International Phase I Trial of Dinutuximab Beta With VDC/IE in GD2-Positive Ewing Sarkoma

Inclusion Criteria:

1. Histologically confirmed, newly diagnosed Ewing Sarcoma (m/f/d) or so-called Ewing-like sarcoma (i.e. translocation-positive small blue round cell sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue with evidence of EWS translocation by fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), or next-generation sequencing (NGS) assay
2. High risk stratification (metastatic disease)
3. Centrally confirmed GD2-positive tumor (biopsy of original and/or residual tumor or liquid biopsy in peripheral blood)
4. Availability of fresh frozen tumor tissue for central GD2-detection
5. Age ≥12 months
6. Start of first line treatment according to standard induction treatment (Cycle 1-4: VDC - IE - VDC - IE)
7. Wash-out phase with a minimum of 14 days after the last the dose of the last chemotherapy
8. Lansky (\<16 years) Performance Score ≥70% or ECOG (≥16 years) ≤ 2
9. Adequate bone marrow function as evidenced by meeting all the following requirements:

   1. White blood cell count \> 2000/μl
   2. ANC ≥1000 cells/μL (G-CSF allowed)
   3. Platelet count 75,000 cells/μL without the use of platelet transfusion within the last 2 days
   4. Hemoglobin ≥9 g/dL without the use of red blood cell transfusion within the last 2 days
10. Adequate hepatic function as evidenced by meeting all the following requirements:

    1. Serum total bilirubin ≤1.5 x upper limit of normal (ULN)
    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
11. Adequate cardiac function: confirmed by echocardiography with a left ventricular ejection fraction (LVEF) of ≥ 50%
12. Adequate renal function: creatinine clearance or glomerular filtration rate (GFR) \> 60 mL/min/1.73 m2
13. No known active HIV, HBV, or HCV infection
14. No severe neurological impairment, particularly no motor or sensory deficits, except for neurological deficits caused by Ewing sarcoma
15. Female patients of childbearing potential must present with a negative serum pregnancy test and agree to employ adequate birth control measures for the duration of the study and until 3 months after the end of treatment. Female patients who are lactating must agree to stop breast-feeding from the start of study treatment until 1 month after the end of treatment.
16. Patient or their legal representative is willing and able to comply with the requirements of the study protocol

Exclusion Criteria:

1. Relapsed or refractory Disease state
2. Patients with hypersensitivity against at least 1 component of the investigational medicinal product
3. Significant illnesses and/or any of the following:

   * significant psychiatric disabilities or uncontrolled seizure disorders
   * active uncontrolled peptic ulcer disease
   * clinically significant neurologic deficit or objective peripheral neuropathy
   * clinically significant, symptomatic fluid in a third space
4. Active and uncontrolled CNS metastases (indicated by clinical symptoms, cerebral edema, corticosteroid and/or anticonvulsant requirement, or progressive disease); for controlled CNS metastases, patient should have been off corticosteroids for at least 28 days without overt evidence of significant neurological deficits prior to enrollment
5. Significant cardiac conduction abnormalities, including known familial prolonged QT syndrome, or screening QTc \>480 msec
6. Active, uncontrolled infection or an unexplained fever \>38.5°C which in the Investigator's opinion might compromise the patient's participation in the study or affect the study outcome
7. Chronic Grade ≥2 diarrhea
8. Diagnosis of any malignancy other than the disease under study
9. Any other medical or social condition deemed by the Investigator to be likely to interfere with a patient's ability to cooperate and participate in the study or interfere with the interpretation of the results.