A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS)

NCT02441309 | Terminated Phase 2 Results DMC

• 1 other identifier: OCTO_039
• Study Type: interventional
• Target: 8
• Locations: 5 countries
• Sites: 8

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.

Conditions

Osteosarcoma

Keywords

Metastatic and/or Recurrent Osteosarcoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Objective Radiological Response Based on RECIST v1.1

  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)

  Up to 42 weeks

• Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4)

  Up to 42 weeks

• Disease Specific Overall Survival

  Up to 42 weeks

• Progression Free Survival

  Up to 42 weeks

Study Arms (3)

A. Mifamurtide only

EXPERIMENTAL

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

B. Ifosfamide (Followed by Mifamurtide)

EXPERIMENTAL

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; Drug: Ifosfamide

C. Ifosfamide + Mifamurtide

EXPERIMENTAL

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; Drug: Ifosfamide

Interventions

Mifamurtide DRUG

A. Mifamurtide only; B. Ifosfamide (Followed by Mifamurtide); C. Ifosfamide + Mifamurtide

Ifosfamide DRUG

B. Ifosfamide (Followed by Mifamurtide); C. Ifosfamide + Mifamurtide

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead
• Millennium: The Takeda Oncology Company: collaborator
• National Institute for Health Research, United Kingdom: collaborator
• Oxford University Hospitals NHS Trust: collaborator
• European Commission: collaborator

Study Sites (8)

Pediatric Hematology and Oncology, University Hospital Münster

Münster, 48149, Germany

Location

Istituti Ortopedici Rizzoli

Bologna, Emilia-Romagna, 40136, Italy

Location

Department of Clinical Oncology, Leiden University Medical Center

Leiden, Postzone K1-P, P.O. Box 9600, Netherlands

Location

Radium Hospital, Oslo University

Oslo, 0310, Norway

Location

Leeds Teaching Hospitals NHS Trust

Leeds, LS9 7TF, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, NW1 2BU, United Kingdom

Location

Christie Hospital NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Oxford University Hospitals NHS Foundations Trust

Oxford, OX3 7LE, United Kingdom

Location

MeSH Terms

Conditions

Osteosarcoma

Interventions

mifamurtide; Ifosfamide

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Early termination leading to small numbers of subjects analyzed. This was due to a poor recruitment speed.

Results Point of Contact

• Title: Joint Research Office
• Organization: University of Oxford

ctrg@admin.ox.ac.uk

+441865572245

Study Officials

• Bass Hassan, BMBCh FRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2015
• First Posted: May 12, 2015
• Study Start: October 1, 2014
• Primary Completion: November 4, 2016
• Study Completion: November 4, 2016
• Last Updated: September 13, 2019
• Results First Posted: September 13, 2019

Record last verified: 2018-03

Locations

IT (1); NO (1); DE (1); GB (4); NL (1)