Osteosarcoma
Conditions
Keywords
Metastatic and/or Recurrent Osteosarcoma
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.
Interventions
DRUGMifamurtide
DRUGIfosfamide
Sponsors
Millennium: The Takeda Oncology Company
National Institute for Health Research, United Kingdom
Oxford University Hospitals NHS Trust
European Commission
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biological Response Data Based on Pharmacodynamic Endpoints on Tumour Biopsy Material | 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. |
| Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Change from Baseline to after 6 weeks of treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4) | Up to 42 weeks | 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 | Up to 42 weeks | Median time from death attributed to the disease. Censored at last known time alive or death from other causes. |
| Objective Radiological Response Based on RECIST v1.1 | Change from Baseline to after 12, 18, 24 & 36 weeks and end of treatment visit | 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 |
| Biological Response (Systemic Levels of Mifamurtide Activated Cytokines). | During screening, and weeks 1, 4, 6 and 7. Then every 3 weeks during treatment. | Biological response based on systemic levels of mifamurtide activated cytokines. |
| Progression Free Survival | 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 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. |
| Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0) | Up to 42 weeks | 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. |
Countries
Germany, Italy, Netherlands, Norway, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Mifamurtide | 3 |
| 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.
Mifamurtide
Ifosfamide | 2 |
| 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.
Mifamurtide
Ifosfamide | 3 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Disease progression | 2 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | A. Mifamurtide Only | B. Ifosfamide (Followed by Mifamurtide) | C. Ifosfamide + Mifamurtide | Total |
|---|---|---|---|---|
| Age, Continuous | 21 years | 23 years | 57 years | 25 years |
| Disease stage at screening - Metastatic | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Histology/Cytological type Chondroblastic OS - 9181/3 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Histology/Cytological type Osteoblastic OS - 9180/3 | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Histology/Cytological type Osteosarcoma NOS - 9180/3 | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Primary Site Axial | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Primary Site Limb | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Prior chemotherapy No | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Prior chemotherapy Yes | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Prior radiotherapy No | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Prior radiotherapy Yes | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Prior surgery No | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Prior surgery Yes | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Italy | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Netherlands | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Norway | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Tumour size at baseline (sum of longest diameters) (mm) | 84 mm | 37 mm | 99 mm | 82 mm |
| WHO Performance Status 0 | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| WHO Performance Status 1 | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 | 2 / 3 |
| other Total, other adverse events | 1 / 3 | 2 / 2 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 2 / 2 | 2 / 3 |
Outcome results
Primary
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.
Time frame: Change from Baseline to after 6 weeks of treatment
Population: Insufficient number of participants for events for both primary and secondary objectives. The study stopped prematurely because of poor recruitment, meaning that no complete statistical analysis was possible as there were insufficient events and data were not collected.
Primary
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
Time frame: Change from Baseline to after 6 weeks of treatment
Population: All patients are included since this is an intention to treat analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| A. Mifamurtide Only | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Patient progressed prior to time point | 2 Participants |
| A. Mifamurtide Only | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Patient did not reach endpoint | 1 Participants |
| A. Mifamurtide Only | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Progressive Disease (PD) | 0 Participants |
| A. Mifamurtide Only | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Stable Disease (SD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Stable Disease (SD) | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Progressive Disease (PD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Patient did not reach endpoint | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Patient progressed prior to time point | 0 Participants |
| C. Ifosfamide + Mifamurtide | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Progressive Disease (PD) | 1 Participants |
| C. Ifosfamide + Mifamurtide | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Patient progressed prior to time point | 0 Participants |
| C. Ifosfamide + Mifamurtide | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Stable Disease (SD) | 1 Participants |
| C. Ifosfamide + Mifamurtide | Radiological Response Defined as Complete or Partial Response and Assessed Using RECIST Criteria | Patient did not reach endpoint | 1 Participants |
Secondary
Biological Response (Systemic Levels of Mifamurtide Activated Cytokines).
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.
Population: Insufficient number of participants for events for both primary and secondary objectives. The study stopped prematurely because of poor recruitment, meaning that no complete statistical analysis was possible as there were insufficient events and data were not collected.
Secondary
Disease Specific Overall Survival
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
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A. Mifamurtide Only | Disease Specific Overall Survival | 0.7 months |
| B. Ifosfamide (Followed by Mifamurtide) | Disease Specific Overall Survival | 9.2 months |
| C. Ifosfamide + Mifamurtide | Disease Specific Overall Survival | 2.8 months |
Secondary
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.
Time frame: Up to 42 weeks
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A. Mifamurtide Only | Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0) | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0) | 2 Participants |
| C. Ifosfamide + Mifamurtide | Number of Patients Experiencing a Grade 3 or More Severe Adverse Event (Graded According to CTCAE Criteria v4.0) | 2 Participants |
Secondary
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).
Time frame: Up to 42 weeks
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A. Mifamurtide Only | Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Number of Patients Experiencing a Laboratory Abnormality (Grade 3-4) | 0 Participants |
Secondary
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
Time frame: Change from Baseline to after 12, 18, 24 & 36 weeks and end of treatment visit
Population: The end of treatment visit was completed by patients who were deemed to progress or withdrew from trial treatment at a time that a scheduled scan was not due to be taken. This end of treatment visit was used to confirm radiological progression.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Progressive Disease (PD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Stable Disease (SD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Patient did not reach endpoint | 3 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Stable Disease (SD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Stable Disease (SD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Progressive Disease (PD) | 2 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Patient did not reach endpoint | 3 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Progressive Disease (PD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Patient did not reach endpoint | 3 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Progressive Disease (PD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Stable Disease (SD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Stable Disease (SD) | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Patient did not reach endpoint | 0 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Patient did not reach endpoint | 3 Participants |
| A. Mifamurtide Only | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Progressive Disease (PD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Patient did not reach endpoint | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Stable Disease (SD) | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Progressive Disease (PD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Patient did not reach endpoint | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Stable Disease (SD) | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Progressive Disease (PD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Patient did not reach endpoint | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Stable Disease (SD) | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Progressive Disease (PD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Patient did not reach endpoint | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Stable Disease (SD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Progressive Disease (PD) | 1 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Stable Disease (SD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Progressive Disease (PD) | 0 Participants |
| B. Ifosfamide (Followed by Mifamurtide) | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Patient did not reach endpoint | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Stable Disease (SD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Progressive Disease (PD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Progressive Disease (PD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Stable Disease (SD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Patient did not reach endpoint | 2 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 36 | Patient did not reach endpoint | 3 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Patient did not reach endpoint | 2 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Stable Disease (SD) | 1 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Stable Disease (SD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Progressive Disease (PD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Stable Disease (SD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 12 | Progressive Disease (PD) | 0 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 24 | Patient did not reach endpoint | 3 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | Week 18 | Progressive Disease (PD) | 1 Participants |
| C. Ifosfamide + Mifamurtide | Objective Radiological Response Based on RECIST v1.1 | End of Treatment visit (prior to week 6) | Patient did not reach endpoint | 0 Participants |
Secondary
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.
Time frame: Up to 42 weeks
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A. Mifamurtide Only | Progression Free Survival | NA months |
| B. Ifosfamide (Followed by Mifamurtide) | Progression Free Survival | NA months |
| C. Ifosfamide + Mifamurtide | Progression Free Survival | 7.0 months |