| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients ≤50 years old with high-risk osteosarcoma (defined as metastatic osteosarcoma at diagnosis or localised osteosarcoma with poor histological response) after pre-operative chemotherapy and surgery of the primary tumour and lung metastases (if applicable). |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the impact on efficacy (event-free survival, EFS) of mifamurtide administered during 36 weeks as add-on treatment to post-operative chemotherapy, compared to post-operative chemotherapy alone, in first-line treatment of patients ≤ 50 years with high-risk osteosarcoma (metastatic at diagnosis or localised with poor histological response to pre-operative chemotherapy). |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the impact on overall survival of mifamurtide administered during 36 weeks, in addition to post-operative chemotherapy, compared to chemotherapy alone, in patients with high-risk osteosarcoma
2. To evaluate the feasibility of mifamurtide administration during and after post-operative chemotherapy, for a total duration of 36 weeks, in patients with high-risk osteosarcoma
3. To evaluate the safety of mifamurtide administration during and after post-operative chemotherapy, for a total duration of 36 weeks, in patients with high-risk osteosarcoma, in comparison with chemotherapy alone.
4. To evaluate mifamurtide effect on tumour immunity in patients with sequential surgery of lung metastases.
5. To evaluate through an associated translational research program
6. To evaluate the tumour microenvironment in osteosarcoma and correlate it to clinical characteristics and outcome
7. To identify potential new therapeutic targets for future combinations |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biological ancillary studies :
- Immunological ancillary studies
- Molecular ancillary studies
- Allelotyping
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| E.3 | Principal inclusion criteria |
These criteria must be met at diagnosis for registration in the study:
1. All newly diagnosed, biopsy-proven, high-grade osteosarcoma, whatever the initial extension of the disease
2. Age ≤50 years;
3. Normal haematological, renal, cardiac and hepatic functions
4. Planned neoadjuvant chemotherapy as follows:
a. Methotrexate-Etoposide-Ifosfamide (M-EI regimen) for patients ≤ 25 years
b. 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 FOR THE RANDOMISATION
1. Patient with a histologically proven, confirmed by expert 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:
a. presence of distant metastases or skip metastases at diagnosis
b. 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
a. Methotrexate-Etoposide-Ifosfamide (M-EI regimen) for patients ≤ 25 years
b. 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 :
a. Absolute neutrophil count ≥ 1 x 109/L
b. Platelets ≥ 100 x 109/L
c. Haemoglobin ≥ 8.0 g/mL
d. ALT/AST ≤ 2.5 x ULN in the absence of liver metastases or ≤ 5.0 x ULN in the presence of liver metastases
e. Total bilirubin ≤ 2 x ULN (except Gilbert Syndrome : < 3.0 mg/dL) or ≤ 5.0 x ULN in the presence of liver metastases
f. Creatinine clearance ≥ 60 mL/min/1.73 m² according to the Schwartz or Cockroft 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
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| E.4 | Principal exclusion criteria |
NON-INCLUSION CRITERIA FOR THE RANDOMISATION
1. Low grade osteosarcoma, parosteal or periosteal osteosarcoma
2. Prior history of other malignancies other than osteosarcoma (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 post-operative chemotherapy
6. Fractional Shortening < 28% or LVEF< 50% before treatment (only for API post-operative chemotherapy) by echocardiogram or Muga scan
7. Pregnancy or breast-feeding
8. Hypersensitivity to the active substance or to any of the excipients
9. Concurrent use of immunodrepressive treatment such as ciclosporine, 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Event-free survival (EFS) estimated from the randomisation date to the time of first event (loco-regional or distant relapse or progression, second malignancy, death from any cause). Observations will be censored at the date of last follow-up visit for the patients remaining in first complete remission. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Duration from the randomisation date to the time of first event. |
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| E.5.2 | Secondary end point(s) |
- Overall survival (OS) from the randomisation date to the date of death, whatever the cause of death.
- Feasibility of the planned treatment with calculation of cumulative dose and dose intensity of mifamurtide and chemotherapy
- Acute (NCI-CTCAE v4) and long-term toxicity
- Biomarkers to evaluate mifamurtide mechanisms of action and resistance
• Surrogate markers of pharmacological activity
• Predictive markers for response and/or toxicity
* In serum: cytokines and chemokines analysis, at diagnosis and during treatment by ELISA
* In blood: circulating immune system cells analysis, at diagnosis and during treatment by flow-cytometry
* In tumour tissue (paraffine embedded tissues, frozen samples): tumour microenvironment (immune cells, stromal cells, angiogenesis) by WES, RNAseq and IHC
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Biological ancillary studies :
- Immunological ancillary studies
- Molecular ancillary studies
- Allelotyping |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Control arm : post operative treatment only |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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