A Study of Olaratumab and Doxorubicin in Participants With Advanced Soft Tissue Sarcoma

Study Overview
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Brief Summary
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The purpose of this study is to assess how the body handles olaratumab when it is given with another drug called doxorubicin. The safety and tolerability of these drugs will be studied. Each participant will complete two 21-day cycles in a fixed order. Participants who complete Cycle 2 may continue to receive olaratumab + doxorubicin for an additional six 21-day cycles and then may receive olaratumab alone until discontinuation criteria are met. Screening is required within 21 days prior to first dose. Part B was added in October, 2015 to assess how the body handles a higher dose of olaratumab when given with doxorubicin. Participants may only enroll in one part.

Official Title
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An Open-Label Study to Evaluate the Pharmacokinetics of Doxorubicin Following the Concomitant Intravenous Administration of Olaratumab (IMC-3G3) to Patients With Advanced Soft Tissue Sarcoma

Conditions
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Sarcoma, Soft Tissue

Intervention / Treatment
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* Drug: Olaratumab
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histological or cytological evidence of a diagnosis of soft tissue sarcoma (STS) that is advanced and/or metastatic Have the presence of measurable and/or nonmeasurable disease Have given written informed consent prior to any study-specific procedures Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale Have discontinued previous treatments for cancer and recovered from the acute effects of therapy Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures Exclusion Criteria: Have received treatment within 28 days of the initial dose of study drug with an investigational product or non-approved use of a drug or device for noncancer indications Have received prior treatment with doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones Have active central nervous system (CNS) metastasis. Participants with treated CNS metastases are eligible for this study if they are not currently receiving corticosteroids Have unstable hepatic disease with a grade equal to or greater than Child-Pugh B Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis Have a history of another primary cancer, with the exception of a) curatively resected nonmelanoma 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 Have a history of chronic heart failure or left ventricular dysfunction Have a resting heart rate of less than (<)50 beats per minute (bpm) or greater than (>)100 bpm Have a history of radiation therapy involving the mediastinal/pericardial area. Previous radiation therapy is allowed but must not have included whole pelvis radiation

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Doxorubicin Alone: On Cycle 1, Day 1, participants received 75 milligram/square meter (mg/m2) of doxorubicin intravenously (IV). Olaratumab Alone: On Cycle 1, Day 10, participants received 15 milligram/kilogram (mg/kg) of olaratumab IV. Olaratumab + Doxorubicin: For Cycles 2 to 8, participants received 15 mg/kg of olaratumab on Days 1 and 8 of each 21-day cycle, IV and 75 mg/m2 of doxorubicin IV immediately following the completion of the olaratumab infusion. Participants continued to receive olaratumab monotherapy (on days 1 and 8 of each cycle) for Cycle 9 onward, until discontinuation criteria are met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;Drug: Doxorubicin<br>* Administered IV<br>|
| Experimental: Part B<br>Doxorubicin Alone: On Cycle 1, Day 1, participants received doxorubicin 75 mg/m2 IV Olaratumab Alone: On Cycle 1, Day 10, participants received 20 mg/kg of olaratumab IV. Olaratumab + Doxorubicin: For Cycle 2, participants received 20 mg of olaratumab on Days 1 and 8 of each 21-day cycle, IV. On Day 1 of Cycle 2, doxorubicin 75 mg/m2 was administered IV immediately following the completion of the olaratumab infusion. For Cycles 3 - 8, Day 1 and 8, olaratumab 15 mg/kg was administered and on Day 1 doxorubicin 75 mg/m2 was administered IV immediately following the completion of the olaratumab infusion. Participants continued to receive olaratumab monotherapy (on days 1 and 8 of each cycle) for Cycle 9 onwards, until discontinuation criteria are met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;Drug: Doxorubicin<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Area Under The Concentration Curve Zero to Infinity (AUC[0-∞]) Doxorubicin |  | Cycle(C)1 and (C)2, Day(D)1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hours (Hrs) Post dose | 
| PK: Maximum Concentration (Cmax) Doxorubicin |  | C1 and C2, D1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hrs Post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK:Time of Maximum Observed Concentration (Tmax) Doxorubicin |  | C1 and C2, D1: Predose, 0.5, 1, 2, 4, 8, 24, 48, 72, 96 Hrs Post dose | 
| PK: AUC Zero to Time t, Where t is the Last Time Point (0-tLast) Olaratumab | PK: AUC (0-tLast) with a measurable concentration. PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin. | C1 D10: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose | 
| PK: Cmax Olaratumab | PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin. | C1 D10:Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose | 
| PK: Tmax Olaratumab | Tmax times are relative to the start of the approximately 60-minute IV infusion of olaratumab. PK data includes Part A Olaratumab alone and Part B Olaratumab + Doxorubicin. | C1 D10: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose; C2 D1: Predose, 0, 1, 4, 24, 48, 72, 96 Hrs Post dose | 
| Percentage of Participants With Olaratumab Antibodies | The formation of anti-drug antibodies (ADA) was assessed using validated ELISAs, following a 4-tier approach. Both the ADA screening assay and the neutralizing antibody assay were validated in accordance with the US Food and Drug Administration (FDA) Guidance for Industry. Participants who had positive samples for treatment emergence due to being <4-fold difference from baseline or occurred prior to drug exposure are reported. | Preinfusion on Day 1 of Cycles 1 through 3 and Preinfusion on Day 1 of Every Second Cycle Thereafter, Up to 30-Day Follow Up | 
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | The percentage of participants with a best overall response achieving CR or PR (ORR) was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter of target lesions. The methodology for the confidence interval calculation is the exact F method. | Baseline to Measured Progressive Disease, Study Discontinuation or Death (Up to 24 Months) |