Clinical trial NCT02441309: A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS)
Official title: A Mechanistic Study Of Mifamurtide (MTP-PE) In Patients With Metastatic And/Or Recurrent Osteosarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Osteosarcoma
Keywords: Metastatic and/or Recurrent Osteosarcoma
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Millennium: The Takeda Oncology Company
name: National Institute for Health Research, United Kingdom
name: Oxford University Hospitals NHS Trust
name: European Commission
First posted: 2015-05-12
Enrollment: 8
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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.

Primary outcomes:
measure: Biological Response Data Based on Pharmacodynamic Endpoints on Tumour Biopsy Material
timeFrame: Change from Baseline to after 6 weeks of treatment
measure: Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria
timeFrame: Change from Baseline to after 6 weeks of treatment
Secondary outcomes:
measure: Objective Radiological Response Based on RECIST v1.1
timeFrame: Change from Baseline to after 12, 18, 24 & 36 weeks and end of treatment visit
measure: Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0)
timeFrame: Up to 42 weeks
measure: Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4)
timeFrame: Up to 42 weeks
measure: Disease Specific Overall Survival
timeFrame: Up to 42 weeks
measure: Progression Free Survival
timeFrame: Up to 42 weeks
measure: Biological Response (Systemic Levels of Mifamurtide Activated Cytokines).
timeFrame: During screening, and weeks 1, 4, 6 and 7. Then every 3 weeks during treatment.
Other outcomes:
Locations:
city: Münster
country: Germany
facility: Pediatric Hematology and Oncology, University Hospital Münster
city: Bologna
country: Italy
facility: Istituti Ortopedici Rizzoli
state: Emilia-Romagna
city: Leiden
country: Netherlands
facility: Department of Clinical Oncology, Leiden University Medical Center
state: Postzone K1-P
city: Oslo
country: Norway
facility: Radium Hospital, Oslo University
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundations Trust
Study officials:
affiliation: University of Oxford
name: Bass Hassan, BMBCh FRCP
role: PRINCIPAL_INVESTIGATOR
References: