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

Overview

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.

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.

Interventions

• Drug Ribociclib
• Drug Topotecan
• Drug Temozolomide
• Drug Everolimus
• Drug Adavosertib
• Drug Carboplatin
• Drug Olaparib
• Drug Irinotecan
• Drug Vistusertib
• Drug Nivolumab

Primary outcome measures

• Recommended phase II dose (RP2D) [Time frame: During the first cycle]
• Maximum Tolerated Dose (MTD) [Time frame: During the first cycle]
• Objective Response Rate (ORR) [Time frame: During treatment period]

Secondary outcome measures (3)

• Pharmacokinetics (PK) [Time frame: Depending on the treatment arm]
• Progression Free Survival (PFS) [Time frame: 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]

Eligibility criteria

Inclusion criteria

• 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.
• 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.
• 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:

• 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.
• Able to comply with scheduled follow-up and with management of toxicity.
• 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"
• 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.
• 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.
• Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 10 centers

• Gustave Roussy — Villejuif
• CHU Angers — Angers
• CHU Pellegrin — Bordeaux
• Centre Oscar Lambret — Lille
• Centre Léon Bérard — Lyon
• Hôpital de La Timone — Marseille
• CHU Nantes — Nantes
• Institut Curie — Paris
• … and 2 more centers

United Kingdom · 5 centers

• Birmingham Children's Hospital — Birmingham
• Great Ormond Street Hospital — London
• Royal Manchester Children's Hospital — Manchester
• Royal Victoria Infirmary — Newcastle
• Pediatric and Adolescent Oncology The Royal Marsden Hospital — Sutton

Italy · 3 centers

• Istituto Giannina Gaslini — Genova
• Fondazione IRCCS Istituto Nazionale dei Tumori — Milan
• Ospedale Infantile Regina Margherita — Torino

Spain · 3 centers

• Vall d'Hebron — Barcelona
• Hospital del Nino Jesus — Madrid
• Hospital Universitario La Fe — Valencia

Denmark · 1 center

• Rigshospitalet — Copenhagen

Netherlands · 1 center

• Prinses Maxima Centrum — Utrecht

Publications

• 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;21(2):199-211. doi: 10.1007/s11523-026-01208-1. Epub 2026 Mar 16. PMID 41838385
• 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 Medici PMID 35292802
• 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 t PMID 34543871
• 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 PMID 34347542
• 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 I PMID 33892407
• 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

Identifiers

NCT: NCT02813135 · 2016-000133-40 · 2016/2396 · 2024-514791-40-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗