Phase I/II trial of Dinutuximab beta in combination with Irinotecan and Rapamycin in pediatric, adolescents and adult patients with relapsed/refractory bone tumors. BONE DINIRRA

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 dose of study treatment.
• Radiotherapy (non-palliative) within 21 days prior to the first study dose.
• Major surgery or significant traumatic injury within 21 days of the first study 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.
• Prior administration of mTOR inhibitors
• Concomitant treatment with medications or substances that are inhibitors or inducers of cytochrome CYP450 3A4.
• Concomitant treatment with corticosteroids within 14 days prior to the first dose of study treatment.
• Prior medical history of uncontrolled hypertension defined as follows: • Patients aged ≤ 17 years: greater than 95th percentile systolic and diastolic blood pressure based on age and weight which is not controlled by one anti-hypertensive medication. • Patients aged > 17 years: systolic blood pressure > 150mmHg and/or diastolic > 90 mmHg that is not controlled by one anti-hypertensive medication.

Other illness

• Active viral hepatitis (serologically Hepatitis B virus (HBV) and Hepatitis C virus (HCV)) or known human immunodeficiency virus (HIV) infection or any other uncontrolled active clinically serious infection of grade ≥2 defined by CTCAE v6.0.
• Serious non-healing wound, ulcer, or bone fracture at enrolment.
• History of another malignancy or any medical condition which in the opinion of the principal investigator could represent a risk for the patient or adversely affect the study objectives.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., chronic inflammatory bowel disease, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome
• Clinically significant uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality), congestive heart failure > class II NYHA with 12 months of screening, unstable angina or new-onset angina
• Evidence of interstitial lung disease

Lab values

• Type I diabetes or non-controlled diabetes (fasting glycemia >1.5 ULN).
• Non-controlled hyperlipidemia: At fasting: Serum cholesterol >3 g/L or 7.75mmol/L and Triglycerides >2.5 ULN.

Other

• Absence of tumor target(s): for Phase I: absence of visible and evaluable target; for Phase II: absence of evaluable target.
• Presence of any persistent grade ≥2 treatment-related toxicity with the exception of lymphopenia of any grade, alopecia, ototoxicity or peripheral neuropathy
• Current therapeutic anticoagulation with Vitamin K antagonists.
• Thrombotic or embolic events within the past 6 months
• Constitutional abnormality of coagulation and/or hemostasis.

• Biopsy proven osteosarcomas, Ewing sarcomas, other primitive bone cancers (chondrosarcomas, CIC-DUX4 bone sarcomas, Ewing-like tumors with rare fusions). Patients with relapsed tumors presenting with disease that is either resectable since study entry after week 16 or considered potentially resectable following study treatment are eligible.
• Females of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to first dose of study treatment.
• -Sexually active WOCBP must agree to use a highly effective contraception method during the study treatment and for at least 6 months after the last study treatment administration. -Sexually active male patients must agree to use condoms during the study and at least 3 months after the last study treatment administration. Acceptable contraception methods are listed in X.1 Contraception.
• 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.
• Patients able to comply with study procedures, scheduled follow-up and with management of toxicity.
• Patient affiliated to a social security regimen or beneficiary of the same according to local requirements
• Refractory or relapsed sarcomas with no brain metastasis.
• 1 to 3 prior treatments for metastatic or locally advanced sarcoma.
• Age ≥ 6 and ≤ 40 years at inclusion.
• Performance status: Lansky Play score (for patients ≤ 16 years of age) or Karnofsky score (for patients > 16 years of age) ≥ 70%.
• Life expectancy expected ≥ 4 months.
• For Phase I exclusively, patients must have radiographically documented evaluable or measurable progressive disease by CT-scan, IRM or PET-scan 18F-FDG (measure of SUL and extension). -For Phase II exclusively, patients must have radiographically documented measurable and evaluable progressive disease. At least one site of disease might be measurable as follows: • CT-scan, physical exam ≥10 mm • Chest X-ray ≥20 mm • Lymph node short axis ≥10 mm • Bone and marrow invasion on PET-scan FDG (measure of SUL and extension) All radiology studies must be performed between 7 and 28 days before the first dose of study treatment (C1D1).
  • Adequate cardiac function with a shortening fraction ≥29% (>35% for children <3 years) and left ventricular ejection fraction ≥50% at baseline (between 7 and 28 days before the first dose of study treatment (C1D1)), as determined by echocardiography.
  • Adequate organ function within 21 days prior to first dose of study treatment: Hematologic criteria: • Peripheral absolute neutrophil count (ANC) ≥1.0 × 109/L (unsupported), • Absolute granulocytes ≥1.0 × 109/L, • Platelets ≥100 × 109/L (unsupported), • INR (International normalized ratio) ≤1.5 and aPTT (activated partial thromboplastin time) within normal limits. Biochemistry: • Serum creatinine ≤1.5 x upper limit of normal (ULN) for age or creatinine clearance (CKD-EPI/Schwartz) ≥ 60 mL/min/1.73 m2, • Total bilirubin ≤1.5 x ULN (≤3.0 x ULN for patients with Gilbert’s syndrome), • Alanine aminotransferase (ALT)/Serum glutamic pyruvic transaminase (SGPT) ≤2.5 × ULN and Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT) ≤2.5 × ULN, except in patients with documented tumor involvement of the liver who must have ALT/SGPT and AST/SGOT ≤5 x ULN.