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

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. 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.
6. Life expectancy >= 3 months
7. 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.
8. Able to comply with scheduled follow-up and with management of
toxicity.
9. 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
is listed in Appendix 12.
10. 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.
11. 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.
12. Patient affiliated to a social security regimen or beneficiary of the
same according to local requirements.

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.