European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
NCT ID: NCT02813135
Last Updated: 2026-01-16
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE1/PHASE2
472 participants
INTERVENTIONAL
2016-08-03
2031-02-28
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
Ribociclib
Topotecan
Temozolomide
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.
Ribociclib
Everolimus
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.
Adavosertib
Carboplatin
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.
Olaparib
Irinotecan
Arm E. Vistusertib single agent
Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle.
Vistusertib
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.
Topotecan
Temozolomide
Vistusertib
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.
Nivolumab
Cyclophosphamide
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.
Vistusertib
Selumetinib
Arm I. Enasidenib
Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle.
Enasidenib
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
Nivolumab
Lirilumab
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
Temozolomide
Fadraciclib
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
Fadraciclib
Cytarabine
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.
Ribociclib
Everolimus
Dexamethasone
Arm N. Ceralasertib (AZD6738) + Olaparib
Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle
Olaparib
Ceralasertib
Arm O. Futibatinib (TAS-120)
Futibatinib tablets orally on a continuous dosing QD per 28 day cycle
Futibatinib
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.
Everolimus
Capmatinib
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
Temozolomide
Avelumab
Peposertib
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.
Capivasertib
Vinorelbine
Interventions
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Ribociclib
Topotecan
Temozolomide
Everolimus
Adavosertib
Carboplatin
Olaparib
Irinotecan
Vistusertib
Nivolumab
Cyclophosphamide
Selumetinib
Enasidenib
Lirilumab
Fadraciclib
Cytarabine
Dexamethasone
Ceralasertib
Futibatinib
Capmatinib
Avelumab
Peposertib
Capivasertib
Vinorelbine
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
ALL
No
Sponsors
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National Cancer Institute, France
OTHER_GOV
Fight Kids Cancer
OTHER
Fondation ARC
OTHER
Gustave Roussy, Cancer Campus, Grand Paris
OTHER
Responsible Party
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Principal Investigators
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Birgit Geoerger, MD
Role: STUDY_CHAIR
Gustave Roussy, Cancer Campus, Grand Paris
Locations
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Rigshospitalet
Copenhagen, , Denmark
Gustave Roussy
Villejuif, Val De Marne, France
CHU Angers
Angers, , France
CHU Pellegrin
Bordeaux, , France
Centre Oscar Lambret
Lille, , France
Centre Léon Bérard
Lyon, , France
Hôpital de La Timone
Marseille, , France
CHU Nantes
Nantes, , France
Institut Curie
Paris, , France
Hôpital Armand Trousseau
Paris, , France
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, , Italy
Ospedale Infantile Regina Margherita
Torino, , Italy
Prinses Maxima Centrum
Utrecht, , Netherlands
Vall d'Hebron
Barcelona, , Spain
Hospital del Nino Jesus
Madrid, , Spain
Hospital Universitario La Fe
Valencia, , Spain
Birmingham Children's Hospital
Birmingham, , United Kingdom
Great Ormond Street Hospital
London, , United Kingdom
Royal Manchester Children's Hospital
Manchester, , United Kingdom
Royal Victoria Infirmary
Newcastle, , United Kingdom
Pediatric and Adolescent Oncology The Royal Marsden Hospital
Sutton, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
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.
Other Identifiers
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2016/2396
Identifier Type: OTHER
Identifier Source: secondary_id
2024-514791-40-00
Identifier Type: CTIS
Identifier Source: secondary_id
2016-000133-40
Identifier Type: -
Identifier Source: org_study_id
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