Overview
Sponsor-declared trial summary
Phase
Phase I and Phase II (Integrated) - Other
Status
Ongoing, recruiting
Participants planned
470
Countries
5
Sites
18
pediatric cancer
Based on results from a comparative review (Paoletti 2013), we hypothesize that if the toxicity profile and the PK parameters observed in children treated at the adult RP2D are similar to those in adults; escalating to the MTD is not necessarily required, unless a dose-activity relationship has been documented in adult…
Key facts
- Sponsor
- Institut Gustave Roussy
- Participant type
- Pediatric, Patients
- Age range
- 0-17 years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Neoplasms [C04]
- Trial duration
- 3 Aug 2016 → ongoing
- Decision date (initial)
- 2024-10-21
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
External identifiers
- EU CT number
- 2024-514791-40-00
- EudraCT number
- 2016-000133-40
- ClinicalTrials.gov
- NCT02813135
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Safety, Efficacy
Based on results from a comparative review (Paoletti 2013), we hypothesize that if the toxicity profile and the PK parameters observed in children treated at the adult RP2D are similar to those in adults; escalating to the MTD is not necessarily required, unless a dose-activity relationship has been documented in adults. Therefore, for each agent or combination of agents being investigated, there will be two co-primary objectives:
1. Phase I: To define or validate that the adult RP2D of the selected drug or combination of drugs is safe in children/adolescents and equivalent to that seen in adults, in pediatric/adolescent patients with malignancies which are recurrent or refractory to standard therapy.
2. Phase II: To determine the preliminary activity (as measured by objective tumor response) of these agents in patients harboring specific molecular alterations or tumor types that may be associated with the mechanism of action of these drugs (i.e. molecularly enriched patient cohorts, where possible) and non-enriched patients (if included in the arm design).
Secondary objectives 7
- To characterize the toxicity profile of the agent(s) in pediatric/ adolescent patients.
- To characterize single or multiple-dose PK of the agent(s).
- To evaluate the progression free survival and incidence of long-term responders (>6 months) and duration of response.
- To evaluate whether the response rate is higher in the enriched population as compared to the non-enriched population overall, by targeted treatment and by arm.
- Exploratory: - To explore, define and/or validate pharmacodynamic (Pd) biomarkers of target inhibition or immune markers, where possible and potentially relevant.
- exploratory: To explore relationships between measures of tumor expression of the molecular target(s), circulating tumor DNA and tumor growth.
- Secondary and exploratory objectives specific to a treatment arm are specified separately in protocol section 3.2.
Conditions and MedDRA coding
pediatric cancer
Regulatory references
- EMA paediatric investigation plan (PIP)
- EMEA-001798-PIP02-16
- Plan to share IPD
- Yes
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 13
- Patients must be diagnosed with hematologic or solid tumor malignancy that has progressed or relapsed despite standard therapy, or for which no effective standard therapy exists.
- Age <18 years at inclusion.
- 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.
- Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥70%.
- Life expectancy ≥3 months.
- Adequate organ function as defined in section 3.1.1 of the protocol.
- 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 patients must agree to use highly effective method of contraception.
- For all oral medications patients must be able to comfortably swallow whole capsules or tablets (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.
- For a complete list of eligibility criteria, see the sections corresponding to inclusion and exclusion criteria in the protocol.
Exclusion criteria 16
- 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.
- Major surgery within 21 days of the first dose.
- Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
- Known hypersensitivity to any study drug or component of the formulation.
- Pregnant or nursing (lactating) females
- Vaccinated with live, attenuated vaccines,including yellow fever, within 4 weeks of the first dose of study drug.
- For a complete list of eligibility criteria, see the sections corresponding to inclusion and exclusion criteria in the protocol. Additional inclusion and enrichment and exclusion criteria for each treatment arm are specified separately in protocol section 3.2.
- 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).
- Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias).
- 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 lymphopenia G3, 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).
- Increasiong dose of Steroids over the last 7 days and with a maximum of 0.5 mg/kg /days
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- The recommended phase II dose (RP2D) will be defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and 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).
Secondary endpoints 9
- The maximum tolerated dose (MTD) will be defined as the dose associated with or closest to 25% of DLTs in cycle 1.
- Dose Limiting Toxicities (DLT) will be defined using NCI CTCAE v4.03.
- Overall response rate (ORR) will be defined as percentage of patients achieving confirmed CR or confirmed PR as per standard methods for the underlying disease.
- Duration of response (DOR) will be defined as the time period between the first documented response (PR or CR) and the time of first documented progression (clinically or radiologically – Appendix 3 to 7) or death from any cause, whichever comes first. Duration of response for patients free of progression at the cut-off date will be censored at the last assessment date.
- Progression-free survival (PFS) will be defined as the time from treatment initiation until the date of first documented progression or death from any cause, whichever comes first. Patients alive and free of progression at the cut-off date will be censored at the last assessment date.
- Overall survival (OS) will be defined as the time from treatment initiation until the date of death from any cause. Patients alive at the cut-off date will be censored at the date of last news.
- Adverse events according to the NCI CTCAE V4.03 in all cycles of treatment.
- PK parameters, including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, Clearance, Half-life time.
- Relationship between the molecular profile of the tumor samples, circulating tumor DNA and tumor growth.
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 18
Votubia 3 mg dispersible tablets
PRD2380269 · Product
- Active substance
- Everolimus
- Pharmaceutical form
- ORAL SUSPENSION
- Route of administration
- ORAL
- Authorisation status
- Authorised
- ATC code
- L01EG02 — -
- Marketing authorisation
- EU/1/11/710/012
- MA holder
- NOVARTIS EUROPHARM LIMITED
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Votubia 2 mg dispersible tablets
PRD2380266 · Product
- Active substance
- Everolimus
- Pharmaceutical form
- ORAL SUSPENSION
- Route of administration
- ORAL
- Authorisation status
- Authorised
- ATC code
- L01EG02 — -
- Marketing authorisation
- EU/1/11/710/009
- MA holder
- NOVARTIS EUROPHARM LIMITED
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Votubia 5 mg dispersible tablets
PRD2380271 · Product
- Active substance
- Everolimus
- Pharmaceutical form
- ORAL SUSPENSION
- Route of administration
- ORAL
- Authorisation status
- Authorised
- ATC code
- L01EG02 — -
- Marketing authorisation
- EU/1/11/710/014
- MA holder
- NOVARTIS EUROPHARM LIMITED
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
PRD5134827 · Product
- Active substance
- Capmatinib
- Pharmaceutical form
- FILM COATED TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- NOVARTIS PHARMA AG
- Paediatric formulation
- No
- Orphan designation
- No
PRD5134826 · Product
- Active substance
- Capmatinib
- Pharmaceutical form
- FILM COATED TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- NOVARTIS PHARMA AG
- Paediatric formulation
- No
- Orphan designation
- No
VINORELBINE ACCORD 30 mg, capsule molle
PRD10121161 · Product
- Active substance
- Vinorelbine
- Pharmaceutical form
- CAPSULE, SOFT
- Route of administration
- OCULAR USE
- Authorisation status
- Authorised
- ATC code
- L01CA04 — VINORELBINE
- Marketing authorisation
- 34009 302 653 9 0
- MA holder
- ACCORD HEALTHCARE FRANCE SAS
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
VINORELBINE ACCORD 20 mg, capsule molle
PRD10121160 · Product
- Active substance
- Vinorelbine Tartrate
- Substance synonyms
- VINORELBINE DITARTRATE, 5´-NOR-ANHYDROVINBLASTINE TARTRATE
- Pharmaceutical form
- CAPSULE, SOFT
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- L01CA04 — VINORELBINE
- Marketing authorisation
- 34009 302 653 8 3
- MA holder
- ACCORD HEALTHCARE FRANCE SAS
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Bavencio 20 mg/mL concentrate for solution for infusion
PRD5432331 · Product
- Active substance
- Avelumab
- Substance synonyms
- MSB0010718C, Recombinant human monoclonal IgG1 antibody against programmed death ligand-1, MSB 0010718C
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Authorisation status
- Authorised
- ATC code
- L01FF04 — -
- Marketing authorisation
- EU/1/17/1214/001
- MA holder
- MERCK EUROPE B.V.
- MA country
- Norway
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
PRD11516323 · Product
- Active substance
- Peposertib
- Substance synonyms
- (S)-(2-CHLORO-4-FLUORO-5-(7-(MORPHOLIN-4-YL)QUINAZOLIN-4- YL)PHENYL)(6-METHOXYPYRIDAZIN-3-YL)METHANOL, MSC2490484A, (S)-{2-CHLORO-4-FLUORO-5-[7-(MORPHOLIN-4-YL)QUINAZOLIN4-YL]PHENYL}(6-METHOXYPYRIDAZIN-3-YL)METHANOL, MSC 2490484A, M-3814, NEDISERTIB
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- MERCK HEALTHCARE KGAA
- Paediatric formulation
- No
- Orphan designation
- No
TEMOZOLOMIDE VIATRIS 5 mg, gélule
PRD10141214 · Product
- Active substance
- Temozolomide
- Pharmaceutical form
- CAPSULE, HARD
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- L01AX03 — TEMOZOLOMIDE
- Marketing authorisation
- 34009 577 103 8 5
- MA holder
- VIATRIS SANTE
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
TEMOZOLOMIDE VIATRIS 100 mg, gélule
PRD10141216 · Product
- Active substance
- Temozolomide
- Pharmaceutical form
- CAPSULE, HARD
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- L01AX03 — TEMOZOLOMIDE
- Marketing authorisation
- 34009 577 107 3 6
- MA holder
- VIATRIS SANTE
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
TEMOZOLOMIDE VIATRIS 20 mg, gélule
PRD10141215 · Product
- Active substance
- Temozolomide
- Pharmaceutical form
- CAPSULE, HARD
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- L01AX03 — TEMOZOLOMIDE
- Marketing authorisation
- 34009 577 105 0 7
- MA holder
- VIATRIS SANTE
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
PRD9585495 · Product
- Active substance
- Futibatinib
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- TAIHO ONCOLOGY, INC.
- Paediatric formulation
- No
- Orphan designation
- No
PRD10312009 · Product
- Active substance
- Capivasertib
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Authorisation status
- Not Authorised
- MA holder
- ASTRAZENECA AB
- Paediatric formulation
- No
- Orphan designation
- No
PRD12048151 · Product
- Active substance
- Capivasertib
- Pharmaceutical form
- FILM COATED TABLET
- Route of administration
- ORAL USE
- Authorisation status
- Not Authorised
- MA holder
- ASTRAZENECA AB
- Paediatric formulation
- No
- Orphan designation
- No
PRD10312011 · Product
- Active substance
- Capivasertib
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Authorisation status
- Not Authorised
- MA holder
- ASTRAZENECA AB
- Paediatric formulation
- No
- Orphan designation
- No
PRD11286460 · Product
- Active substance
- Enasidenib Mesilate
- Substance synonyms
- ENASIDENIB MESYLATE, 2-METHYL-1-((4-(6-(TRIFLUOROMETHYL)PYRIDIN-2-YL)- 6-((2-(TRIFLUOROMETHYL)PYRIDIN-4-YL)AMINO)-1,3,5-TRIAZIN- 2-YL)AMINO)PROPAN-2-OL METHANESULFONATE
- Pharmaceutical form
- SPRINKLE CAPSULE
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- BRISTOL-MYERS SQUIBB INTERNATIONAL CORPORATION
- Paediatric formulation
- No
- Orphan designation
- No
PRD11286343 · Product
- Active substance
- Enasidenib Mesilate
- Substance synonyms
- ENASIDENIB MESYLATE, 2-METHYL-1-((4-(6-(TRIFLUOROMETHYL)PYRIDIN-2-YL)- 6-((2-(TRIFLUOROMETHYL)PYRIDIN-4-YL)AMINO)-1,3,5-TRIAZIN- 2-YL)AMINO)PROPAN-2-OL METHANESULFONATE
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- BRISTOL-MYERS SQUIBB INTERNATIONAL CORPORATION
- Paediatric formulation
- No
- Orphan designation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Institut Gustave Roussy
- Sponsor organisation
- Institut Gustave Roussy
- Address
- 114 Rue Edouard Vaillant
- City
- Villejuif
- Postcode
- 94800
- Country
- France
Scientific contact point
- Organisation
- Institut Gustave Roussy
- Contact name
- Regulatory Affairs Officer
Public contact point
- Organisation
- Institut Gustave Roussy
- Contact name
- Regulatory Affairs Officer
Third parties 1
| Organisation | City, country | Duties |
|---|---|---|
| Frederiksberg Hospital ORG-100028217
|
Frederiksberg, Denmark | On site monitoring |
Locations
5 EU/EEA countries · 18 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Denmark | Ongoing, recruiting | 26 | 1 |
| France | Ongoing, recruiting | 276 | 10 |
| Italy | Ongoing, recruiting | 25 | 3 |
| Netherlands | Ongoing, recruiting | 23 | 1 |
| Spain | Ongoing, recruiting | 48 | 3 |
| Rest of world
United Kingdom, Switzerland
|
— | 72 | — |
Investigational sites
Rigshospitalet
Paediatrics & Adolescent Medicine, Blegdamsvej 9, 2100, Copenhagen Oe
Centre Hospitalier Universitaire De Nantes
pediatric oncology, 7 Quai Moncousu, 44000, Nantes
Pellegrin Hospital
Onco-Haematological pediatry, Place Amelie Raba Leon, 33000, Bordeaux
Centre Hospitalier Universitaire D'Angers
Pediatric oncology, 4 Rue Larrey, 49100, Angers
Institut Gustave Roussy
pediatric oncology, 114 Rue Edouard Vaillant, 94800, Villejuif
Trousseau Hospital
haematological and pediatric oncology, 26 Avenue Du Docteur Arnold Netter, 75012, Paris
Institut Des Neurosciences De La Timone
Haematological and oncological pediatry, 27 Boulevard Jean Moulin, 13005, Marseille
Centre Oscar Lambret
pediatric oncology, 3 Rue Frederic Combemale, 59000, Lille
Centre Leon Berard
pediatric oncology, 28 Rue Laennec, 69008, Lyon
Les Hopitaux Universitaires De Strasbourg
pediatric oncology, 1 Avenue Moliere, Bp 49, Strasbourg Cedex 2
Institut Curie
pediatric oncology, 26 Rue D Ulm, 75005, Paris
IRCCS Istituto Giannina Gaslini
pediatric oncology, Via Gerolamo Gaslini 5, 16147, Genoa
Fondazione IRCCS Istituto Nazionale Dei Tumori
pediatric oncology, Via Giacomo Venezian 1, 20133, Milan
Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino
pediatric oncology, Piazza Polonia 94, 10126, Turin
Prinses Maxima Centrum voor Kinderoncologie B.V.
Trial en Data Center, Heidelberglaan 25, 3584 CS, Utrecht
Hospital Infantil Universitario Nino Jesus
Pediatrics Onco-hematology, Avenida Menendez Pelayo 65, 28009, Madrid
Hospital Universitario Y Politecnico La Fe
Pediatrics Onco-hematology, Avenida De Fernando Abril Martorell 106, 46026, Valencia
Hospital Universitari Vall D Hebron
Pediatrics Onco-hematology, Passeig De La Vall D'Hebron 119-129, 08035, Barcelona
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Denmark | 2024-04-04 | 2024-04-04 | |||
| France | 2016-08-03 | 2016-08-03 | |||
| Italy | 2021-07-04 | 2021-07-04 | |||
| Netherlands | 2018-04-25 | 2018-04-25 | |||
| Spain | 2020-01-23 | 2020-01-23 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 16 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2024-514791-40-00_biffe | 9.0 |
| Recruitment arrangements (for publication) | A1_2024-514791-40-00_AcSe-ESMART_Blank_Document_Assessed under CTD | NA |
| Recruitment arrangements (for publication) | A1_blank document for transferral_2024-514791-40-00_AcSe-ESMART | NA |
| Recruitment arrangements (for publication) | A1_blank document for transferral_2024-514791-40-00_AcSe-ESMART | NA |
| Recruitment arrangements (for publication) | A1_blank document for transferral_2024-514791-40-00_AcSe-ESMART | NA |
| Recruitment arrangements (for publication) | K1_Recruitment and Informed consent procedure | NA |
| Recruitment arrangements (for publication) | K2_Document Additionnel_2024-514791-40-00_AcSe-ESMART_for publication | NA |
| Subject information and informed consent form (for publication) | A1_blank document confidential_2024-514791-40-00_AcSe-ESMART | 1 |
| Subject information and informed consent form (for publication) | A1_blank document confidential_2024-514791-40-00_AcSe-ESMART | 1 |
| Subject information and informed consent form (for publication) | A1_blank document confidential_2024-514791-40-00_AcSe-ESMART | NA |
| Subject information and informed consent form (for publication) | A1_blank document confidential_2024-514791-40-00_AcSe-ESMART | 1 |
| Subject information and informed consent form (for publication) | A1_blank document confidential_2024-514791-40-00_AcSe-ESMART | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC Temozolomide | NA |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC Vinorelbine | NA |
| Synopsis of the protocol (for publication) | A1_blank document confidential_2024-514791-40-00_AcSe-ESMART | NA |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis 2024-514791-40-00_IT_biffe | 9.0 |
Application history
4 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-08-20 | France | Acceptable 2024-10-18
|
2024-10-18 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2025-02-14 | France | Acceptable 2025-05-15
|
2025-05-15 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2025-07-10 | France | Acceptable 2025-09-04
|
2025-09-04 |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2025-11-17 | France | Acceptable 2026-01-28
|
2026-01-28 |