A Study of R1507 in Participants With Recurrent or Refractory Sarcoma

Study Overview
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Brief Summary
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The study was primarily designed to determine objective response, progression-free survival (PFS), and the safety and tolerability of R1507 in participants with recurrent or refractory Ewing's sarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas including alveolar soft part sarcoma, desmoplastic small round cell tumor, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and myxoid liposarcoma.

Official Title
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A Phase II Trial of R1507, a Recombinant Human Monoclonal Antibody to the Insulin-Like Growth Factor-1 Receptor for the Treatment of Participants With Recurrent or Refractory Ewing's Sarcoma, Osteosarcoma, Synovial Sarcoma, Rhabdomyosarcoma and Other Sarcomas.

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: RG1507


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: progressive, recurrent or refractory Ewing's sarcoma, or recurrent or refractory osteosarcoma, synovial sarcoma, rhabdomyosarcoma, or other sarcomas of the following sub-types: alveolar soft part sarcoma, desmoplastic small round cell tumor, extraskeletal myxoid chondrosarcoma, clear cell sarcoma and myxoid liposarcoma; Cohort 3 only: age must be >= 2 and <= 21 years Exclusion Criteria: clinically significant unrelated systemic illness which would compromise the participant's ability to tolerate the investigational agent, or interfere with the study procedures or results; known hypersensitivity to any of the components of R1507 or prior hypersensitivity reactions to monoclonal antibodies; treatment (within the past 2 weeks) with pharmacologic doses of corticosteroids or other immunosuppressive agents; current or prior therapy with insulin-like growth factor (IGF) inhibitor (monoclonal or specific kinase inhibitor); history of solid organ transplant; other malignant disease diagnosed within the previous 5 years, excluding intra-epithelial cervical neoplasia or non-melanoma skin cancer; active central nervous system disease

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Ewings Sarcoma Primary Cohort<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 1 includes individuals with Ewing's sarcoma who have relapsed within 24 weeks after diagnosis and have received two or more prior chemotherapy regimens. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 2: Ewings Sarcoma Secondary Cohort<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 2 includes individuals with Ewing's sarcoma who have relapsed more than 24 weeks after diagnosis and have only received one prior chemotherapy regimen. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 3: Ewings Sarcoma Expanded Cohort<br>Participants 2 to 21 years of age with recurrent or refractory sarcoma receive R1507 as 27 mg/kg via IV infusion every 3 weeks until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 3 includes individuals with Ewing's sarcoma who were enrolled and treated following safety evaluation in other cohorts. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 4: Osteosarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 4 includes individuals with osteosarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 5: Synovial Sarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 5 includes individuals with synovial sarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 6: Rhabdomyosarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 6 includes individuals with rhabdomyosarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 7a: Alveolar Soft Part Sarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 7a includes individuals with alveolar soft part sarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 7b: Desmoplastic Small Round Cell Tumors.<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 7b includes individuals with desmoplastic small round cell tumors. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 7c: Extraskeletal Myxoid Chondrosarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 7c includes individuals with extraskeletal myxoid chondrosarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 7d: Clear Cell Sarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 7d includes individuals with clear cell sarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 7e: Myxoid Liposarcoma<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 7e includes individuals with myxoid liposarcoma. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|
| Experimental: Cohort 8: Diagnosis Not Specified<br>Participants 2 years of age and older with recurrent or refractory sarcoma receive R1507 as 9 mg/kg via IV infusion once weekly until disease progression, intercurrent illness, unacceptable toxicity, prolonged (2-week) time off treatment, withdrawal, loss to follow-up, investigator decision, or death. Cohort 8 includes individuals with subtypes of sarcoma not specified in the protocol. | Drug: RG1507<br>* Participants will receive R1507 IV infusion as 9 mg/kg once weekly or 27 mg/kg every 3 weeks, depending upon the cohort in which the participants are enrolled.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Partial Response, According to World Health Organization (WHO) Criteria in Cohorts 2 to 8 | Complete response is the disappearance of all known disease, determined by two consecutive observations not less than 4 weeks apart. Partial response is >=50% decrease in the total tumor load of the lesions that have been measured to determine the effect of therapy not less than four weeks apart. The observations must be consecutive. | Baseline up to 6 years (assessed at baseline, every 6 weeks for 24 weeks, then every 12 weeks until disease progression) | 
| Progression-Free Survival (PFS) Rate According to WHO Response Criteria at 18 Weeks From Start of R2607 Treatment in Cohort 1 | The PFS survival rate is a landmark analysis of progression-free survival at 18 weeks from start of treatment. Progression-free survival rate at 18 weeks is a dichotomous endpoint, with a patient categorized as alive (with either stable disease or objective response) at 18 weeks from start of treatment. | Baseline up to 18 weeks (assessed at baseline, every 6 weeks until disease progression) | 
| Percentage of Participants With Adverse Events (AEs) in Cohort 1 and 2 |  | Baseline up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Partial Response According to WHO Response Criteria in Cohort 1 | Complete response is the disappearance of all known disease, determined by two consecutive observations not less than 4 weeks apart. Partial response is >=50% decrease in the total tumor load of the lesions that have been measured to determine the effect of therapy not less than four weeks apart. The observations must be consecutive. | Baseline, every 6 weeks for 24 weeks, then every 12 weeks until disease progression (up to 6 years) | 
| PFS Rate According to WHO Response Criteria at 18 Weeks From Start of R1507 Treatment in Cohorts 2 to 8 | The PFS survival rate is a landmark analysis of progression-free survival at 18 weeks from start of treatment. Progression-free survival rate at 18 weeks is a dichotomous endpoint, with a patient categorized as alive (with either stable disease or objective response at 18 weeks) from start of treatment. | Baseline, every 6 weeks until disease progression (up to 18 weeks) | 
| Percentage of Participants With AEs in Cohorts 3-8 |  | Baseline up to 6 years | 
| Duration of Response (DOR) According to WHO Response Criteria in Cohorts 1 to 8 | The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Complete response is the disappearance of all known disease, determined by two consecutive observations not less than 4 weeks apart. Partial response is >=50% decrease in the total tumor load of the lesions that have been measured to determine the effect of therapy not less than four weeks apart. The observations must be consecutive. | Baseline, every 6 weeks for 24 weeks, then every 12 weeks until disease progression (up to 6 years) | 
| Time to Progression (TTP) According to WHO Response Criteria in Cohorts 1 to 8 | TTP is defined as the time from date of randomization until objective tumor progression. According to the WHO Response Criteria, objective tumor progression is > 25% increase in the area of one or more measurable lesions or the appearance of new lesions. | Baseline, every 6 weeks for 24 weeks, then every 12 weeks until disease progression (up to 6 years) | 
| Failure-Free Survival (FFS) According to WHO Response Criteria in Cohorts 1 to 8 | FFS was measured from the date of treatment start to the date of documented disease progression, relapse, or death from any cause. | Baseline, every 6 weeks for 24 weeks, then every 12 weeks until disease progression (up to 6 years) | 
| Overall Survival (OS) in Cohorts 1 to 8 | OS was measured from the time of study registration to the date of death or was censored at the date of last contact. | Baseline until death (up to 6 years) | 
| PFS According to WHO Response Criteria in Cohorts 1 to 8 | PFS is defined as the duration of time from start of treatment to time of objective progression or death. | Baseline, every 6 weeks for 24 weeks, then every 12 weeks until disease progression (up to 6 years) | 
| Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of R1507 |  | Predose (0 hours [h]), end of 60-90 minutes infusion (EOI), postdose (2, 24, 72-96 h) in Week 1; predose (0 h) and EOI in Weeks 2, 4, 6, 9; predose (0 h), EOI, postdose (48 h) in Week 12; predose (0 h) in Week 13, at final visit (up to 6 years) | 
| Pharmacokinetics: Clearance (CL) of R1507 |  | Predose (0 h), EOI (infusion over 60-90 minutes), postdose (2, 24, 72-96 h) in Week 1; predose (0 h) and EOI in Weeks 2, 4, 6, 9; predose (0 h), EOI, postdose (48 h) in Week 12; predose (0 h) in Week 13, at final visit (up to 6 years) |