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

Inclusion Criteria:

1. Patients must be diagnosed with a haematologic or solid tumor malignancy that hasprogressed despite standard therapy, or for which no effective standard therapyexists.

2. Age < 18 years at inclusion; patients 18 years and older may be included afterdiscussion with the sponsor if they have a pediatric recurrent/refractorymalignancy.

3. Patient must have had advanced molecular profiling (i.e. WES/WGS +/- RNAseq) oftheir recurrent or refractory tumor i.e. at the time of disease progression/relapse;exceptionally patients with advanced molecular profiling at diagnosis may beallowed.

4. Evaluable or measurable disease as defined by standard imaging criteria for thepatient's tumor type (RECIST v1.1, RANO criteria for patients with HGG, INRCcriteria 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) orLansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable towalk because of paralysis or stable neurological disability, but who are up in awheelchair, will be considered ambulatory for the purpose of assessing theperformance 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 leftventricular ejection fraction (LVEF) ≥50% at baseline, as determined byechocardiography (mandatory only for patients who have received cardiotoxictherapy).

• Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using theFridericia correction [QTcF formula]) or other clinically significantventricular 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) ≤ 2,5x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetictransaminase/SGOT ≤ 2,5 x ULN except in patients with documented tumorinvolvement 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 testwithin 72 hours prior to initiation of treatment. Sexually active women ofchildbearing potential must agree to use acceptable and appropriate contraceptionduring the study and for at least 6 months after the last study treatmentadministration. Sexually active males patients must agree to use condom during thestudy and for at least 6 months (7 months for arm J) after the last study treatmentadministration. 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 orgastrostomy feeding tube administration is allowed only if indicated.

12. Written informed consent from parents/legal representative, patient, andage-appropriate assent before any study-specific screening procedures are conductedaccording to local, regional or national guidelines.

13. Patient affiliated to a social security regimen or beneficiary of the same accordingto local requirements.

Exclusion Criteria:

1. Patients with symptomatic central nervous system (CNS) metastases who areneurologically unstable or require increasing doses of corticosteroids or localCNS-directed therapy to control their CNS disease. Patients on stable doses ofcorticosteroids for at least 7 days prior to receiving study drug may be included.

2. Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter 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 cardiacarrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conductionabnormality, unstable ischemia,congestive heart failure within 12 months ofscreening)

4. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or anyother uncontrolled infection.

5. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception ofalopecia, ototoxicity or peripheral neuropathy.

6. Systemic anticancer therapy within 21 days of the first study dose or 5 times itshalf-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 (orwithin 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).

10. Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritonealshunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venousaccess devices are not considered major surgery, but for these procedures, a 48 hourinterval must be maintained before the first dose of the investigational drug isadministered.

11. Currently taking medications with a known risk of prolonging the QT interval orinducing 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 ofthe 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 studydrug.