A Study of Olaratumab (LY3012207), Doxorubicin, and Ifosfamide in Participants With Advanced or Metastatic Soft Tissue Sarcoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of ifosfamide when added to the combination regimen of olaratumab and doxorubicin in participants with advanced or metastatic soft tissue sarcoma (STS).

Official Title
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A Phase 1b Study of Olaratumab, Doxorubicin and Ifosfamide in the Treatment of Patients With Advanced or Metastatic Soft Tissue Sarcoma

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Olaratumab
* Drug: Doxorubicin
* Drug: Ifosfamide
* Drug: Mesna


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a histological diagnosis of advanced STS (by local pathology review), for which treatment with doxorubicin, ifosfamide and mesna is deemed appropriate by the investigator. Have measurable or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Have adequate hematologic, organ and coagulation function within 2 weeks (14 days) prior to enrollment. Have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group scale. Have received no prior lines of systemic therapy and are suitable to receive doxorubicin, ifosfamide and mesna. All previous anticancer treatments must have completed ≥3 weeks (21 days) prior to the first dose of study treatment. Have left ventricular ejection fraction (LVEF) ≥50% assessed within 28 days prior to enrollment. Have resolution of Adverse Events (AEs), with the exception of alopecia, and of all clinically significant toxic effects of prior locoregional therapy, surgery or radiotherapy to ≤Grade 1, by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0. Have sufficient available material from archived formalin-fixed paraffin-embedded tumor tissue for biomarker-related studies. If such tissue is not available, a newly obtained core or excisional biopsy of a tumor lesion must be performed. If male, must be sterile or agree to use an effective method of contraception or a highly effective method of contraception during the study and for at least 12 weeks following the last dose of study treatment. If female and of child-bearing potential, must: have a negative serum pregnancy test at the time of enrollment, have a negative urine pregnancy test within 24 hours prior to the first dose of study treatment, and agree to use a highly effective method of contraception during the study and for 3 months following the last dose of study treatment. Have a life expectancy of at least 3 months, in the opinion of the investigator. Exclusion Criteria: Are currently enrolled in a clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. Have participated within the past 30 days in a clinical trial involving an investigational product. If the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed. Have previously completed or withdrawn from any study investigating olaratumab. Have received prior treatment with olaratumab, doxorubicin, or ifosfamide, or have participated in other trials investigating olaratumab. Have received prior radiotherapy of the mediastinal/pericardial area or whole pelvis radiation. Have known urinary outflow obstruction, or inflammation of the urinary bladder (cystitis). Are diagnosed with gastrointestinal stromal tumor or Kaposi sarcoma. Have active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment. Participants with a history of CNS metastasis (previously treated with curative intent [for example, stereotactic radiation or surgery]) that has 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 a history of another primary malignancy, with the exception of: curatively treated non-melanomatous skin cancer curatively treated cervical carcinoma in situ Have an active fungal, bacterial and/or known viral infection including human immunodeficiency virus or viral (A, B, or C) hepatitis (screening is not required). Have Grade 3 or 4 peripheral neuropathy per NCI-CTCAE Version 4.0. Have a serious cardiac condition. Have a resting heart rate of >100 beats per minute (bpm). Have a Fridericia's QT corrected interval (QTcF) interval of >450 milliseconds (msec) for males and >470 msec for females on screening electrocardiogram (ECG) utilizing Fridericia's correction. Have uncontrolled intercurrent illness including, but not limited to, an ongoing/active infection requiring parenteral antibiotics. Have a psychiatric illness/social situation that would limit compliance with study requirements. Have electively planned or will require major surgery during the course of the study. Are females who are 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaratumab + Doxorubicin + Ifosfamide + Mesna<br>Olaratumab 15 milligrams per kilogram (mg/kg) on Days 1 and 8 of a 21-day cycle, in combination with doxorubicin and ifosfamide was administered. When the safety of the 15-mg/kg dose of olaratumab was established, a 20-mg/kg loading dose cycle of olaratumab on Days 1 and 8 of a 21-day cycle in Cycle 1 only, followed by 15 mg/kg on Days 1 and 8 of subsequent cycles in combination with doxorubicin and ifosfamide plus mesna, was administered. | Drug: Olaratumab<br>* Administered IV<br>* Other names: LY3012207;Drug: Doxorubicin<br>* Administered IV<br>Drug: Ifosfamide<br>* Administered IV<br>Drug: Mesna<br>* Administered per standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Olaratumab Dose Limiting Toxicities (DLTs) | A Dose Limiting Toxicity is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfills any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: Grade 3 or 4 febrile neutropenia, or sepsis., or Grade 4 neutropenia lasting 7 days or longer. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage. Nonhematologic Grade ≥3 toxicity, except for toxicities (such as nausea, vomiting, transient electrolyte abnormalities, or diarrhoea) that can be controlled with optimal medical management within 48 hours or clinically non-significant laboratory abnormalities. | Cycle 1 (Up To 24 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | PK: Cmax of olaratumab. | Cycle 1 - Day 1 (predose, end of infusion, 2 hours post olaratumab (olara), 6 hours post olara, 24 hours post olara, 72 hours post olara), Day 8 (predose, end of infusion, 2 hours post-olara, 6 hours post olara, 48 hours post olara, 168 hours post olara) | 
| PK: Maximum Serum Concentration (Cmax,ss) of Olaratumab at Steady-state | PK: Cmax of olaratumab at steady-state. | Cycle 3 - Day 1 (predose, end of infusion, 2 hours post olara, 5 hours post olara, 24 hours post olara, 72 hours post olara), Day 8 (predose, end of infusion, 2 hours post-olara, 5 hours post olara, 48 hours post olara, 168 hours post olara) | 
| PK: Trough Serum Concentration (Cmin) | PK: Cmin of olaratumab. | Cycle 1 - Day 1 (predose, end of infusion, 2 hours post olaratumab (olara), 6 hours post olara, 24 hours post olara, 72 hours post olara), Day 8 (predose, end of infusion, 2 hours post-olara, 6 hours post olara, 48 hours post olara, 168 hours post olara) | 
| PK: Trough Serum Concentration (Cmin,ss) of Olaratumab at Steady-state | PK: Cmin of olaratumab at steady-state. | Cycle 3 - Day 1 (predose, end of infusion, 2 hours post olara, 5 hours post olara, 24 hours post olara, 72 hours post olara), Day 8 (predose, end of infusion, 2 hours post-olara, 5 hours post olara, 48 hours post olara, 168 hours post olara) | 
| Number of Participants With Anti-Olaratumab Antibodies | Participants with treatment-emergent anti-drug antibody (TE ADA) positive were 1) a participant with a 4-fold (2 dilutions) increase over a positive baseline antibody titer; or 2) for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. | Baseline through Follow-up (Up To 21 Months) | 
| Objective Response Rate (ORR): Number of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) | Objective response rate is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. | Baseline up to Short-Term Follow-Up Period (Up To 21 Months) | 
| Progression Free Survival (PFS) | Progression-free survival time was measured from randomization until the date of objective progression as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1), or death from any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Participants who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of randomization if no post-baseline radiographic assessment is available. | Baseline to Objective Disease Progression or Death Due to Any Cause (Up To 21 Months) | 
| Duration of Response (DoR) | Duration of response is defined as the time from the date measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective progression is observed, per RECIST 1.1, or the date of death from any cause in the absence of objectively determined disease progression or recurrence. Participants known to be alive and without disease progression will be censored at the time of the last adequate tumor assessment. | Date of Complete Response (CR) or Partial Response (PR) to Objective Disease Progression or Death Due to Any Cause (Up To 21 Months) | 
| Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) | Disease control rate (DCR) is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline until Disease Progression or Death Due to Any Cause (Up To 21 Months) | 
| Overall Survival (OS) | Overall survival is defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact. | Baseline to Date of Death Due to Any Cause (Up To 21 Months) |