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

Primary Purpose

Osteosarcoma

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Mifamurtide

Ifosfamide

About this trial

This is an interventional treatment trial for Osteosarcoma focused on measuring Metastatic and/or Recurrent Osteosarcoma

Eligibility Criteria

16 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Pediatric Hematology and Oncology, University Hospital Münster
Istituti Ortopedici Rizzoli
Department of Clinical Oncology, Leiden University Medical Center
Radium Hospital, Oslo University
Leeds Teaching Hospitals NHS Trust
University College London Hospitals NHS Foundation Trust
Christie Hospital NHS Foundation Trust
Oxford University Hospitals NHS Foundations Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

A. Mifamurtide only

B. Ifosfamide (Followed by Mifamurtide)

C. Ifosfamide + Mifamurtide

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

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

Secondary Outcome Measures

Objective Radiological Response Based on RECIST v1.1

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.

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).

Disease Specific Overall Survival

Median time from death attributed to the disease. Censored at last known time alive or death from other causes.

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.

Biological Response (Systemic Levels of Mifamurtide Activated Cytokines).

Biological response based on systemic levels of mifamurtide activated cytokines.

Full Information

NCT ID

NCT02441309

First Posted

March 16, 2015

Last Updated

August 7, 2019

Sponsor

University of Oxford

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT02441309

Brief Title

A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS)

Acronym

MEMOS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2018

Overall Recruitment Status

Terminated

Why Stopped

Failed to recruit sufficient numbers of patients in the funded period

Study Start Date

October 2014 (Actual)

Primary Completion Date

November 4, 2016 (Actual)

Study Completion Date

November 4, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Oxford

Collaborators

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

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Osteosarcoma

Keywords

Metastatic and/or Recurrent Osteosarcoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

A. Mifamurtide only

Arm Type

Experimental

Arm Description

Arm Title

B. Ifosfamide (Followed by Mifamurtide)

Arm Type

Experimental

Arm Description

Arm Title

C. Ifosfamide + Mifamurtide

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Mifamurtide

Intervention Type

Drug

Intervention Name(s)

Ifosfamide

Primary Outcome Measure Information:

Title

Biological Response Data Based on Pharmacodynamic Endpoints on Tumour Biopsy Material

Description

Biological response data based on pharmacodynamic endpoints on tumour biopsy material including macrophage infiltration and innate immune activation.

Time Frame

Change from Baseline to after 6 weeks of treatment

Title

Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria

Description

Time Frame

Change from Baseline to after 6 weeks of treatment

Secondary Outcome Measure Information:

Title

Objective Radiological Response Based on RECIST v1.1

Description

Time Frame

Change from Baseline to after 12, 18, 24 & 36 weeks and end of treatment visit

Title

Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0)

Description

Time Frame

Up to 42 weeks

Title

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

Description

Time Frame

Up to 42 weeks

Title

Disease Specific Overall Survival

Description

Median time from death attributed to the disease. Censored at last known time alive or death from other causes.

Time Frame

Up to 42 weeks

Title

Progression Free Survival

Description

Time Frame

Up to 42 weeks

Title

Biological Response (Systemic Levels of Mifamurtide Activated Cytokines).

Description

Biological response based on systemic levels of mifamurtide activated cytokines.

Time Frame

During screening, and weeks 1, 4, 6 and 7. Then every 3 weeks during treatment.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bass Hassan, BMBCh FRCP

Organizational Affiliation

University of Oxford

Official's Role

Principal Investigator

Facility Information:

Facility Name

Pediatric Hematology and Oncology, University Hospital Münster

City

Münster

ZIP/Postal Code

48149

Country

Germany

Facility Name

Istituti Ortopedici Rizzoli

City

Bologna

State/Province

Emilia-Romagna

ZIP/Postal Code

40136

Country

Italy

Facility Name

Department of Clinical Oncology, Leiden University Medical Center

City

Leiden

State/Province

Postzone K1-P

ZIP/Postal Code

P.O. Box 9600

Country

Netherlands

Facility Name

Radium Hospital, Oslo University

City

Oslo

ZIP/Postal Code

0310

Country

Norway

Facility Name

Leeds Teaching Hospitals NHS Trust

City

Leeds

ZIP/Postal Code

LS9 7TF

Country

United Kingdom

Facility Name

University College London Hospitals NHS Foundation Trust

City

London

ZIP/Postal Code

NW1 2BU

Country

United Kingdom

Facility Name

Christie Hospital NHS Foundation Trust

City

Manchester

ZIP/Postal Code

M20 4BX

Country

United Kingdom

Facility Name

Oxford University Hospitals NHS Foundations Trust

City

Oxford

ZIP/Postal Code

OX3 7LE

Country

United Kingdom

12. IPD Sharing Statement

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A Eurosarc Study of Mifamurtide in Advanced Osteosarcoma (MEMOS)

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