Osteosarcoma, Sarcoma, Ewing's, Peripheral Neuroectodermal Tumor
Conditions
Keywords
anti-IGF-1R
Brief summary
Participants with relapsed osteosarcoma that can be treated with surgery will be randomized to robatumumab administered intravenously (IV) at one of two dose levels. These participants will first receive robatumumab, have surgery performed, and continue to receive treatment every two weeks until a year of dosing, or until disease progression. Participants with unresectable osteosarcoma or Ewing Sarcoma will receive robatumumab IV once every two weeks until disease progression. Participants who achieve a complete response (CR) or partial response (PR) after tumor evaluations may undergo surgical resection. After surgery, participants are eligible to receive 10 mg/kg robatumumab until disease recurrence/progression or one year of total dosing, whichever occurs first.
Detailed description
Participants with resectable osteosarcoma will be randomized to one of two dose levels of robatumumab to be given intravenously. These participants will first receive robatumumab according to randomized treatment, and have surgery performed 10 to 14 days after initial dosing. Participants will be allowed to recover from surgery four to six weeks prior to additional robatumumab administration at their randomized dose level. robatumumab will then be administered on the same calendar day once every two weeks. Participants will continue to receive robatumumab until disease recurrence, or until completing a year of dosing at the same dose level assigned, whichever occurs first. Participants with unresectable osteosarcoma or Ewing Sarcoma will be assigned treatment to robatumumab IV administered once every two weeks and will continue to receive robatumumab until disease progression. Participants who achieve a CR or PR after tumor evaluations may undergo surgical resection. After surgery, participants are eligible to receive 10 mg/kg robatumumab until disease recurrence/progression or one year of total dosing, whichever occurs first.
Interventions
BIOLOGICALrobatumumab
Robatumumab IV every two weeks until disease progression.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A participant must be 11 years of age or older and may be of any race, and gender; participants between 4 and 10 years of age, inclusive, may be considered on a site-by-site basis. * A participant must have a diagnosis of histologically confirmed osteosarcoma or Ewing sarcoma; * A participant with either: * relapsed and resectable osteosarcoma * relapsed and unresectable osteosarcoma that is refractory to standard therapy, ie. has relapsed after prior systemic treatment with active chemotherapy agents * Ewing sarcoma that is refractory to standard systemic therapies * A participant \>16 years of age must have an Eastern Cooperative Oncology Group (ECOG) performance status of \<=2; a participant \<=16 years of age must have a Karnofsky performance status between 50% and 100% or a Lansky play scale between 50% and 100% * A participant must have adequate organ function.
Exclusion criteria
* A participant with a history of another malignancy (with the exception of non-melanoma skin cancer or carcinoma in situ of the cervix treated with curative intent at least 2 years prior to start of treatment, or other adequately treated malignancy for which the subject has been disease free for \>=5 years) * A participant who has known treated or untreated leptomeningeal metastasis, or a metastatic central nervous system lesion * A participant with a history of uncontrolled diabetes mellitus * A participant with a recent myocardial infarction (within the past year); or a participant who at the time of Screening presents with unstable or uncontrolled angina, New York Heart Association (NYHA) Class III or IV congestive heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality * A participant with an active infection * A participant with clinically significant hepatitis at Screening, or a participant who is hepatitis C antibody positive, hepatitis B surface antigen positive, or human immunodeficiency virus (HIV) seropositive * A participant who has been treated with an anti-insulin-like growth factor receptor 1 (anti-IGF-1R)- targeted drug or antibody * A participant with known hypersensitivity to other antibodies, or any accompanying excipients associated with these medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving a Complete Response or Partial Response (Group 3 Only) | Up to 1 year following the start of study therapy | This is a measure of the number of participants with a complete response (CR) or partial response (PR) to therapy, confirmed by central review. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria. |
| Number of Participants With >= 25% Change in Tumor Proliferation After Exposure to Robatumumab (Group 1 Only) | Approximately 14 days | Tumor proliferation was measured using Ki-67 levels. Ki-67 is nuclear protein associated with cellular proliferation. |
| Number of Participants Achieving a Complete Response, a Partial Response, or Stable Disease (Group 2 Only) | Up to 1 year following the start of study therapy | Responses to treatment (complete response, partial response, or stable disease) confirmed by central review for Participants in Group 2. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Anti-robatumumab Antibodies | Up to 2 years | For biological agents, it is possible for the host (participant) to develop antibodies to the agent. This outcome measure was planned to find out the number of participants who developed the antibodies after treatment with robatumumab. |
| Number of Participants Experiencing Treatment-Emergent Adverse Events | Up to 2 years | An adverse event is any unfavorable and unintended change in the structure, function, or chemistry of the body whether or not considered related to the study treatment. Treatment-emergent adverse events are those that occur after participants have received study treatment, or existing adverse events that occurred during screening that increase in severity after study treatment. Adverse events in the Group 1: 0.3 mg/kg arm that occurred after switching to the 10 mg/kg dose are displayed under the originally assigned treatment. |
| Overall Survival | From start of treatment until death or data analysis cut off (Up to 3.4 years) | This is a measure of the number of participants known to be alive at the time of data analysis for this study. |
| Overall Survival (Groups 2 and 3 Only) | From start of treatment until death or data analysis cut off (Up to 3.4 years) | This is a measure of the time of survival from first dose to documentation of death |
| Duration of Response (Groups 2 and 3 Only) | From time of documented response until disease progression or data analysis cut off (Up to 3.4 years) | This is a measure of the amount of time in which the tumor responded to therapy. |
| Time to Disease Progression (Groups 2 and 3 Only) | From the start of treatment until disease progression or data analysis cut off (Up to 3.4 years) | This is a measure of the time from the start of the study to the time of documented disease progression. |
| Time Until Tumor Relapse (Group 1 Only) | From start of treatment until relapse or data analysis cut off (Up to 3.4 years) | This is a measure of the time from the start of the study to documented relapse of disease. |
| Area Under the Concentration-time Curve (AUC) of Serum Levels of Robatumumab (Group 1 Only) | End of infusion on Day 1, and then prior to surgery, before and after the 2nd, 3rd, and 8th doses (up to 20 weeks) | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1: 0.3 mg/kg Participants received robatumumab 0.3 mg/kg intravenously (IV) as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 0.3 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin. | 35 |
| Group 1: 10 mg/kg Participants received robatumumab 10 mg/kg IV as a single dose on Day 1, followed by surgery on Day 10 to 14, and four weeks later, resumption of robatumumab 10 mg/kg on the same calendar day (± 3 days) once every 2 weeks until disease recurrence or up to 1 year of dosing. This group comprised participants with resectable osteosarcoma that relapsed within 6 months of prior definitive treatment (eg surgical metastasectomy) and having at least one prior chemotherapy regimen containing a platinum agent and doxorubicin. | 33 |
| Group 2: 10 mg/kg Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with relapsed and unresectable osteosarcoma refractory to prior chemotherapy with a platinum- and doxorubicin-containing regimen. | 35 |
| Group 3: 10 mg/kg Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing's sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine. | 116 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 3 | 8 |
| Overall Study | Lack of Efficacy | 23 | 26 | 30 | 97 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 |
| Overall Study | Not treated | 1 | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 1 | 0 | 0 |
| Overall Study | Treatment ongoing at data cut-off | 0 | 0 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Group 1: 0.3 mg/kg | Group 1: 10 mg/kg | Group 2: 10 mg/kg | Group 3: 10 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 23.7 Years STANDARD_DEVIATION 15.5 | 20.1 Years STANDARD_DEVIATION 10.3 | 27.5 Years STANDARD_DEVIATION 15.3 | 24.6 Years STANDARD_DEVIATION 11.4 | 24.3 Years STANDARD_DEVIATION 12.8 |
| Sex: Female, Male Female | 14 Participants | 13 Participants | 11 Participants | 43 Participants | 81 Participants |
| Sex: Female, Male Male | 21 Participants | 20 Participants | 24 Participants | 73 Participants | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 34 | 30 / 33 | 29 / 34 | 104 / 115 |
| serious Total, serious adverse events | 17 / 34 | 8 / 33 | 12 / 34 | 57 / 115 |
Outcome results
Primary
Number of Participants Achieving a Complete Response, a Partial Response, or Stable Disease (Group 2 Only)
Responses to treatment (complete response, partial response, or stable disease) confirmed by central review for Participants in Group 2. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria.
Time frame: Up to 1 year following the start of study therapy
Population: Group 2 participants with evaluable data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 3: 10 mg/kg | Number of Participants Achieving a Complete Response, a Partial Response, or Stable Disease (Group 2 Only) | 6 Participants |
Primary
Number of Participants Achieving a Complete Response or Partial Response (Group 3 Only)
This is a measure of the number of participants with a complete response (CR) or partial response (PR) to therapy, confirmed by central review. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria.
Time frame: Up to 1 year following the start of study therapy
Population: Participants in Group 3 with evaluable data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 3: 10 mg/kg | Number of Participants Achieving a Complete Response or Partial Response (Group 3 Only) | 6 Participants |
Primary
Number of Participants With >= 25% Change in Tumor Proliferation After Exposure to Robatumumab (Group 1 Only)
Tumor proliferation was measured using Ki-67 levels. Ki-67 is nuclear protein associated with cellular proliferation.
Time frame: Approximately 14 days
Population: Group 1 Participants; this outcome was not evaluated due to early termination of the study.
Secondary
Area Under the Concentration-time Curve (AUC) of Serum Levels of Robatumumab (Group 1 Only)
Time frame: End of infusion on Day 1, and then prior to surgery, before and after the 2nd, 3rd, and 8th doses (up to 20 weeks)
Population: Group 1, both dose levels: this outcome was not evaluated due to early termination of the study.
Secondary
Duration of Response (Groups 2 and 3 Only)
This is a measure of the amount of time in which the tumor responded to therapy.
Time frame: From time of documented response until disease progression or data analysis cut off (Up to 3.4 years)
Population: Group 2 and 3 participants; this outcome was not evaluated due to early termination of the study
Secondary
Incidence of Anti-robatumumab Antibodies
For biological agents, it is possible for the host (participant) to develop antibodies to the agent. This outcome measure was planned to find out the number of participants who developed the antibodies after treatment with robatumumab.
Time frame: Up to 2 years
Population: This outcome was not evaluated due to early termination of the study.
Secondary
Number of Participants Experiencing Treatment-Emergent Adverse Events
An adverse event is any unfavorable and unintended change in the structure, function, or chemistry of the body whether or not considered related to the study treatment. Treatment-emergent adverse events are those that occur after participants have received study treatment, or existing adverse events that occurred during screening that increase in severity after study treatment. Adverse events in the Group 1: 0.3 mg/kg arm that occurred after switching to the 10 mg/kg dose are displayed under the originally assigned treatment.
Time frame: Up to 2 years
Population: All participants receiving study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 3: 10 mg/kg | Number of Participants Experiencing Treatment-Emergent Adverse Events | 31 Participants |
| Group 1: 10 mg/kg | Number of Participants Experiencing Treatment-Emergent Adverse Events | 30 Participants |
| Group 2: 10 mg/kg | Number of Participants Experiencing Treatment-Emergent Adverse Events | 31 Participants |
| Group 3: 10 mg/kg | Number of Participants Experiencing Treatment-Emergent Adverse Events | 112 Participants |
Secondary
Overall Survival
This is a measure of the number of participants known to be alive at the time of data analysis for this study.
Time frame: From start of treatment until death or data analysis cut off (Up to 3.4 years)
Population: All study participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 3: 10 mg/kg | Overall Survival | 17 Participants |
| Group 1: 10 mg/kg | Overall Survival | 16 Participants |
| Group 2: 10 mg/kg | Overall Survival | 7 Participants |
| Group 3: 10 mg/kg | Overall Survival | 28 Participants |
Secondary
Overall Survival (Groups 2 and 3 Only)
This is a measure of the time of survival from first dose to documentation of death
Time frame: From start of treatment until death or data analysis cut off (Up to 3.4 years)
Population: Group 2 and 3 Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 3: 10 mg/kg | Overall Survival (Groups 2 and 3 Only) | 8.18 Months |
| Group 1: 10 mg/kg | Overall Survival (Groups 2 and 3 Only) | 6.93 Months |
Secondary
Time to Disease Progression (Groups 2 and 3 Only)
This is a measure of the time from the start of the study to the time of documented disease progression.
Time frame: From the start of treatment until disease progression or data analysis cut off (Up to 3.4 years)
Population: All participants in Groups 2 and 3; this outcome was not evaluated due to early termination of the study
Secondary
Time Until Tumor Relapse (Group 1 Only)
This is a measure of the time from the start of the study to documented relapse of disease.
Time frame: From start of treatment until relapse or data analysis cut off (Up to 3.4 years)
Population: Group 1 participants; this outcome was not evaluated due to early termination of the study.