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A Study to Determine the Activity of Robatumumab (SCH 717454) in Participants With Relapsed Osteosarcoma or Ewing's Sarcoma (MK-7454-002/P04720)

Primary Purpose

Osteosarcoma, Sarcoma, Ewing's, Peripheral Neuroectodermal Tumor

Status
Terminated
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
robatumumab
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteosarcoma focused on measuring anti-IGF-1R

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Experimental

    Experimental

    Experimental

    Experimental

    Arm Label

    Group 1: 0.3 mg/kg

    Group 1: 10 mg/kg

    Group 2: 10 mg/kg

    Group 3: 10 mg/kg

    Arm Description

    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.

    Participants who 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.

    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.

    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine.

    Outcomes

    Primary Outcome Measures

    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.
    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.
    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.

    Secondary Outcome Measures

    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 Until Tumor Relapse (Group 1 Only)
    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)
    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.
    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 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.
    Overall Survival (Groups 2 and 3 Only)
    This is a measure of the time of survival from first dose to documentation of death
    Duration of Response (Groups 2 and 3 Only)
    This is a measure of the amount of time in which the tumor responded to therapy.

    Full Information

    First Posted
    January 17, 2008
    Last Updated
    July 24, 2018
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00617890
    Brief Title
    A Study to Determine the Activity of Robatumumab (SCH 717454) in Participants With Relapsed Osteosarcoma or Ewing's Sarcoma (MK-7454-002/P04720)
    Official Title
    A Study to Determine the Activity of SCH 717454 in Subjects With Osteosarcoma or Ewing's Sarcoma That Has Relapsed After Standard Systemic Therapy
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2018
    Overall Recruitment Status
    Terminated
    Why Stopped
    The study was prematurely terminated for strategic reasons, not for a safety concern.
    Study Start Date
    February 1, 2008 (Actual)
    Primary Completion Date
    August 31, 2011 (Actual)
    Study Completion Date
    August 31, 2013 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Osteosarcoma, Sarcoma, Ewing's, Peripheral Neuroectodermal Tumor
    Keywords
    anti-IGF-1R

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    219 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Group 1: 0.3 mg/kg
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Group 1: 10 mg/kg
    Arm Type
    Experimental
    Arm Description
    Participants who 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.
    Arm Title
    Group 2: 10 mg/kg
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Group 3: 10 mg/kg
    Arm Type
    Experimental
    Arm Description
    Participants received robatumumab 10 mg/kg IV biweekly until disease recurrence or up to 1 year of dosing. This group comprised participants with Ewing sarcoma refractory to prior treatment with at least 3 of the following agents: ifosfamide, etoposide, cyclophosphamide, doxorubicin, or vincristine.
    Intervention Type
    Biological
    Intervention Name(s)
    robatumumab
    Other Intervention Name(s)
    SCH 717454, SCH 717454 (19D12), MK-7454
    Intervention Description
    Robatumumab IV every two weeks until disease progression.
    Primary Outcome Measure Information:
    Title
    Number of Participants Achieving a Complete Response or Partial Response (Group 3 Only)
    Description
    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
    Title
    Number of Participants With >= 25% Change in Tumor Proliferation After Exposure to Robatumumab (Group 1 Only)
    Description
    Tumor proliferation was measured using Ki-67 levels. Ki-67 is nuclear protein associated with cellular proliferation.
    Time Frame
    Approximately 14 days
    Title
    Number of Participants Achieving a Complete Response, a Partial Response, or Stable Disease (Group 2 Only)
    Description
    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
    Secondary Outcome Measure Information:
    Title
    Overall Survival
    Description
    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)
    Title
    Time Until Tumor Relapse (Group 1 Only)
    Description
    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)
    Title
    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)
    Title
    Incidence of Anti-robatumumab Antibodies
    Description
    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
    Title
    Number of Participants Experiencing Treatment-Emergent Adverse Events
    Description
    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
    Title
    Time to Disease Progression (Groups 2 and 3 Only)
    Description
    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)
    Title
    Overall Survival (Groups 2 and 3 Only)
    Description
    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)
    Title
    Duration of Response (Groups 2 and 3 Only)
    Description
    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)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    4 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    27362300
    Citation
    Anderson PM, Bielack SS, Gorlick RG, Skubitz K, Daw NC, Herzog CE, Monge OR, Lassaletta A, Boldrini E, Papai Z, Rubino J, Pathiraja K, Hille DA, Ayers M, Yao SL, Nebozhyn M, Lu B, Mauro D. A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma. Pediatr Blood Cancer. 2016 Oct;63(10):1761-70. doi: 10.1002/pbc.26087. Epub 2016 Jun 30.
    Results Reference
    result
    PubMed Identifier
    22682017
    Citation
    Asmane I, Watkin E, Alberti L, Duc A, Marec-Berard P, Ray-Coquard I, Cassier P, Decouvelaere AV, Ranchere D, Kurtz JE, Bergerat JP, Blay JY. Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas. Eur J Cancer. 2012 Nov;48(16):3027-35. doi: 10.1016/j.ejca.2012.05.009. Epub 2012 Jun 7.
    Results Reference
    derived
    Available IPD and Supporting Information:
    Available IPD/Information Type
    CSR Synopsis
    Available IPD/Information URL
    http://www.merck.com/clinical-trials/study.html?id=P04720&kw=P04720&tab=access

    Learn more about this trial

    A Study to Determine the Activity of Robatumumab (SCH 717454) in Participants With Relapsed Osteosarcoma or Ewing's Sarcoma (MK-7454-002/P04720)

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