A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS)

Study Overview
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Brief Summary
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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.

Detailed Description
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Osteosarcoma (OS) is the most common primary tumour arising from bones. There is currently no approved treatment other than surgery for metastatic or recurrent osteosarcoma refractory to chemotherapy. Patients deemed unresectable normally receive chemotherapy prior to attempted resection. The addition of chemotherapy to surgery for metastatic or recurrent osteosarcoma may improve response rates. MEPACT (Mifamurtide, MTP-PE) is licensed for use in the adjuvant osteosarcoma setting; indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post-operative multi-agent chemotherapy. This is a Bayesian designed multi-arm, multi-centre open-label phase II study in patients with metastatic and/or recurrent osteosarcoma, which will investigate why some patients with osteosarcoma may respond better than others to mifamurtide given alone or in combination with ifosfamide. Patients with relapsed or metastatic osteosarcoma will be divided into three treatment groups (Arms). Depending on their current disease status, patients may be either Registered to Arm A (resectable group), to receive Mifamurtide alone; or Randomised to Arm B/C (non-resectable group), to receive mifamurtide in combination with ifosfamide. Arm A - Mifamurtide alone; Arm B - Ifosfamide alone for 6 weeks then Ifosfamide + mifamurtide for 6 weeks, then mifamurtide alone for 30 weeks; Arm C - Ifosfamide + mifamurtide for 12 weeks then mifamurtide alone for 24 weeks. All participants will receive 36 weeks or more of mifamurtide. Biopsies (or resected tumour samples) will be obtained before and after 6 weeks of therapy interval in order to determine the pharmacodynamic endpoints. The target sample size is 40 patients. An interim analysis will be performed for the primary efficacy endpoint.

Official Title
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A Mechanistic Study Of Mifamurtide (MTP-PE) In Patients With Metastatic And/Or Recurrent Osteosarcoma

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: Mifamurtide
* Drug: Ifosfamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed osteosarcoma (first, second, third or any relapse, patient has recovered from chemotherapy and any other investigational drug/agent treatment, radiotherapy or surgical procedure). Histological confirmed diagnosis of osteosarcoma at original presentation. Tumour at biopsy accessible or resectable site. Progressive disease documented by imaging within 3 months of entry into the trial. At least one measurable lesion on CT scan (RECIST) performed in past 21 days prior to trial entry. Male or female, age ≥ 16 years to 65 (or ≥18 based on institutional practice for Teenage and Young Adult Cancer patients). Life expectancy of at least 3 months. WHO performance score of 0 - 2. The patient is willing and able to comply with the protocol and scheduled follow-up visits and examinations. Written (signed and dated) informed consent. Cardiac shortening fraction ≥ 28% or ejection fraction ≥ 45% Renal function is adequate for ifosfamide treatment (GFR as per table below, other renal function screening tests as per local practice) 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: 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). 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. Contraindications to lung biopsies. Hypersensitivity to ifosfamide or any component of the formulation. Previously diagnosed brain metastases. 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 Treatment with any other investigational agent, or participation in another interventional clinical trial within 21 days prior to enrolment. Major surgery within 21 days prior to first study biopsy Currently taking high-dose non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroid treatment Concurrent use of ciclosporin or other calcineurin inhibitors. 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. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions. 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.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A. Mifamurtide only<br>Treatment Weeks 1-6 (post 1st biopsy/resection): Mifamurtide 2mg/m2, IV infusion, twice/week, with each infusion given at least 3 days apart, for 6 weeks. Treatment Weeks 7-12 (post 2nd biopsy/resection): Mifamurtide 2mg/m2, IV infusion, twice/week, with each infusion given at least 3 days apart, for 6 weeks. Treatment Weeks 13-36: Mifamurtide 2mg/m2, IV infusion, once/week. | Drug: Mifamurtide<br> <br> |
| Experimental: B. Ifosfamide (Followed by Mifamurtide)<br>Treatment Weeks 1-6: Day 1 of 21: Ifosfamide 12-15g/m2 IV infused over 4-5 days as per local practice. Repeated every 21 days for 2 cycles (3 weeks=1 cycle). Treatment Weeks 7-12 (post 2nd biopsy/resection): Day 1 of 21: Ifosfamide 12-15g/m2 IV infused over 4-5 days once every 21 days for two cycles (3 weeks=1 cycle). Ifosfamide administered as per local practice, including concurrent dosing with mesna. Plus mifamurtide 2mg/m2, IV infusion, twice/week. Ifosfamide infusion started 24 hours prior to mifamurtide. Mifamurtide given on day 2 and either day 5 or day 6. Treatment Weeks 13-18: Mifamurtide 2mg/m2, IV infusion, twice/week. Treatment Weeks 19-42: Mifamurtide 2mg/m2, IV infusion, once/week. | Drug: Mifamurtide<br> <br> Drug: Ifosfamide<br> <br> |
| Experimental: C. Ifosfamide + Mifamurtide<br>Treatment Weeks 1-6: Day 1 of 21: Ifosfamide 12-15g/m2 IV infusion over 4-5 days once every 21 days for two cycles (3 weeks=1 cycle). Plus Mifamurtide 2mg/m2, IV infusion, twice per week, each given at least 3 days apart, for 6 weeks. Ifosfamide infusion started 24 hours prior to mifamurtide. Mifamurtide given on day 2 and either day 5 or day 6. Treatment Weeks 7-12 (post 2nd biopsy/resection): Day 1 of 21: Ifosfamide 12-15g/m2 IV infusion over 4-5 days once every 21 days for two cycles (3 weeks = 1 cycle). Plus Mifamurtide 2mg/m2, IV infusion, twice per week, given at least 3 days apart, for 6 weeks. Ifosfamide infusion started 24 hours prior to mifamurtide. Mifamurtide given on day 2 and either day 5 or day 6. Treatment Weeks 13-36: Mifamurtide 2mg/m2, IV infusion, once/week. | Drug: Mifamurtide<br> <br> Drug: Ifosfamide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological Response Data Based on Pharmacodynamic Endpoints on Tumour Biopsy Material | Biological response data based on pharmacodynamic endpoints on tumour biopsy material including macrophage infiltration and innate immune activation. | Change from Baseline to after 6 weeks of treatment | 
| Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) assessed by CT or MRI: Complete Response (CR): Disappearance of all target and non-target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions, AND no evidence of progression in non-target lesions, AND no new lesions Stable Disease (SD): sum of longest diameter of target lesions between PR and PD values, AND no evidence of progression in non-target lesions, AND no new lesions Progressive Disease (PD): >20% increase in the sum of the longest diameter of target lesions, OR evidence of progression in non-target lesions, OR evidence of new lesions | Change from Baseline to after 6 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Radiological Response Based on RECIST v1.1 | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) assessed by CT or MRI: Complete Response (CR): Disappearance of all target and non-target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions, AND no evidence of progression in non-target lesions, AND no new lesions Stable Disease (SD): sum of longest diameter of target lesions between PR and PD values, AND no evidence of progression in non-target lesions, AND no new lesions Progressive Disease (PD): >20% increase in the sum of the longest diameter of target lesions, OR evidence of progression in non-target lesions, OR evidence of new lesions | Change from Baseline to after 12, 18, 24 & 36 weeks and end of treatment visit | 
| Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0) | Toxicity measured and graded according to Common Terminology Criteria for Adverse Events v4.0 (CTCAE) Grade refers to the severity of the adverse event. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 Severe; medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling or limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | Up to 42 weeks | 
| Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4) | A laboratory abnormality is defined as an adverse event of grade 3 or 4 identified by a laboratory test of participant blood samples. Adverse events were graded according to Common Terminology Criteria for Adverse Events v4.0 (CTCAE). | Up to 42 weeks | 
| Disease Specific Overall Survival | Median time from death attributed to the disease. Censored at last known time alive or death from other causes. | Up to 42 weeks | 
| Progression Free Survival | Time from randomisation for deemed non-resectable groups, or time from registration for deemed resectable group to first event, where an event is Progressive Disease as (defined by RECIST criterion v1.1) or death due to any cause. Patients who have not had an event will be censored at their last follow-up date. Patients lost to follow-up without an event will be censored at the date of their last consultation. Progressive disease according to RECIST v1.1 is defined as a >=20% increase in the sum of long diameters of target lesions, OR progression of non-target lesions, OR evidence of new lesions. | Up to 42 weeks | 
| Biological Response (Systemic Levels of Mifamurtide Activated Cytokines). | Biological response based on systemic levels of mifamurtide activated cytokines. | During screening, and weeks 1, 4, 6 and 7. Then every 3 weeks during treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic and/or Recurrent Osteosarcoma