ESMART

Phase 1

Active, not recruiting

Conditions: Relapsed or refractory tumours in children including leukaemias
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2016-000133-40-GB

Lead Sponsor: Gustave Roussy

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Not specified

Target Recruitment: 280

Inclusion Criteria

1. Patients must be diagnosed with a haematologic or solid tumour 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 tumour 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 tumour type (RECIST v1.1, RANO criteria for patients with High Grade Glioma, INRC criteria for patients with Neuroblastoma, 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:
Haematologic criteria (Leukemia patients are excluded from haematological criteria):
- Peripheral absolute neutrophil count (ANC) =1000/µL (unsupported)
- Platelet count =100,000/µL (unsupported)
- Haemoglobin =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 tumour 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 tub

Exclusion Criteria

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 haematopoietic 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, tumour 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 halflife 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.