A Study of Olaratumab (LY3012207) in Participants With Soft Tissue Sarcoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate potential biomarkers and method of action, efficacy and safety of olaratumab in participants with soft tissue sarcoma (STS).

Official Title
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A Phase 1b Trial to Assess the Modulation of Biological Markers in Patients With Potentially Resectable Soft Tissue Sarcoma Treated With Olaratumab Monotherapy Followed by Olaratumab Plus Doxorubicin Combination Therapy

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Olaratumab
* Drug: Doxorubicin
* Radiation: External Beam Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a histologically confirmed diagnosis of STS for which olaratumab and doxorubicin would be appropriate therapy. Participants with a diagnosis of Grade 1 liposarcoma are eligible if there is histological or radiographic evidence of evolution to more aggressive disease. Participants with Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded. Participants must have potentially resectable disease (as assessed by the study investigator) and have a primary tumor lesion deemed amenable to serial biopsy. For radiotherapy addendum only: Have a histologically confirmed diagnosis of STS of the extremities, Grade 2 or 3, >5 centimeters, for which olaratumab and radiotherapy would be appropriate therapy. Participants with Kaposi's sarcoma, GIST or myxoid liposarcoma will be excluded. Have consented to undergo mandatory serial peripheral whole blood and tumor tissue sampling. Exclusion Criteria: Have active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment. Participants with a history of a CNS metastasis previously treated with curative intent (for example, stereotactic radiation or surgery) that have not progressed on follow-up imaging, have been asymptomatic for at least 60 days and are not receiving systemic corticosteroids and or/anticonvulsants, are eligible. Participants with signs or symptoms of neurological compromise should have appropriate radiographic imaging performed before enrollment to rule out brain metastasis. Have received prior treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or anthracenediones; the participant has received treatment with olaratumab or has participated in a prior olaratumab trial. For radiotherapy addendum only: Have received previous radiotherapy in the primary tumor lesion and/or prior treatment with olaratumab or has participated in a prior olaratumab trial.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaratumab + Doxorubicin<br>Cycle 1: Olaratumab 20 milligram per kilogram (mg/kg) given intravenously (IV) on Day 1 and Day 8 (21 day cycle). Cycle 2: Olaratumab 20 mg/kg given IV on Day 1 and Day 8 plus doxorubicin 75 mg/m2 given IV on Day 1 (21 day cycle). Cycle 3 through Cycle 7: Olaratumab 15 mg/kg given IV on Day 1 and Day 8 plus doxorubicin 75 mg/m2 given IV on Day 1 (21 day cycles). | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Drug: Doxorubicin<br>* Administered IV<br>|
| Experimental: Olaratumab + Radiotherapy Addendum<br>Olaratumab given IV on Day 1 and Day 8 (21 day cycle) concurrently with radiotherapy. Radiotherapy addendum was not implemented. | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Radiation: External Beam Radiotherapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Enumeration of Circulating Tumor Cells (CTCs) in Whole Blood | Enumeration of CTCs pre- and post- treatment with olaratumab may be a useful biomarker given the predilection for sarcomas to spread hematogenously. | Baseline, End of Cycle 1 (21 days) | 
| Percent Change From Baseline in Gene Expression of Platelet-Derived Growth Factor Receptor Alpha (PGDFRα) and PGDFR Beta (β) in Tumor Tissue | Over-activity of PDGF signaling is associated with the development of certain malignant diseases. Olaratumab is an IgG1 antagonist of PDGFRα. | Baseline, End of Cycle 1 (21 days) | 
| Percent Change From Baseline in Gene Expression of PDGF A, PDGF B, PDGF C, and PDGF-D Canonical Ligands in Tumor Tissue | PDGF A, PDGF B, PDGF C, and PDGF D are platelet-derived growth factor canonical ligands associated with activation of PDGFR α and β. | Baseline, End of Cycle 1 (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression-free survival (PFS) is defined as the time from the date of first study dose to the first date of radiologic disease progression or death due to any cause. Progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression. | Baseline to Objective Progression or Death from Any Cause (Up to 18 Months) | 
| Objective Response Rate (ORR): Percent of Participants With Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) | Overall Response Rate (ORR) is defined as the percentage of participants achieving a best overall response of either Complete Response (CR) or Partial Response (PR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as a disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to <10 mm and normalization of tumor marker results; PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. The best overall response is the best response from the start of the treatment until progressive disease (PD)/recurrence. | Baseline to Measured Progressive Disease (Up to 18 Months) | 
| Disease Control Rate (DCR): Percent of Participants Who Exhibit Stable Disease (SD), CR or PR | Disease control rate (DCR) is defined as the percentage of participants achieving a best overall response of CR, PR, or SD as determined by RECIST 1.1. CR is defined as a disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to <10 mm and normalization of tumor marker results; PR is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters; SD is defined as neither sufficient shrinking to qualify as PR nor sufficient increase to qualify for PD. Participants who do not have any post-baseline tumor response assessments for any reason are considered non-responders and are included in the denominator when calculating the response rate. | Baseline to Measured Progressive Disease (Up to 18 Months) | 
| Percentage of Participants With Resectable Tumors (Resectability Rate) | Resectability rate is obtained when the total number of participants with resectable tumors is divided by the total number of participants. Resectability of a tumor is determined by the surgeon and multi-disciplinary team and dependent on tumor stage and the participants coexisting medical conditions. | Cycle 1 through Cycle 7 (Up to 6 Months) | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab Monotherapy | Summary of Cmax of olaratumab monotherapy on Cycle 1 Day 1 and Day 8 | Cycle 1 Days 1 and 8: Predose; 5 minutes(m) post-infusion | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Olaratumab | Cmax of olaratumab Cycles 2 and 3 Day 1 and 8 of a 21-day cycle. | Cycle 2 Day 1: Predose, 5 minutes(m) post-infusion, 24 hours(h), 96h; Day 8:Predose, 5 m, and 24h, 48h, 96h, and 240h postdose; Cycle 3 Day 1 and Day 8: Predose and 5m post-infusion | 
| Number of Participants With Anti-Olaratumab Antibodies | A participant is counted as positive if they had at least one anti-olaratumab antibody positive result during the study. | Predose Cycle 1 Day 1 through Follow-Up (Up to 8 Months) |