A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS)
Condition: Osteosarcoma
MeSH terms: Osteosarcoma
Intervention: Mifamurtide; Ifosfamide
Intervention MeSH terms: Ifosfamide; Mifamurtide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 16 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Metastatic and/or Recurrent Osteosarcoma

Summary:

      This is a Bayesian designed multi-arm, multi-centre, open label phase II study. The target
      sample size of 40 patients will be recruited from up to 8 EU countries, but this may be
      revised in light of the interim analysis. Patients with relapsed or metastatic osteosarcoma
      will be divided into three treatment groups. They will all either have surgery or a biopsy
      before and after six weeks exposure to either Mifamurtide alone, Ifosfamide alone, or
      Mifamurtide combined with Ifosfamide. They will then receive further treatment to a maximum
      of 42 or 36 weeks in total (depending on Arm), with all patients being able to receive 36
      weeks of Mifamurtide treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Relapsed osteosarcoma (first, second, third or any relapse, patient has recovered from
             chemotherapy and any other investigational drug/agent treatment, radiotherapy or
             surgical procedure).

          2. Histological confirmed diagnosis of osteosarcoma at original presentation.

          3. Tumour at biopsy accessible or resectable site.

          4. Progressive disease documented by imaging within 3 months of entry into the trial.

          5. At least one measurable lesion on CT scan (RECIST) performed in past 21 days prior to
             trial entry.

          6. Male or female, age ≥ 16 years to 65 (or ≥18 based on institutional practice for
             Teenage and Young Adult Cancer patients).

          7. Life expectancy of at least 3 months.

          8. WHO performance score of 0 - 2.

          9. The patient is willing and able to comply with the protocol and scheduled follow-up
             visits and examinations.

         10. Written (signed and dated) informed consent.

         11. Cardiac shortening fraction ≥ 28% or ejection fraction ≥ 45%

         12. Renal function is adequate for ifosfamide treatment (GFR as per table below, other
             renal function screening tests as per local practice)

         13. Haematological and biochemical indices within the ranges shown below:

        Lab Test Value required

          -  Haemoglobin (Hb) ≥ 9 g/dL (Previous transfusion is allowed)

          -  Absolute neutrophil count (ANC) >=1.0 x 10*9/L without growth factor support

          -  Platelet count > 80.x 10*9/L (Previous transfusion is allowed)

          -  Total bilirubin <1.5 times the upper limit of normal (ULN) for age (except for
             Gilbert's syndrome patients)

          -  Serum alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) <2.5 ×
             ULN for age, <2.5 × ULN for age

          -  Serum creatinine Normal range for age

          -  Glomerular filtration rate (GFR) (calculated as 51Cr-EDTA/99mTc-DTPA clearance)
             >40ml/min if deemed resectable (for Arm A), >60ml/min if not deemed resectable (for
             Arm B or C)

        Exclusion Criteria:

          1. Pregnant or breast-feeding woman. Men or women of childbearing potential unless
             effective methods of contraception are used during study treatment and for at least 7
             days after the last mifamurtide dose (see section 5.1 Informed consent -
             Contraceptive/ Pregnancy counselling).

          2. Previous treatment with mifamurtide or a mifamurtide-like drug* in a clinical trial
             setting for the treatment of metastatic and/or recurrent osteosarcoma in the six
             months prior to registration.

          3. Contraindications to lung biopsies.

          4. Hypersensitivity to ifosfamide or any component of the formulation.

          5. Previously diagnosed brain metastases.

          6. Significant active cardiac disease including: uncontrolled high blood pressure (no
             greater than 2 standard deviations above the mean for age for systolic blood pressure
             (SBP) and diastolic blood pressure (DBP), unstable angina, congestive heart failure,
             myocardial infarction within the previous 6 months, or serious cardiac arrhythmias and
             with a history of pericarditis and myocarditis

          7. Treatment with any other investigational agent, or participation in another
             interventional clinical trial within 21 days prior to enrolment.

          8. Major surgery within 21 days prior to first study biopsy

          9. Currently taking high-dose non-steroidal anti-inflammatory drugs (NSAIDs) or
             corticosteroid treatment

         10. Concurrent use of ciclosporin or other calcineurin inhibitors.

         11. Any psychological, social or medical condition, physical examination finding or a
             laboratory abnormality that the Investigator considers would make the patient a poor
             trial candidate or could interfere with protocol compliance or the interpretation of
             trial results.

         12. Any other active malignancy, with the exception of adequately treated cone-biopsied in
             situ carcinoma of the cervix uteri and non-melanoma skin lesions.

         13. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or
             HIV.

               -  mifamurtide-like drugs include GCSF, GMCSF, interferon and other macrophage
                  activating molecules.