A Study of Olaratumab in Soft Tissue Sarcoma

Study Overview
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Brief Summary
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The main purpose of this study is to gather information about the use of an investigational drug called olaratumab with a drug for soft tissue sarcoma called doxorubicin.

Official Title
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A Phase 1b/2, With Phase 2 Randomized, Study Evaluating the Efficacy of Doxorubicin With or Without a Human Anti-PDGFRα Monoclonal Antibody (IMC-3G3) in the Treatment of Advanced Soft Tissue Sarcoma

Conditions
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Sarcoma, Soft Tissue

Intervention / Treatment
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* Biological: Olaratumab
* Drug: doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has histologically- or cytologically-confirmed malignant soft tissue sarcoma The participant has advanced soft tissue sarcoma (STS), not amenable to treatment with surgery or radiotherapy The participant's Eastern Cooperative Oncology Group (ECOG) performance status is 0-2 The participant has available tumor tissue from either the primary or metastatic tumor for determination of PDGFRα expression The participant has adequate hematologic function as defined by an absolute neutrophil count (ANC) ≥ 1500 μL, hemoglobin ≥ 9.0 g/dL, and a platelet count of 100,000/μL obtained within 2 weeks prior to study entry The participant has adequate hepatic function as defined by a total bilirubin ≤ 1.5 mg/dL, and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times the upper limit of normal (ULN) The participant has adequate renal function as defined by serum creatinine ≤ 1.5 × the institutional ULN. If creatinine is above the ULN, the participant's creatinine clearance is ≥ 45 mL/min Because the teratogenicity of Olaratumab is not known, women of childbearing potential (WOCBP) and sexually active males 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 Criteria: The participant has histologically- or cytologically-confirmed Kaposi's sarcoma The participant has untreated central nervous system metastases The participant received prior treatment with doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones (ie, mitoxantrone) The participant received prior radiation therapy to the mediastinal/pericardial area The participant has a history of another primary cancer, with the exception of a) curatively resected nonmelanomatous skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years prior to study entry The participant is receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemo-embolization, targeted therapy, or an investigational agent The participant has an elective or a planned major surgery to be performed during the course of the study The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, requiring parenteral antibiotics, symptomatic congestive heart failure, severe myocardial insufficiency, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements The participant has unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction 6 months prior to study entry The participant has known immunodeficiency virus (HIV) infection The participant, if female, is pregnant or lactating The participant has a known allergy to any of the treatment components

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Olaratumab + doxorubicin<br>All cycles are 21 days. Cycles 1-8: Olaratumab 15 mg/kg on days 1+8, and doxorubicin 75 mg/m2 on day 1 All subsequent cycles until progression: Olaratumab 15 mg/kg on days 1+8 | Biological: Olaratumab<br>* Olaratumab 15 mg/kg by intravenous transfusion (I.V.) on days 1+8 of a 21-day cycle<br>* Other names: IMC-3G3;Drug: doxorubicin<br>* Doxorubicin 75 mg/m2 by intravenous injection on day 1 of the 21-day cycle.<br>|
| Experimental: Phase 2: Olaratumab and doxorubicin<br>All cycles are 21 days. Cycles 1-8: Olaratumab 15 mg/kg on days 1+8, and doxorubicin 75 mg/m2 on day 1 All subsequent cycles until progression: Olaratumab 15 mg/kg on days 1+8 | Biological: Olaratumab<br>* Olaratumab 15 mg/kg by intravenous transfusion (I.V.) on days 1+8 of a 21-day cycle<br>* Other names: IMC-3G3;Drug: doxorubicin<br>* Doxorubicin 75 mg/m2 by intravenous injection on day 1 of the 21-day cycle.<br>|
| Active Comparator: Phase 2: Doxorubicin: Optional Olaratumab After Progression<br>All cycles are 21 days. Cycles 1-8: doxorubicin 75 mg/m2 on day 1 until disease progression. At disease progression: optional Olaratumab 15 mg/kg on days 1+8 until further progression. | Drug: doxorubicin<br>* Doxorubicin 75 mg/m2 by intravenous injection on day 1 of the 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is measured from randomization until the first radiographic documentation of progression of disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) or death from any cause. Participants who died without PD was considered to have progressed on the day of death. The following censoring rules applied: If no radiologic assessment at baseline or post baseline, participant was censored at the date of randomization. Participants were censored at the day of their last tumor assessment if no PD and were lost to follow up; If death or PD occurred after 2 or more consecutive missing radiographic visits, censoring occurred at the date of the last adequate radiographic visit. If participant started new treatment before PD, the participant was censored at the date of last tumor assessment prior to new therapy. If treatment was discontinued for reasons other than PD and no further assessment, censoring occurred at last tumor assessment. | Randomization Until the First Radiographic Documentation of Objective Progression (Up to 29 Months) | 
| Number of Participants With Treatment Related Adverse Events (TEAE), Adverse Events (AE) or Serious Adverse Events (SAE) for Safety for the Phase 1b Portion of the Study | All Phase 1b participants who experienced at least 1 TEAE in the Phase 1b portion of the study. Adverse Event with missing relationship to study is counted as related. A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module. | Baseline Up to 30 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With AEs and SAEs for Phase 2 Portion | A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module. | Baseline, Up to 30 Months | 
| Overall Survival (OS) | OS was defined as the date of randomization to the date of death from any cause. Reasons for censoring OS were that participant was known to be alive, participant was lost to follow up during the study or participant withdrew consent to follow up. | Randomization to the Date of Death From Any Cause (Up To 47 Months) | 
| Percentage of Participants With Objective Response (Objective Response Rate) | Objective Response Rate (ORR) is confirmed best overall tumor response of CR or PR. According to RECIST v1.1, PR defined as a >30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD; CR was defined as the disappearance of all target and non-target lesions. Percentage of participants was calculated as: total number of participants with a best tumor response of PR or CR among participants counted in the denominator/total number of participants treated with any amount of study drug, who has a complete radiographic assessment at baseline, and who has at least 1 complete radiographic assessment at postbaseline x 100%. | Randomization Until Progressive Disease (Up to 30 Months) | 
| Percentage of Participants Who Are Progression-Free (PFS) at 3 Months | (PFS) rate is defined as the percentage of participants that are alive and progression-free 3 months after randomization. PFS is measured from randomization until the first radiographic progressive disease as defined by RECIST (version 1.1) or death from any cause. Participants who died without PD were considered to have progressed on the day of death. Censoring applied: If no radiologic assessment at baseline or post baseline, participant was censored at the date of randomization or the day of their last tumor assessment if no PD and were lost to follow up; If death or PD occurred after 2 or more consecutive missing radiographic visits, censoring occurred at the date of the last radiographic visit. If participant started new treatment before PD, participant was censored at the date of last tumor assessment prior to new therapy. If treatment was discontinued for reasons other than PD and no further assessment, censoring occurred at last tumor assessment. | Randomization Until First Radiographic PD or Death from Any Cause (Up to 3 Months) | 
| Pharmacokinetic (PK) Maximum Concentration (Cmax) Cycle 1 Day 1, Cycle 3 Day 1 of Olaratumab |  | Cycle 1 Day 1: Preinfusion, End of Infusion,1hr,48hr,72hr,168 hr Post infusion; Cycle 3 Day 1:Preinfusion, End of Infusion,1hr,24hr,48hr,72hr,168hr Post Infusion | 
| PK: Minimum Concentration (Cmin) Cycle 1 Day 8, Cycle 3 Day 8 of Olaratumab |  | Cycle 1 Day 8: Preinfusion, 1hr,72hr,168hr Post Infusion; Cycle 3 Day 8: Preinfusion,1hr, 24hr,72hr,168hr Post Infusion | 
| PK: Area Under Concentration Curve Versus Time (AUCτ) Cycle 1 Day 8, Cycle 3 Day 8 of Olaratumab | AUCτ = area under the concentration versus time curve during one dosing interval with a measurable concentration. | Cycle 1 Day 8:Preinfusion,1hr,72hr,168hr Post Infusion; Cycle 3 Day 8: Preinfusion,1hr,24hr,72hr,168hr Post Infusion | 
| PK: Half-Life (T1/2) Cycle 1 Day 8, Cycle 3 Day 8 of Olaratumab |  | Cycle 1 Day 8:Preinfusion,1hr,72hr,168hr Post Infusion; Cycle 3 Day 8: Preinfusion,1hr,24hr,72hr,168hr Post Infusion | 
| Percentage of Participants With Anti-Olaratumab Antibody Assessment | Participants with Treatment Emergent (TE) anti-olaratumab 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. | Baseline, Up to 30 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcoma, Soft Tissue, Advanced Soft Tissue Sarcoma