Mifamurtide Combined With Post-operative Chemotherapy for Newly Diagnosed High Risk Osteosarcoma Patients

Phase 2

Active, not recruiting

• Conditions: Osteosarcoma
• Interventions: Drug: Mifamurtide; Combination Product: EI or M-API regimen depending on patient age

• Registration Number: NCT03643133
• Lead Sponsor: UNICANCER

Brief Summary

Trial evaluating the impact on efficacy of mifamurtide as add-on treatment to post-operative chemotherapy compared to post-operative chemotherapy alone in first-line treatment of patients with high-risk osteosarcoma (defined as metastatic osteosarcoma at diagnosis or localised osteosarcoma with poor histological response).

Detailed Description

Multicentre, randomised, open-label, phase II trial, with 2 parallel groups. After pre-operative chemotherapy and surgery of the primary tumour and lung metastases (if applicable), patients presenting high-risk osteosarcoma (defined as metastatic osteosarcoma at diagnosis or localised osteosarcoma with poor histological response) will be randomised between 2 arms:

* Control arm: post-operative chemotherapy alone (with regimens adapted to the age of patient)

* Experimental arm : post-operative chemotherapy combined with mifamurtide

This randomised trial is part of a study recruiting all patients ≤50 years old with a newly diagnosed high-grade osteosarcoma.

Study Timeline

• Study First Submitted: 2018-07-11
• Study First Submitted QC: 2018-08-21
• Study First Posted: 2018-08-22
• Study Start: 2018-10-23
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-06
• Last Update Posted: 2024-11-08
• Primary Completion: 2025-03
• Study Completion: 2033-10

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Patient with a histologically proven, confirmed by experts pathologists panel (before surgery at the latest), high-grade osteosarcoma

2. Registered at diagnosis into the study

3. Primary tumour resected after pre-operative chemotherapy

4. Osteosarcoma classified as high risk because of at least one risk factor:

   1. presence of distant metastases or skip metastases at diagnosis
   2. and/or poor histological response to pre-operative chemotherapy (>10% residual viable cells on the analysis of the primary tumour surgical specimen)

5. Pre-operative chemotherapy combining

   1. Methotrexate-Etoposide-Ifosfamide (M-EI regimen) for patients ≤25 years
   2. Doxorubicin-Cisplatin-Ifosfamide (API-AI regimen) for patients 26-50 years

6. Screening laboratory values must meet the following criteria (using CTCAE v4) and should be obtained within 7 days prior to randomisation:

   1. Absolute neutrophil count ≥1.0 x 10⁹/L
   2. Platelets ≥100 x 10⁹/L
   3. Haemoglobin ≥8.0 g/mL
   4. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) in the absence of liver metastases or ≤5 x ULN in the presence of liver metastases
   5. Total Bilirubin ≤2 x ULN (except Gilbert Syndrome: <3.0 mg/dL) or Total Bilirubin ≤5.0 x ULN in the presence of liver metastases
   6. Creatinine clearance ≥60 mL/min/1.73 m² according to the Schwartz or Cockcroft formula according to patient's age

7. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) done within 7 days prior to randomisation

8. Provision of dated and signed written informed consent for the randomised trial prior to any study specific procedures, sampling and analyses.

9. Patient fit to undergo protocol treatment and follow-up

10. Affiliation to a social insurance regimen

Exclusion Criteria

1. Low grade osteosarcoma, parosteal or periosteal osteosarcoma
2. Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of the disease for at least 3 years.
3. Osteosarcoma with multiple metastases for whom complete removal is not expected to be feasible even after shrinkage with chemotherapy
4. Progressive disease at any site under initial chemotherapy, confirmed before randomisation time, and not totally resected during surgery
5. Any medical condition precluding treatment with protocol chemotherapy
6. Fractional Shortening <28% or left ventricular ejection fraction (LVEF) 50% before treatment (only for API post-operative chemotherapy) by echocardiogram or multigated acquisition (MUGA) scan
7. Pregnancy or breast-feeding
8. Hypersensitivity to the active substance or to any of the excipients
9. Concurrent use of immunodepressive treatment such as cyclosporine, tacrolimus or other calcineurin inhibitors
10. Concurrent use with high-dose non-steroidal anti-inflammatory drugs (NSAIDs, cyclooxygenase inhibitors)
11. Inflammatory or auto-immune disease, allergy or asthma requiring a chronic use of steroid treatment that cannot be stopped.
12. Patients with positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
13. Patients with positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental arm	EI or M-API regimen depending on patient age	Post-operative chemotherapy (EI or M-API regimen) combined with Mifamurtide 2 mg/m² twice weekly post-randomisation for 12 weeks then weekly for 24 weeks
Control arm	EI or M-API regimen depending on patient age	Post-operative chemotherapy alone (EI or M-API regimen depending on patient age) : M-API regimen (≤25 years) : Doxorubicin 60 mg/m², Day 1 Ifosfamide 3 g/m² Day 1 and 2 Cisplatin 100 mg/m², Day 2 EI regimen (26-50 years) : Etoposide 75 mg/m²/d, Day 1-4 Ifosfamide 3 g/m²/d, Day 1-4
Experimental arm	Mifamurtide	Post-operative chemotherapy (EI or M-API regimen) combined with Mifamurtide 2 mg/m² twice weekly post-randomisation for 12 weeks then weekly for 24 weeks

Primary Outcome Measures

Name	Time	Method
Compare event-free survival in the treatment arms	Expected average duration of 3 years from randomization	Event-free survival defined as the time duration from randomisation to time of first event (loco-regional or distant relapse or progression, second malignancy, death from any cause)

Secondary Outcome Measures

Name	Time	Method
Compare actual and planned cumulative dose and dose intensity of mifamurtide	Up to 36 weeks from randomization (until end of treatment)	Calculation of actual cumulative dose and dose intensity compared to the planned treatment administration schedule
Compare overall survival in the treatment arms	Up to 10 years from randomization	Overall survival defined as the time duration from randomisation to death, whatever the cause of death
Compare the incidence of adverse events in the treatment arms	Up to 40 weeks from randomization (4 weeks after end of treatment)	Evaluation of toxicity (graded by NCI-CTCAE v4)

Trial Locations

Locations (31)

CHU de Nice - Service d'oncologie hématologie pédiatrique; 🇫🇷 Nice, France

CHU Toulouse - Hôpital des Enfants - Service d'Hémato-Immuno-Oncologie; 🇫🇷 Toulouse, France

CHU de Caen - Service d'oncologie hématologie pédiatrique; 🇫🇷 Caen, France

Hôpital Armand Trousseau - Service d'hématologie et d'oncologie pédiatrique; 🇫🇷 Paris, France

Hôpital de la Timone - service d'oncologie médicale; 🇫🇷 Marseille, France

Hôpital de la Timone - Service d'oncologie pédiatrique; 🇫🇷 Marseille, France

Institut régional du Cancer de Montpellier - Service d'oncologie médicale; 🇫🇷 Montpellier, France

Hôpital de Hautepierre - Onco-hématologie adulte; 🇫🇷 Strasbourg, France

Institut Bergonié - Service d'oncologie médicale; 🇫🇷 Bordeaux, France

CHU Arnaud de Villeneuve - Onco-hématologie pédiatrique; 🇫🇷 Montpellier, France

CHU de Nantes - Service d'oncologie hématologie pédiatrique; 🇫🇷 Nantes, France

Hôpital Charles Nicolle - Hémato-Immuno-Oncologie Pédiatrique; 🇫🇷 Rouen, France

Institut Curie - Service d'oncologie médicale; 🇫🇷 Paris, France

CHU d'Angers - Service d'oncologie pédiatrique; 🇫🇷 Angers, France

CHU de Grenoble - Service d'oncologie hématologie pédiatrique; 🇫🇷 La Tronche, France

CHRU de Nancy - Onco-hématologie pédiatrique; 🇫🇷 Vandœuvre-lès-Nancy, France

Centre Léon Bérard - Service d'oncologie médicale; 🇫🇷 Lyon, France

Hôpital Cochin; 🇫🇷 Paris, France

CHU Amiens-Picardie - Service d'oncologie hématologie pédiatrique; 🇫🇷 Amiens, France

Centre Oscar Lambret - Unité d'onco-pédiatrie; 🇫🇷 Lille, France

Centre Eugène Marquis - Service d'oncologie médicale; 🇫🇷 Rennes, France

Institut de Cancérologie de l'Ouest (Site René Gauducheau) - Service d'oncologie médicale; 🇫🇷 Saint-Herblain, France

Institut Claudius Regaud - service d'oncologie médicale; 🇫🇷 Toulouse, France

Centre Léon Bérard - IHOPE; 🇫🇷 Lyon, France

Hôpital Hautepierre - Onco-hématologie pédiatrique; 🇫🇷 Strasbourg, France

Hôpital Clocheville - Hématologie et oncologie pédiatrique; 🇫🇷 Tours, France

CHU Bretonneau - Service d'oncologie médicale; 🇫🇷 Tours, France

Institut Gustave Roussy - Service d'oncologie médicale; 🇫🇷 Villejuif, France

Institut de Cancérologie de Lorraine - Service d'oncologie médicale; 🇫🇷 Vandœuvre-lès-Nancy, France

Institut Gustave Roussy - Service de cancérologie de l'enfant et de l'adolescent; 🇫🇷 Villejuif, France

Institut Curie - Service d'oncologie pédiatrique; 🇫🇷 Paris, France