Clinical trial NCT03643133: Mifamurtide Combined With Post-operative Chemotherapy for Newly Diagnosed High Risk Osteosarcoma Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Osteosarcoma
Keywords: Bone
Neoplasm, bone tissue
Acetylmuramyl-Alanyl-Isoglutamine
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2018-08-22
Enrollment: 60
Sex: ALL
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Compare event-free survival in the treatment arms
timeFrame: Expected average duration of 3 years from randomization
Secondary outcomes:
measure: Compare overall survival in the treatment arms
timeFrame: Up to 10 years from randomization
measure: Compare actual and planned cumulative dose and dose intensity of mifamurtide
timeFrame: Up to 36 weeks from randomization (until end of treatment)
measure: Compare the incidence of adverse events in the treatment arms
timeFrame: Up to 40 weeks from randomization (4 weeks after end of treatment)
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens-Picardie - Service d'oncologie hématologie pédiatrique
city: Angers
country: France
facility: CHU d'Angers - Service d'oncologie pédiatrique
city: Bordeaux
country: France
facility: Institut Bergonié - Service d'oncologie médicale
city: Caen
country: France
facility: CHU de Caen - Service d'oncologie hématologie pédiatrique
city: La Tronche
country: France
facility: CHU de Grenoble - Service d'oncologie hématologie pédiatrique
city: Lille
country: France
facility: Centre Oscar Lambret - Unité d'onco-pédiatrie
city: Lyon
country: France
facility: Centre Léon Bérard - IHOPE
city: Lyon
country: France
facility: Centre Léon Bérard - Service d'oncologie médicale
city: Marseille
country: France
facility: Hôpital de la Timone - service d'oncologie médicale
city: Marseille
country: France
facility: Hôpital de la Timone - Service d'oncologie pédiatrique
city: Montpellier
country: France
facility: CHU Arnaud de Villeneuve - Onco-hématologie pédiatrique
city: Montpellier
country: France
facility: Institut régional du Cancer de Montpellier - Service d'oncologie médicale
city: Nantes
country: France
facility: CHU de Nantes - Service d'oncologie hématologie pédiatrique
city: Nice
country: France
facility: CHU de Nice - Service d'oncologie hématologie pédiatrique
city: Paris
country: France
facility: Institut Curie - Service d'oncologie médicale
city: Paris
country: France
facility: Hôpital Armand Trousseau - Service d'hématologie et d'oncologie pédiatrique
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Institut Curie - Service d'oncologie pédiatrique
city: Rennes
country: France
facility: Centre Eugène Marquis - Service d'oncologie médicale
city: Rouen
country: France
facility: Hôpital Charles Nicolle - Hémato-Immuno-Oncologie Pédiatrique
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest (Site René Gauducheau) - Service d'oncologie médicale
city: Strasbourg
country: France
facility: Hôpital de Hautepierre - Onco-hématologie adulte
city: Strasbourg
country: France
facility: Hôpital Hautepierre - Onco-hématologie pédiatrique
city: Toulouse
country: France
facility: CHU Toulouse - Hôpital des Enfants - Service d'Hémato-Immuno-Oncologie
city: Toulouse
country: France
facility: Institut Claudius Regaud - service d'oncologie médicale
city: Tours
country: France
facility: CHU Bretonneau - Service d'oncologie médicale
city: Tours
country: France
facility: Hôpital Clocheville - Hématologie et oncologie pédiatrique
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU de Nancy - Onco-hématologie pédiatrique
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine - Service d'oncologie médicale
city: Villejuif
country: France
facility: Institut Gustave Roussy - Service de cancérologie de l'enfant et de l'adolescent
city: Villejuif
country: France
facility: Institut Gustave Roussy - Service d'oncologie médicale
Study officials:
affiliation: Gustave Roussy Cancer Campus
name: Nathalie MD GASPAR, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Curie
name: Sophie MD PIPERNO-NEUMANN, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.