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

NCT07853105 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: 9422
• Study Type: interventional
• Target: 89
• Locations: 1 country
• Sites: 12

Brief Summary

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 The cell-surface molecule was highly expressed in 22 out of 32 diagnostic samples (unpublished data).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 Recent and unpublished preclinical data in our Lab (UMR-CNRS7021, Strasbourg) envisioned the proof-of-concept combining Sirolimus, Irinotecan and Dinutuximab beta in osteosarcoma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.

Conditions

Osteosarcomas; Bone Cancer; Ewing Sarcomas

Keywords

anti GD2; dinutuximab beta

Outcome Measures

Primary Outcomes (2)

• Phase 1: Determination of the maximum tolerated dose (MTD) of Dinutuximab beta, given in combination with iv. Irinotecan (day 1 and day 15) and daily oral Sirolimus

  From the first dose of treatment to the end of cycle 1 (28 days)

• Phase 2:

  Determination of the Progression Free Survival rate, based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST 1.1) version 1.1 and/or PET Response Criteria In Solid Tumor version 1.0 (PERCIST 1.0).

  At or before 16 weeks after the first dose of study drug

Study Arms (1)

Experimental arm

EXPERIMENTAL

In Phase I, the dose escalation part will determine the maximum tolerated dose (MTD) of Dinutuximab beta in combination with fixed doses of Sirolimus and Irinotecan. For the Phase II part, the RP2D (recommended phase 2 dose) dose of Dinutuximab beta will be used in combination with the fixed dose of Sirolimus and Irinotecan combination.

Drug: Dinutuximab beta, Sirolimus and Irinotecan

Interventions

Dinutuximab beta, Sirolimus and Irinotecan DRUG

The dose escalation (Phase I) part will determine the maximum tolerated dose (MTD) of Dinutuximab beta in combination with fixed doses of Sirolimus and Irinotecan (RAPIRI), as follows: iv. irinotecan on days 1 and 15 (125 mg/m2/dose) and oral Sirolimus given daily (1.5 mg/m2/dose) in 28-day courses. The Dinutuximab beta will be administered for 4 days from D1 to D4 and D15 to D18 as an iv. infusion. The combination of Sirolimus and Irinotecan plus Dinutuximab beta will be during the 6 first courses and from C7, the Sirolimus and Irinotecan combination will be administered as detailed above during the last 6 months or courses. For the Phase II part, the RP2D dose of Dinutuximab beta will be used in combination with the fixed dose of Sirolimus and Irinotecan combination as described above. The same scheme during the 12 months will be planned: triple combination during 6 courses and then a maintenance with 6 courses of Sirolimus and Irinotecan treatment.

Experimental arm

Eligibility Criteria

• Age: 6 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• Refractory or relapsed sarcomas with no brain metastasis.
• to 3 prior treatments for metastatic or locally advanced sarcoma.
• 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: 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).
• 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.
• 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:

You may not qualify if:

• Absence of tumor target(s): for Phase I: absence of visible and evaluable target; for Phase II: absence of evaluable target.
• Prior administration of mTOR inhibitors.
• 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.
• Prior medical history of uncontrolled hypertension defined as follow:
• 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.
• Thrombotic or embolic events within the past 6 months.
• Evidence of interstitial lung disease.
• Non-controlled hyperlipidemia: At fasting: Serum cholesterol \>3 g/L or 7.75mmol/L and Triglycerides \>2.5 ULN).
• Constitutional abnormality of coagulation and/or hemostasis.
• Type I diabetes or non-controlled diabetes (fasting glycemia \>1.5 ULN).
• 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.
• Serious non-healing wound, ulcer, or bone fracture at enrolment.
• Presence of any persistent grade ≥2 treatment-related toxicity with the exception of lymphopenia of any grade, alopecia, ototoxicity or peripheral neuropathy.

Sponsors & Collaborators

• National Cancer Institute, France: collaborator
• Ministry of Health, France: collaborator
• University Hospital, Strasbourg, France: lead
• Recordati Rare Diseases Inc: collaborator

Study Sites (12)

Oncologie Médicale-Institut Bergonié

Bordeaux, France

Location

Unité d'Hémato-Oncologie Pédiatrique (UHOP) -CHU de Bordeaux - GH Pellegrin

Bordeaux, France

Location

Oncologie - Unité pédiatrique Centre Oscar Lambret

Lille, 59000, France

Location

Institut d'hématologie et d'oncologie Pédiatrique iHOPE

Lyon, France

Location

Oncologie médicale adulte- Centre Léon Bérard

Lyon, France

Location

Hématologie, Immunologie et Oncologie Pédiatrique (HIOP), CHU Timone Enfants,

Marseille, France

Location

Onco-hématologie pédiatrique- CHRU NANCY-BRABOIS

Nancy, France

Location

Oncologie Médicale - Institut Curie

Paris, France

Location

Oncopédiatrie-SIREDO - Institut Curie

Paris, France

Location

Oncologie médicale, Hôpitaux Universitaires de Strasbourg

Strasbourg, 67000, France

Location

Onco-hématologie pédiatrique- Hôpitaux Universitaires de Strasbourg

Strasbourg, 67098, France

Location

Unité d'Hématologie Immunologie Oncologie Pédiatrique, CHU Toulouse

Toulouse, France

Location

MeSH Terms

Conditions

Osteosarcoma; Bone Neoplasms

Interventions

dinutuximab; Sirolimus; Irinotecan

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Neoplasms by Site; Bone Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Camptothecin; Alkaloids; Heterocyclic Compounds

Study Officials

• Natacha ENTZ WERLE, MD PhD

  Hopitaux Universitaires de Strasbourg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sarah HUSTACHE

CONTACT

03 88 11 54 15; dpidrci@chru-strasbourg.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2026
• First Posted: October 1, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): February 1, 2031
• Study Completion (Estimated): February 1, 2033
• Last Updated: October 1, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

FR (12)