A Study of Olaratumab (IMC-3G3) in Previously Treated Participants With Unresectable and/or Metastatic Gastrointestinal Stromal Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the tumor response of stable disease (SD), partial response (PR), or complete response (CR) [according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1 criteria)] at 12 weeks in participants with Gastrointestinal Stromal Tumors (GIST) harboring platelet-derived growth factor receptor alpha (PDGFRα) mutations and patients with GIST not harboring PDGFRα mutations.

Official Title
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A Phase 2 Study of a Human Anti-PDGFRα Monoclonal Antibody (IMC-3G3) in Previously Treated Patients With Unresectable and/or Metastatic Gastrointestinal Stromal Tumors (GIST)

Conditions
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Gastrointestinal Stromal Tumor (GIST)

Intervention / Treatment
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* Biological: Olaratumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has histologically or cytologically confirmed, unresectable and/or metastatic GIST Participant has measurable disease Participant has documented objective progression following, or intolerance to, treatment with both imatinib and sunitinib Participant's Eastern Cooperative Oncology Group (ECOG) performance status (PS) is 0 to 2 Participant has either: prior results from growth factor receptor associated with tyrosine kinase activity (KIT) and PDGFRα mutation analysis that meet analytical criteria as defined for the on-study analysis of these mutations and tumor tissue (from either primary or metastatic tumor) that can be submitted for analysis within 30 days after the first dose of study therapy; or if prior results from KIT and PDGFRα mutation analysis are not available or do not meet analytical criteria as above, then tumor tissue (from either primary or metastatic tumor) must be submitted for genotype testing at the latest 28 days prior to the first dose of study therapy Participant has adequate hematologic, hepatic, renal and coagulation function Women of childbearing potential and sexually active males must agree to use adequate contraception prior to study and for at least 12 weeks after the last dose of IMC-3G3 Participant has a life expectancy of ≥ 3 months Exclusion Criteria: Participant has untreated central nervous system metastases, and as a result, is clinically unstable with regard to neurologic function Participant has a history of another primary cancer Participant has received any investigational therapy within 14 days prior to registration, or is currently enrolled in any other type of medical research Participant is receiving concurrent treatment with other anticancer therapy Participant has known human immunodeficiency virus (HIV) infection Participant has undergone major surgery within 28 days prior to registration If female, participant is pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: PDGFRα mutation negative<br>Participants with GIST with genotypes that do not have a PDGFRα mutation given 20 milligrams per kilogram (mg/kg) Olaratumab intravenously (IV) every 14 days. | Biological: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;|
| Experimental: PDGFRα mutation positive<br>Participants with GIST with genotypes that have a PDGFRα mutation given 20 mg/kg Olaratumab IV every 14 days. | Biological: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Tumor Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Clinical Benefit Rate) at 12 Weeks | Clinical benefit was defined as CR, PR, or SD using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST, v1.1) criteria. CR: disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 millimeters (mm). PR: ≥30% decrease in sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD: neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. PD: increase ≥20% in sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or appearance of 1 or more new lesions was considered progression. Percentage of participants=(participants with CR+PR+SD/participants in group) *100. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS defined as the duration from date of first dose of study drug until first radiographic documentation of PD using RECIST, v1.1 criteria or death from any cause. PD defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions was progression. Participants who died with no prior PD were considered to have progressed on day of death. Participants who did not progress or were lost to follow-up were censored at date of last radiographic tumor assessment; if no assessment was available censoring was at date of registration. If death or PD occurred after 2 consecutive missing radiographic visits censoring was date of last radiographic visit prior to missed visits. Use of new anticancer therapy prior to PD, censoring was date of last radiographic assessment prior to new therapy. | Baseline to the first date of objectively determined PD or death from any cause up to 35.9 weeks | 
| Percentage of Participants With CR or PR [Radiographic Objective Response Rate (ORR)] | The ORR was the best overall response of CR and PR using RECIST, v1.1 criteria. Participants who did not have a tumor response assessment for any reason were considered nonresponders and were included in the denominator that calculated the response rate. Percentage of participants = (number of participants achieving a response/total of participants treated) * 100. | Baseline up to 35.9 weeks and post study discontinuation 30-day follow-up | 
| Overall Survival (OS) | OS was defined as the time from the date of first dose of study drug to the date of death from any cause. Participants who were alive at the end of the post-study follow-up or were lost to follow-up were censored on the last date the participant was known to be alive. | Date of first dose of study drug to the date of death from any cause up to 57.3 weeks | 
| Number of Participants With Adverse Events (AE) and Participants Who Died | Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs, regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The number of participants who died due to an AE or disease progression are also reported. | Baseline up to 57.3 weeks and 30-day post study-discontinuation follow-up | 
| Percentage of Participants With CR, PR or SD [Disease Control Rate (DCR)] | DCR defined as CR, PR or SD using RECIST v1.1 criteria. CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify PD, taking as reference the smallest sum diameter since the treatment started. PD defined as ≥20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or the appearance of 1 or more new lesions was considered progression. Percentage of participants=(number of participants with CR+PR+SD/number of participants in group) * 100. | Baseline up to 35.9 weeks | 
| Maximum Concentration (Cmax) |  | Day 1 of Cycles 1 and 3 (14-day cycles) | 
| Area Under the Curve (AUC) |  | Day 1 of Cycles 1 and 3 (14-day cycles) | 
| Half Life (t½) |  | Day 1 of Cycles 1 and 3 (14-day cycles) | 
| Clearance (CL) |  | Day 1 of Cycles 1 and 3 (14-day cycles) | 
| Volume of Distribution at Steady State (Vss) |  | Day 1 of Cycles 1 and 3 (14-day cycles) | 
| Percentage of Participants With Human Anti-Olaratumab (IMC-3G3) Antibody Results | Participants with Treatment Emergent (TE) anti-olaratumab (IMC-3G3) antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. | Day 1 of Cycles 1, 3, 6, 12 and 18 prior to infusion (14-day cycles) |