Mifamurtide Combined With Post-operative Chemotherapy for Newly Diagnosed High Risk Osteosarcoma Patients (SARCOME13)

Multicentre, Randomised, Phase 2 Trial of Mifamurtide Combined With Post-operative Chemotherapy for Newly Diagnosed High Risk Osteosarcoma Patients (Metastatic Osteosarcoma at Diagnosis or Localised Disease With Poor Histological Response)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Osteosarcoma
• Intervention / Treatment: Combination product: EI or M-API regimen depending on patient age; Drug: Mifamurtide

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 Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Céline MAHIER; Phone Number: +33144235584; Email: c-mahier@unicancer.fr

Study Locations

• France
  • Amiens, France
    • CHU Amiens-Picardie - Service d'oncologie hématologie pédiatrique
  • Angers, France
    • CHU d'Angers - Service d'oncologie pédiatrique
  • Bordeaux, France
    • INSTITUT BERGONIE - Service d'Oncologie Médicale
  • Caen, France
    • CHU de Caen - Service d'oncologie hématologie pédiatrique
  • La Tronche, France
    • CHU de Grenoble - Service d'oncologie hématologie pédiatrique
  • Lille, France
    • Centre Oscar Lambret - Unité d'onco-pédiatrie
  • Lyon, France
    • Centre Léon Bérard - IHOPE
  • Lyon, France
    • Centre Leon Berard - Service d'Oncologie Medicale
  • Marseille, France
    • Hôpital de la Timone - service d'oncologie médicale
  • Marseille, France
    • Hôpital de la Timone - Service d'oncologie pédiatrique
  • Montpellier, France
    • CHU Arnaud de Villeneuve - Onco-hématologie pédiatrique
  • Montpellier, France
    • Institut régional du Cancer de Montpellier - Service d'oncologie médicale
  • Nantes, France
    • CHU de Nantes - Service d'oncologie hématologie pédiatrique
  • Nice, France
    • CHU de Nice - Service d'oncologie hématologie pédiatrique
  • Paris, France
    • Hopital Cochin
  • Paris, France, 75000
    • Institut Curie - Service d'oncologie médicale
  • Paris, France
    • Hôpital Armand Trousseau - Service d'hématologie et d'oncologie pédiatrique
  • Paris, France
    • Institut Curie - Service d'oncologie pédiatrique
  • Rennes, France
    • Centre Eugène Marquis - Service d'oncologie médicale
  • Rouen, France
    • Hôpital Charles Nicolle - Hémato-Immuno-Oncologie Pédiatrique
  • Saint-Herblain, France
    • Institut de Cancérologie de l'Ouest (Site René Gauducheau) - Service d'oncologie médicale
  • Strasbourg, France
    • Hôpital de Hautepierre - Onco-hématologie adulte
  • Strasbourg, France
    • Hôpital Hautepierre - Onco-hématologie pédiatrique
  • Toulouse, France
    • CHU Toulouse - Hôpital des Enfants - Service d'Hémato-Immuno-Oncologie
  • Toulouse, France
    • Institut Claudius Regaud - service d'oncologie médicale
  • Tours, France
    • CHU Bretonneau - Service d'oncologie médicale
  • Tours, France
    • Hôpital Clocheville - Hématologie et oncologie pédiatrique
  • Vandœuvre-lès-Nancy, France
    • CHRU de Nancy - Onco-hématologie pédiatrique
  • Vandœuvre-lès-Nancy, France
    • Institut de Cancérologie de Lorraine - Service d'oncologie médicale
  • Villejuif, France, 94800
    • Institut Gustave Roussy - Service de cancérologie de l'enfant et de l'adolescent
  • Villejuif, France
    • Institut Gustave Roussy - Service d'oncologie médicale

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 50 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Registration Criteria:

1. All newly diagnosed, biopsy-proven, high-grade osteosarcoma, whatever the initial extension of the disease
2. Age >2 years and ≤50 years;
3. Normal haematological, renal, cardiac and hepatic functions

4. Planned neoadjuvant chemotherapy as follows:

   1. Methotrexate-Etoposide-Ifosfamide (M-EI regimen) for patients ≤25 years
   2. Doxorubicin-Cisplatin-Ifosfamide (API-AI regimen) for patients 26-50 years
5. Written informed consent from patients and/or their parents/guardians before enrolment and any study-related procedure
6. Affiliation to a social insurance regimen

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control arm; 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	Combination product: EI or M-API regimen depending on patient age; M-API regimen: One course of high-dose Methotrexate (optional) followed by 5 courses of API, every 21 days EI regimen : 5 course of EI, every 21 days
Experimental: Experimental arm; 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	Combination product: EI or M-API regimen depending on patient age; M-API regimen: One course of high-dose Methotrexate (optional) followed by 5 courses of API, every 21 days EI regimen : 5 course of EI, every 21 days; Drug: Mifamurtide; 48 doses overall over 36 weeks; Other Names: MEPACT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare event-free survival in the treatment arms	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)	Expected average duration of 3 years from randomization

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Nathalie MD GASPAR, PhD, Gustave Roussy Cancer Campus; Principal Investigator: Sophie MD PIPERNO-NEUMANN, PhD, Institut Curie

Publications and helpful links

General Publications

• Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.
• Brard C, Piperno-Neumann S, Delaye J, Brugieres L, Hampson LV, Le Teuff G, Le Deley MC, Gaspar N. Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma. BMJ Open. 2019 May 19;9(5):e025877. doi: 10.1136/bmjopen-2018-025877.

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2018
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2033

Study Registration Dates

• First Submitted: July 11, 2018
• First Submitted That Met QC Criteria: August 21, 2018
• First Posted (Actual): August 22, 2018

Study Record Updates

• Last Update Posted (Estimated): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Bone; Neoplasm, bone tissue; Acetylmuramyl-Alanyl-Isoglutamine
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Mifamurtide
• Other Study ID Numbers: UC-0150/1704; 2017-001165-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared at an individual level, they will be part of the study database including all enrolled patients.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No