Phase I/II Trial of Dinutuximab Beta in Combination With Irinotecan and Rapamycin in Pediatric, Adolescents and Adult Patients With Relapsed/Refractory Bone Tumors.

Osteosarcomas, like other primitive bone tumors, remain hard-to-treat malignancies, especially after failure of first-line treatments. Multiple mechanisms are initiating or rendering bone tumor cells resistant to the chemotherapies leading to the drastic reduction of treatment possibilities in case of relapses. Among the list of extra-tumoral mechanisms enabling this cancer cell resistance, hypoxia and tumor-associated macrophage modulation seem to be in the top ranks. Based on that, we generated by the past tumor data where the study of hypoxic biomarkers' expressions and the presence of protumoral macrophages were influencing the prognosis of osteosarcoma patients. In fact, the association of HIF1 hyperexpression and a high number of M2 phenotype macrophages (e.g., protumoral cells) were predictive markers of the worst outcome. We recently redone this translational approach in other bone tumors like Ewing sarcomas (EWS) showing the same prognostic tendency. Furthermore, a past pediatric phase I trial, named RAPIRI, targeting both mTor and HIF1, with combination of Sirolimus and Irinotecan, was able to provide in the relapsing bone cancers a partial response or stable disease in more than 50% of patients and particularly in patients with blood concentrations of Sirolimus between 5 and 15 µg/L. To go further and understand the potential links between macrophages and hypoxic resistant tumors, recent preliminary exploration, with an immunofluorescent assessment targeting GD2 expression on tumor cell membranes, was underlining osteosarcomas but also EWS with standard fusions and CIC-DUX4 cancers as hyperexpressing cancers for this disialoganglioside. The cell-surface molecule was highly expressed in 22 out of 32 diagnostic samples (unpublished data). This glycosphingolipid usually presenting a restricted pattern of expression on normal tissues seems to be frequently hyperexpressed in some cancers and therefore amenable to targeting by the monoclonal antibody Dinutuximab beta. The anti-GD2 effect of this drug relies on complement and immune effector cells to mediate cancer cell killing. Recent and unpublished preclinical data in our Lab (UMR-CNRS7021, Strasbourg) envisioned the proof-of-concept combining Sirolimus, Irinotecan and Dinutuximab beta in osteosarcoma models and afford sustainable results to conclude to a clear efficiency of this triple combination stopping completely osteosarcoma cell proliferation and reducing drastically their invasion in microenvironment. Gathering all those prerequisite data and, as the monoclonal therapeutic antibody (Dinutuximab beta) now is extensively evaluated in clinics in multiple indications (e.g., neuroblastomas, Ewing sarcomas and other sarcomas), we propose here a phase I/II trial with this combination of treatments targeting hypoxia and GD2 in bone tumors focusing on relapsing bone tumors with endpoints determining accurate dose to give to patients and its efficacy at 16 weeks of treatment.

Inclusion Criteria: 1. Biopsy proven osteosarcomas, Ewing sarcomas, other primitive bone cancers (chondrosarcomas, CIC-DUX4 bone sarcomas, Ewing-like tumors with rare fusions). Patients with relapsed refractory tumors are eligible whether the target tumor(s) is(are) considered resectable or unresectable at study entry, provided that immediate surgery is not considered medically required or immediately feasible. For tumors considered potentially resectable, resectability will be reassessed after study treatment, particularly at week 16, within a multidisciplinary tumor board. 2. Refractory or relapsed sarcomas with no brain metastasis. 3. 1 to 3 prior treatments for metastatic or locally advanced sarcoma. 4. Age ≥ 6 and ≤ 40 years at inclusion. 5. Performance status: Lansky Play score (for patients ≤ 16 years of age) or Karnofsky score (for patients \> 16 years of age) ≥ 70%. 6. Life expectancy expected ≥ 4 months. 7. \- 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: i. CT-scan, physical exam ≥10 mm ii. Chest X-ray ≥20 mm iii. Lymph node short axis ≥10 mm iv. 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). 8. Adequate cardiac function with a shortening fraction ≥29% 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. 9. Adequate organ function within 21 days prior to first dose of study treatment: Hematologic criteria: 10. Peripheral absolute neutrophil count (ANC) ≥1.0 × 109/L (unsupported), 11. Absolute granulocytes ≥1.0 × 109/L, 12. Platelets ≥100 × 109/L (unsupported), 13. INR (International normalized ratio) ≤1.5 and aPTT (activated partial thromboplastin time) within normal limits. Biochemistry: 14. Serum creatinine ≤1.5 x upper limit of normal (ULN) for age or creatinine clearance (CKD-EPI/Schwartz) ≥ 60 mL/min/1.73 m2, 15. Total bilirubin ≤1.5 x ULN (≤3.0 x ULN for patients with Gilbert's syndrome), 16. 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. 17. Females of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to first dose of study treatment. 18. 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. 19. 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. 20. Patients able to comply with study procedures, scheduled follow-up and with management of toxicity. 21. Patient affiliated to a social security regimen or beneficiary of the same according to local requirement Exclusion Criteria: 1. Absence of tumor target(s): for Phase I: absence of visible and evaluable target; for Phase II: absence of evaluable target. 2. Prior administration of mTOR inhibitors. 3. 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). 4. 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. 5. Prior medical history of uncontrolled hypertension defined as follow: 1. 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. 2. Patients aged \> 17 years: systolic blood pressure \> 150mmHg and/or diastolic \> 90 mmHg that is not controlled by one anti-hypertensive medication. 6. Thrombotic or embolic events within the past 6 months. 7. Evidence of interstitial lung disease. 8. Non-controlled hyperlipidemia: At fasting: Serum cholesterol \>3 g/L or 7.75mmol/L and Triglycerides \>2.5 ULN). 9. Constitutional abnormality of coagulation and/or hemostasis. 10. Type I diabetes or non-controlled diabetes (fasting glycemia \>1.5 ULN). 11. Active viral hepatitis (serologically Hepatitis B virus (HBV) and/or 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. 12. Serious non-healing wound, ulcer, or bone fracture at enrolment. 13. Presence of any persistent grade ≥2 treatment-related toxicity with the exception of lymphopenia of any grade, alopecia, ototoxicity or peripheral neuropathy. 14. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less. 15. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first dose of study treatment. 16. Radiotherapy (non-palliative) within 21 days prior to the first study dose. 17. 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. 18. 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. 19. Current therapeutic anticoagulation with Vitamin K antagonists. 20. Concomitant treatment with medications or substances that are inhibitors or inducers of cytochrome CYP450 3A4. 21. Concomitant treatment with corticosteroids within 14 days prior to the first dose of study treatment. 22. Known hypersensitivity to any study drugs or components of the formulation. 23. Pregnant or nursing lactating females. 24. Vaccinated with live, attenuated vaccines, within 4 weeks of the first dose of study drug. 25. Participation in other interventional clinical trials. 26. Patient who has difficulty reading or understanding French 27. Patient receiving government medical aid (Aide Médicale d'Etat - AME). 28. Incompetent participant (subject to a legal protection measure: curatorship, guardianship, future protection mandate, family habilitation).