Adipocytic Sarcoma, Ewing's Sarcoma /Peripheral Neuroectodermal Tumor (PNET), Leiomyosarcoma, Rhabdomyosarcoma, Synovial Sarcoma
Conditions
Keywords
Sarcoma, Ewing's sarcoma / peripheral neuroectodermal tumor (PNET);, rhabdomyosarcoma;, leiomyosarcoma;, adipocytic sarcoma, synovial sarcoma
Brief summary
This multicenter study will enroll approximately 185 participants with metastatic or advanced sarcoma, to assess the effectiveness and safety of IMC-A12 monotherapy for this indication. Participants will be stratified into five tiers according to diagnosis: 1. Ewing's sarcoma/peripheral neuroectodermal tumor (PNET) 2. rhabdomyosarcoma 3. leiomyosarcoma 4. adipocytic sarcoma 5. synovial sarcoma. A total of 85 participants will be enrolled initially, 17 in each tier. Participants will receive single agent IMC-A12 every 2 weeks. A treatment cycle will be defined as 6 weeks, with radiological evaluation at every cycle. Safety and response in the initial 17 participants in each tier will be used to determine whether to extend enrollment to the target total of 37 participants per tier.
Detailed description
The purpose of this study is to determine the progression-free survival (PFS) rate assessed 12 weeks after the initiation of IMC-A12 monotherapy, administered every 2 weeks to participants with previously-treated, advanced or metastatic soft tissue and Ewing's sarcoma/PNET.
Interventions
BIOLOGICALIMC-A12 (cixutumumab)
Ewing's Sarcoma/PNET 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every two weeks. A treatment cycle will be defined as 6 weeks, with radiological evaluation at every cycle.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: * Histologically or cytologically-confirmed sarcoma of one of the following histologies: (1) Ewing's sarcoma / PNET; (2) rhabdomyosarcoma; (3) leiomyosarcoma; (4) adipocytic sarcoma; or (5) synovial sarcoma * Has measurable disease, at least one lesion ≥ 2 centimeters (cm) on conventional measurement techniques or ≥ 1 cm on spiral computed tomography (CT) scan * Has at least one measurable lesion located outside of a previously irradiated area * Has radiographic documentation of disease progression within 6 months prior to study entry * Has relapsed, refractory, and/or metastatic disease, incurable by surgery, radiotherapy, or other conventional systemic therapy * Been considered ineligible for systemic chemotherapy or received at least one previous regimen for relapsed, refractory, and/or metastatic disease * Adequate hematologic function * Has adequate hepatic function * Has adequate coagulation function * Has adequate renal function * Has fasting serum glucose \< 120 milligrams per deciliter (mg/dL) or below the upper limit of normal (ULN) * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation Exclusion: * Has uncontrolled brain or leptomeningeal metastases * Not recovered to grade ≤ 1 from adverse events due to agents administered more than 3 weeks prior to study entry * Is receiving any other investigational agent(s) * Major surgery, hormonal therapy (other than replacement), chemotherapy, radiotherapy, or any form of investigational therapy within 3 weeks prior to enrollment * History of treatment with other agents targeting the insulin-like growth factor-I receptor (IGF-IR) * History of allergic reactions attributed to compounds of chemical or biologic composition similar to that of IMC-A12 * Has poorly controlled diabetes mellitus * Is receiving therapy with immunosuppressive agents * Is pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | Baseline to Disease Progression or Death Due to Any Cause Up To 12 Weeks | PFS at 12 weeks was reported by disease condition and defined as the percentage of participants who have neither experienced disease progression nor died at 12 weeks after the date of first dose. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. Progressive Disease (PD) was defined as having at least a 20% increase in sum of the longest diameter of target lesions or the appearance of new lesions. Percentage of participants is calculated as the total number of participants with PFS at 12 weeks divided by the total number of participants treated then multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | Baseline to measured PD (up to 105.4 weeks) | ORR was reported by disease condition and defined as the percentage of participants achieving either CR or PR. Response was defined using RECIST, version 1.0 criteria. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. Percentage of participants is calculated as a total number of participants with CR or PR divided by the total number of participants treated then multiplied by 100. |
| Time to Response | Baseline to first evidence of confirmed CR or PR (up to 105.4 weeks) | — |
| Duration of Response | Date of first response to the date of progression or death due to any cause (up to 105.4 weeks) | — |
| Progression-Free Survival (PFS) | Baseline to measured PD (up to 105.4 weeks) | PFS was reported by disease condition and defined as the interval from the date of first dose until disease progression or death whichever occurred earlier. Response was defined using RECIST, version 1.0 criteria. PD was defined as having at least a 20% increase in sum of the longest diameter of target lesions or the appearance of new lesions. PFS was censored at the date of the last objective progression-free disease assessment for participants who did not experience disease progression or death. |
| Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | Baseline through study completion (up to 105.4 weeks) | CBR was reported by disease condition. Response was defined using RECIST, version 1.0 criteria. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. Stable Disease (SD) was defined as small changes that did not meet the above criteria. Percentage of participants with best overall response is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated then multiplied by 100. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths | Baseline through study completion (up to 112.9 weeks) | TEAEs were defined as serious and other non-serious AEs that occurred or worsened after study treatment (regardless of causality). Data presented are the number of participants who experienced TEAEs, serious TEAEs, and deaths during the study including the 30-day follow-up. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Event module. |
| Serum Anti-IMC-A12 Antibody Assessment (Immunogenicity) | 30-day safety follow-up | — |
| Overall Survival (OS) | Baseline to date of death from any cause (up to 112.9 weeks) | OS was reported by disease condition and defined as the duration from the date of enrollment to the date of death from any cause. For participants who were alive, OS was censored at the date of last follow-up visit or at the date of last contact. |
Countries
Belgium, France, Germany, Netherlands, Poland, Spain, United States
Participant flow
Pre-assignment details
Presented are the reasons the participants discontinued from study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population IMC-A12 (cixutumumab) 10 mg/kg dose administered as intravenous infusion over a period of 1 hour once every 2 weeks (6-week cycle). Participants were stratified into 5 arms according to the disease condition: Ewing's Sarcoma/PNET, rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, and synovial sarcoma.
Treatment was continued until there was evidence of disease progression, unacceptable toxicity, or withdrawal of consent. | 111 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Progressive Disease Before Treatment | 2 |
| Overall Study | Subject Non-compliance | 1 |
| Overall Study | Withdrawal of Consent | 2 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 47.0 years FULL_RANGE 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 102 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Black | 5 Participants |
| Race/Ethnicity, Customized Other | 5 Participants |
| Race/Ethnicity, Customized White | 101 Participants |
| Region of Enrollment Belgium | 23 Participants |
| Region of Enrollment France | 15 Participants |
| Region of Enrollment Germany | 1 Participants |
| Region of Enrollment Netherlands | 6 Participants |
| Region of Enrollment Poland | 7 Participants |
| Region of Enrollment Spain | 9 Participants |
| Region of Enrollment United States | 50 Participants |
| Sex: Female, Male Female | 54 Participants |
| Sex: Female, Male Male | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 97 / 111 |
| serious Total, serious adverse events | 56 / 111 |
Outcome results
Primary
Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks
PFS at 12 weeks was reported by disease condition and defined as the percentage of participants who have neither experienced disease progression nor died at 12 weeks after the date of first dose. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. Progressive Disease (PD) was defined as having at least a 20% increase in sum of the longest diameter of target lesions or the appearance of new lesions. Percentage of participants is calculated as the total number of participants with PFS at 12 weeks divided by the total number of participants treated then multiplied by 100.
Time frame: Baseline to Disease Progression or Death Due to Any Cause Up To 12 Weeks
Population: Enrolled participants who received any quantity of IMC-A12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing's Sarcoma/PNET | Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | 27.3 percentage of participants |
| Rhabdomyosarcoma | Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | 12.5 percentage of participants |
| Leiomyosarcoma | Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | 25.4 percentage of participants |
| Adipocytic Sarcoma | Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | 50.0 percentage of participants |
| Synovial Sarcoma | Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | 21.4 percentage of participants |
| Total | Percentage of Participants With Progression-Free Survival (PFS) at 12 Weeks | 31.9 percentage of participants |
Secondary
Duration of Response
Time frame: Date of first response to the date of progression or death due to any cause (up to 105.4 weeks)
Population: Zero participants analyzed. Duration to Response for CR and PR data was not collected for analysis per study report.
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths
TEAEs were defined as serious and other non-serious AEs that occurred or worsened after study treatment (regardless of causality). Data presented are the number of participants who experienced TEAEs, serious TEAEs, and deaths during the study including the 30-day follow-up. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Event module.
Time frame: Baseline through study completion (up to 112.9 weeks)
Population: Enrolled participants who received any quantity of IMC-A12.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ewing's Sarcoma/PNET | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths | Any TEAE | 108 Participants |
| Ewing's Sarcoma/PNET | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths | Serious TEAE | 56 Participants |
| Ewing's Sarcoma/PNET | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths | Deaths Due to Disease Progression | 10 Participants |
| Ewing's Sarcoma/PNET | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths | Death Due to Other Cause | 1 Participants |
| Ewing's Sarcoma/PNET | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Deaths | Death Due to AE | 1 Participants |
Secondary
Overall Survival (OS)
OS was reported by disease condition and defined as the duration from the date of enrollment to the date of death from any cause. For participants who were alive, OS was censored at the date of last follow-up visit or at the date of last contact.
Time frame: Baseline to date of death from any cause (up to 112.9 weeks)
Population: Enrolled participants who received any quantity of IMC-A12. Five (5) participants in Ewing's sarcoma/PNET, 4 participants in rhabdomyosarcoma, 12 participants in leiomyosarcoma, 11 participants in adipocytic sarcoma, and 5 participants in synovial sarcoma groups were censored for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ewing's Sarcoma/PNET | Overall Survival (OS) | 24.1 weeks |
| Rhabdomyosarcoma | Overall Survival (OS) | 23.6 weeks |
| Leiomyosarcoma | Overall Survival (OS) | NA weeks |
| Adipocytic Sarcoma | Overall Survival (OS) | 46.4 weeks |
| Synovial Sarcoma | Overall Survival (OS) | 56.3 weeks |
| Total | Overall Survival (OS) | 38.4 weeks |
Secondary
Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)]
CBR was reported by disease condition. Response was defined using RECIST, version 1.0 criteria. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. Stable Disease (SD) was defined as small changes that did not meet the above criteria. Percentage of participants with best overall response is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated then multiplied by 100.
Time frame: Baseline through study completion (up to 105.4 weeks)
Population: Enrolled participants who received any quantity of IMC-A12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing's Sarcoma/PNET | Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | 33.3 percentage of participants |
| Rhabdomyosarcoma | Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | 23.5 percentage of participants |
| Leiomyosarcoma | Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | 40.9 percentage of participants |
| Adipocytic Sarcoma | Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | 56.8 percentage of participants |
| Synovial Sarcoma | Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | 35.3 percentage of participants |
| Total | Percentage of Participants With Best Overall Response [Clinical Benefit Rate (CBR)] | 41.4 percentage of participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
ORR was reported by disease condition and defined as the percentage of participants achieving either CR or PR. Response was defined using RECIST, version 1.0 criteria. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. Percentage of participants is calculated as a total number of participants with CR or PR divided by the total number of participants treated then multiplied by 100.
Time frame: Baseline to measured PD (up to 105.4 weeks)
Population: Enrolled participants who received any quantity of IMC-A12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing's Sarcoma/PNET | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 5.6 percentage of participants |
| Rhabdomyosarcoma | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0 percentage of participants |
| Leiomyosarcoma | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0 percentage of participants |
| Adipocytic Sarcoma | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 2.7 percentage of participants |
| Synovial Sarcoma | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0 percentage of participants |
| Total | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 1.8 percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS was reported by disease condition and defined as the interval from the date of first dose until disease progression or death whichever occurred earlier. Response was defined using RECIST, version 1.0 criteria. PD was defined as having at least a 20% increase in sum of the longest diameter of target lesions or the appearance of new lesions. PFS was censored at the date of the last objective progression-free disease assessment for participants who did not experience disease progression or death.
Time frame: Baseline to measured PD (up to 105.4 weeks)
Population: Enrolled participants who received any quantity of IMC-A12. Three (3) participants in Ewing's sarcoma/PNET, 1 participant in rhabdomyosarcoma, 4 participants in leiomyosarcoma, 6 participants in adipocytic sarcoma, and 3 participants in synovial sarcoma groups were censored for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ewing's Sarcoma/PNET | Progression-Free Survival (PFS) | 6.4 weeks |
| Rhabdomyosarcoma | Progression-Free Survival (PFS) | 6.1 weeks |
| Leiomyosarcoma | Progression-Free Survival (PFS) | 6.0 weeks |
| Adipocytic Sarcoma | Progression-Free Survival (PFS) | 12.1 weeks |
| Synovial Sarcoma | Progression-Free Survival (PFS) | 6.4 weeks |
| Total | Progression-Free Survival (PFS) | 6.7 weeks |
Secondary
Serum Anti-IMC-A12 Antibody Assessment (Immunogenicity)
Time frame: 30-day safety follow-up
Population: Zero participants analyzed. Analysis was not performed due to lack of available assay.
Secondary
Time to Response
Time frame: Baseline to first evidence of confirmed CR or PR (up to 105.4 weeks)
Population: Zero participants analyzed. Time to Response for CR and PR data was not collected for analysis per study report.