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Trial record 4 of 7 for:    Acetylmuramyl-Alanyl-Isoglutamine

A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS) (MEMOS)

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ClinicalTrials.gov Identifier: NCT02441309
Recruitment Status : Completed
First Posted : May 12, 2015
Last Update Posted : March 22, 2017
Sponsor:
Collaborators:
Millennium: The Takeda Oncology Company
National Institute for Health Research, United Kingdom
Oxford University Hospitals NHS Trust
European Commission
Information provided by (Responsible Party):
University of Oxford

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.

Condition or disease Intervention/treatment Phase
Osteosarcoma Drug: Mifamurtide Drug: Ifosfamide Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Mechanistic Study Of Mifamurtide (MTP-PE) In Patients With Metastatic And/Or Recurrent Osteosarcoma
Actual Study Start Date : October 2014
Actual Primary Completion Date : November 4, 2016
Actual Study Completion Date : November 4, 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Ifosfamide

Arm Intervention/treatment
Experimental: A. Mifamurtide only

Patients receive Mifamurtide only.

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
Experimental: B. Ifosfamide (Followed by Mifamurtide)

Patients receive Ifosfamide alone initially, followed by ifosfamide plus mifamurtide, then mifamurtide alone.

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 must be started 24 hours prior to mifamurtide. Mifamurtide should be 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
Drug: Ifosfamide
Experimental: C. Ifosfamide + Mifamurtide

Patients receive mifamurtide combined with ifosfamide initially.

Treatment Weeks 1-6:

Day 1 of 21: Ifosfamide 12-15g/m2 IV infusion infused over 4-5 days once every 21 days for two cycles (3 weeks=1 cycle).

Plus Mifamurtide 2 mg/m2, IV infusion, twice per week, with each infusion given at least 3 days apart, for 6 weeks.

Ifosfamide infusion must be started 24 hours prior to mifamurtide. Mifamurtide should be 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 infused over 4-5 days once every 21 days for two cycles (3 weeks = 1 cycle).

Plus Mifamurtide 2mg/m2, IV infusion, twice per week, with each infusion given at least 3 days apart, for 6 weeks. Ifosfamide infusion must be started 24 hours prior to mifamurtide. Mifamurtide should be given on day 2 and either day 5 or day 6.

Treatment Weeks 13-36: Mifamurtide 2mg/m2, IV infusion, once/week.

Drug: Mifamurtide
Drug: Ifosfamide



Primary Outcome Measures :
  1. Biological response data based on pharmacodynamic endpoints on tumour biopsy material [ Time Frame: Change from Baseline to after 6 weeks of treatment ]
    Biological response data based on pharmacodynamic endpoints on tumour biopsy material including macrophage infiltration and innate immune activation.

  2. Radiological response defined as complete or partial response and assessed using RECIST criteria [ Time Frame: Change from Baseline to after 6 weeks of treatment ]
    Radiological response defined as complete or partial response and assessed using RECIST criteria

  3. Objective radiological response based on RECIST 1.1 [ Time Frame: Change from Baseline to after 6, 12, 18, 24 & 36 weeks of treatment ]
    Objective radiological response based on RECIST 1.1


Secondary Outcome Measures :
  1. Toxicity (graded according to the CTCAE criteria) [ Time Frame: Up to 42 weeks ]
    Toxicity measured and graded according to the CTCAE criteria

  2. Laboratory abnormalities (grade 3-4) [ Time Frame: Up to 42 weeks ]
    Laboratory abnormalities grade 3 and 4

  3. Disease specific overall survival [ Time Frame: Up to 42 weeks ]
    The time from registration/randomisation to death due to the disease. Surviving patients and deaths due to other cause 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.

  4. Progression free survival on serial CT scan [ Time Frame: Up to 42 weeks ]
    Time from randomisation for deemed non-resectable groups, or time from registration for deemed resectable group to first event, where an event is progression as (defined by RECIST criterion) 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02441309


Locations
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Germany
Pediatric Hematology and Oncology, University Hospital Münster
Münster, Germany, 48149
Italy
Istituti Ortopedici Rizzoli
Bologna, Emilia-Romagna, Italy, 40136
Netherlands
Department of Clinical Oncology, Leiden University Medical Center
Leiden, Postzone K1-P, Netherlands, P.O. Box 9600
Norway
Radium Hospital, Oslo University
Oslo, Norway, 0310
United Kingdom
Leeds Teaching Hospitals NHS Trust
Leeds, United Kingdom, LS9 7TF
University College London Hospitals NHS Foundation Trust
London, United Kingdom, NW1 2BU
Christie Hospital NHS Foundation Trust
Manchester, United Kingdom, M20 4BX
Oxford University Hospitals NHS Foundations Trust
Oxford, United Kingdom, OX3 7LE
Sponsors and Collaborators
University of Oxford
Millennium: The Takeda Oncology Company
National Institute for Health Research, United Kingdom
Oxford University Hospitals NHS Trust
European Commission
Investigators
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Principal Investigator: Bass Hassan, BSc(Hon) BMBCh MRCP DPhil FRCP University of Oxford

Additional Information:
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02441309     History of Changes
Other Study ID Numbers: OCTO_039
First Posted: May 12, 2015    Key Record Dates
Last Update Posted: March 22, 2017
Last Verified: March 2017

Keywords provided by University of Oxford:
Metastatic and/or Recurrent Osteosarcoma

Additional relevant MeSH terms:
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Acetylmuramyl-Alanyl-Isoglutamine
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Ifosfamide
Isophosphamide mustard
Mifamurtide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs