Randomised trial evaluating mifamurtide in combination with standard chemotherapy in patients with high-grade osteosarcoma at high risk of relapse.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Oct 2018 → ongoing

Decision date (initial)

2024-07-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

PHRC · TAKEDA

External identifiers

EU CT number

2024-514780-26-00

EudraCT number

2017-001165-24

ClinicalTrials.gov

NCT03643133

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

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 >2 years and ≤ 50 years with high-risk osteosarcoma (metastatic at diagnosis or localised with poor histological response to pre-operative chemotherapy).

Secondary objectives 8

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 impact on progression free survival of mifamurtide administered during 36 weeks, in addition to post-operative chemotherapy, compared to chemotherapy alone, in patients with high-risk osteosarcoma
3. 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
4. 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.
5. To evaluate mifamurtide effect on tumour immunity in patients with sequential surgery of lung metastases.
6. To evaluate through an associated translational research program, biomarkers that could be surrogate of mifamurtide pharmacological efficacy, predictive factors of efficacy and/or toxicity of mifamurtide
7. To evaluate the tumour microenvironment in osteosarcoma and correlate it to clinical characteristics and outcome (Stage at diagnosis, metastastic vs localised disease; Response to preoperative chemotherapy; Event-free survival and overall survival)
8. To identify potential new therapeutic targets for future combinations (Genomics/transcriptomics, multiplex IF, constitutional DNA, ctDNA and others technics depending on the state of the art)

Conditions and MedDRA coding

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).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. At diagnosis : All newly diagnosed, biopsy-proven, high-grade osteosarcoma, whatever the initial extension of the disease
2. At diagnosis : Age >2 years and ≤50 years
3. At diagnosis : Normal haematological, renal, cardiac and hepatic functions
4. At diagnosis : Planned neoadjuvant chemotherapy
5. At diagnosis : Written informed consent from patients and/or their parents/guardians before enrolment and any study-related procedure
6. At diagnosis : Affiliation to a social insurance regimen
7. For the randomisation : Patient with a histologically proven, confirmed by expert pathologists panel (before surgery at the latest), high-grade osteosarcoma
8. For the randomisation : Registered at diagnosis into the study
9. For the randomisation : Primary tumour resected after pre-operative chemotherapy
10. For the randomisation : Osteosarcoma classified as high risk because of at least one risk factor
11. For the randomisation : Pre-operative chemotherapy
12. For the randomisation : Screening laboratory values must meet the following criteria (using CTCAE v5) and should be obtained within 7 days prior to randomisation
13. For the randomisation : 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
14. For the randomisation : Provision of dated and signed written informed consent for the randomised trial prior to any study specific procedures, sampling and analyses.
15. For the randomisation : Patient fit to undergo protocol treatment and follow-up
16. For the randomisation : Affiliation to a social insurance regimen

Exclusion criteria 13

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 during initial pre-operative chemotherapy, confirmed before randomisation time, with exception of patients with progressive disease of the primary tumour who had a complete resection at 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 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 6

1. Overall survival (OS) from the randomisation date to the date of death, whatever the cause of death.
2. Progression Free-survival (PFS) from the randomisation date to the date of disease progression (radiological or clinical) or death of any cause, whichever occurs first. Observations will be censored at the date of last follow-up visit for the patients remaining in first complete remission.
3. Feasibility of the planned treatment with calculation of cumulative dose and dose intensity of mifamurtide and chemotherapy
4. Safety : all adverse events (NCI-CTCAE v5) will be analysed except AE unequivocally related to the underlying disease or its progression/relapse.
5. Long-term toxicity
6. Biomarkers to evaluate mifamurtide mechanisms of action and resistance

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 44 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications