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

Prior treatment

• 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
• Major surgery within 21 days of the first dose.
• Vaccinated with live, attenuated vaccines,including yellow fever, within 4 weeks of the first dose of study drug.

Other illness

• 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.
• Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Known hypersensitivity to any study drug or component of the formulation.
• 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).

Lab values

• Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.

Other

• Presence of any ≥CTCAE grade 2 treatment-related toxicity with the exception of lymphopenia G3, alopecia, ototoxicity or peripheral neuropathy.
• Pregnant or nursing (lactating) females
• 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.

• 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.
• 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.
• 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.