYC065) + Temozolomide
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
Other Names:
  • Temodar
Drug: Fadraciclib
Other Names:
  • CYC065
Experimental: Arm L. Fadraciclib (CYC065) + Cytarabine
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: Cytarabine
Other Names:
  • Arabinosylcytosine
  • Cytosar-U
Drug: Fadraciclib
Other Names:
  • CYC065
Experimental: Arm M. Ribociclib + Everolimus +/- Dexamethasone

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: Dexamethasone
Other Names:
  • Decadron
  • Hexadrol
  • Dexasone
  • Maxidex
  • Diodex
Drug: Everolimus
Other Names:
  • Afinitor
  • votubia
Drug: Ribociclib
Other Names:
  • LEE011
  • Kisqali
Experimental: Arm N. Ceralasertib (AZD6738) + Olaparib
Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle
Drug: Olaparib
Other Names:
  • Lynparza
Drug: Ceralasertib
Other Names:
  • AZD6738
Experimental: Arm O. Futibatinib (TAS-120)
Futibatinib tablets orally on a continuous dosing QD per 28 day cycle
Drug: Futibatinib
Other Names:
  • Tas-120
Experimental: Arm P. Capmatinib (INC280) + Everolimus
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
Other Names:
  • Afinitor
  • votubia
Drug: Capmatinib
Other Names:
  • INC280
  • Tabrecta
Experimental: Arm Q. Peposertib + Avelumab and Metronomic Temozolomide
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
Other Names:
  • Temodar
Drug: Avelumab
Other Names:
  • BAVENCIO
Drug: Peposertib
Experimental: Arm R. Capivasertib + metronomic Vinorelbine

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: Vinorelbine
Other Names:
  • Navelbine
Drug: Capivasertib
Other Names:
  • AZD5363
  • TRUQAP

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recommended phase II dose (RP2D)
Time Frame: During the first cycle
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)
Time Frame: During the first cycle
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)
Time Frame: During treatment period

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetics (PK)
Time Frame: Depending on the treatment arm
To characterize single or multiple-dose PK of the agent(s)
Depending on the treatment arm
Progression Free Survival (PFS)
Time Frame: From treatment initiation until the date of first documented progression or death
Defined as the time from treatment initiation until the date of first documented progression (clinically or radiologically) or death from any cause. Patients alive and free of progression at the cut-off date will be censored at the last assessment date.
From treatment initiation until the date of first documented progression or death
Evaluation of duration of response (DoR)
Time Frame: Between the first document response and the time of first documented progression
Defined as the time period between the first documented response (complete response (CR) or partial response (PR)) and the time of progression, according to RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, etc.
Between the first document response and the time of first documented progression

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gustave Roussy, Cancer Campus, Grand Paris

Collaborators

National Cancer Institute, France
Fondation ARC
Fight Kids Cancer

Investigators

  • Study Chair: Birgit Geoerger, MD, Gustave Roussy, Cancer Campus, Grand Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 3, 2016

Primary Completion (Estimated)

February 1, 2031

Study Completion (Estimated)

February 1, 2031

Study Registration Dates

First Submitted

June 16, 2016

First Submitted That Met QC Criteria

June 21, 2016

First Posted (Estimated)

June 24, 2016

Study Record Updates

Last Update Posted (Estimated)

January 16, 2026

Last Update Submitted That Met QC Criteria

January 15, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2016-000133-40
  • 2016/2396 (Other Identifier: CSET Number)
  • 2024-514791-40-00 (Ctis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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