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

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and efficacy of two anti-cancer drugs (gemcitabine and docetaxel) with and without the study drug known as olaratumab in participants with advanced soft tissue sarcoma (STS) or STS that has spread to another part(s) of the body.

Official Title
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A Phase 1b (Open-Label)/Phase 2 (Randomized, Double-Blinded) Study Evaluating Gemcitabine and Docetaxel With or Without Olaratumab in the Treatment of Advanced Soft Tissue Sarcoma

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Olaratumab
* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant may have no more than 2 prior lines of systemic therapies (neoadjuvant and adjuvant therapies will not be considered as a prior line of therapy) for advanced or metastatic disease and is suitable to receive gemcitabine and docetaxel therapy. All previous therapies must have completed ≥ 3 weeks (21 days) prior to first dose of study drug. In the Phase 2 part, prior olaratumab/doxorubicin combination therapy in 1 prior treatment line is allowed. Prior olaratumab therapy must have been received with doxorubicin as indicated on the olaratumab label. Prior olaratumab therapy must have included at least 2 full cycles of olaratumab/doxorubicin (that is, a minimum of 4 doses of olaratumab). Participants, who completed at least 2 cycles of combination olaratumab/doxorubicin therapy then discontinued doxorubicin due to toxicity or maximum dosing and proceeded to olaratumab monotherapy, are eligible. The most recent dose of olaratumab must have been received within 180 days of randomization in this study. Availability of tumor tissue is mandatory for study eligibility. The participant must have consented to provide archived formalin-fixed paraffin-embedded tumor tissue or be subject to a pre-treatment re-biopsy of primary or metastatic tumor tissue for future central pathology review and translational research (if archived tissue is unavailable). The participant has adequate hematologic, organ, and coagulation function within 2 weeks (14 days) prior to enrollment (Phase 1b) or randomization (Phase 2). Exclusion Criteria: The participant is diagnosed with gastrointestinal stromal tumor (GIST) or Kaposi sarcoma. The participant has active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment (Phase 1b) or randomization (Phase 2). 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 (Phase 1b) /randomization (Phase 2) to rule out brain metastasis. The participant has received prior treatment with gemcitabine or docetaxel. Note: Participants previously enrolled in the I5B-MC-JGDJ (NCT02451943) or any other blinded study with olaratumab are not eligible to participate in this trial. The participant has electively planned or will require major surgery during the course of the study. Females who are pregnant or breastfeeding. The participant has an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required).

Ages Eligible for Study
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Minimum Age: 16 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel<br>Participants received intravenous infusions of olaratumab 15 milligrams per kilogram (mg/kg) on days 1, 8 plus gemcitabine 900 milligrams per meter square (mg/m^2) on days 1, 8 plus docetaxel 75 mg/m^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. | Drug: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;Drug: Gemcitabine<br>* Administered IV<br>* Other names: Gemzar;Drug: Docetaxel<br>* Administered IV<br>|
| Experimental: Phase 1b: Cohort 2 overall - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel<br>Participants received intravenous infusions of olaratumab 20 mg/kg on days 1, 8 in combination with gemcitabine 900 mg/m^2 on days 1, 8 and docetaxel 75 mg/m^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met (cohort 2). Following a protocol amendment, additional participants were enrolled into this group to confirm the safety of the 20 mg/kg dose level prior to opening the Phase 2 (cohort 2 expansion). | Drug: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;Drug: Gemcitabine<br>* Administered IV<br>* Other names: Gemzar;Drug: Docetaxel<br>* Administered IV<br>|
| Experimental: Phase 2: Olaratumab + Gemcitabine + Docetaxel<br>Participants received intravenous infusions of olaratumab loading dose 20 mg/kg on days 1, 8 of cycle 1 followed by 15 mg/kg on days 1, 8 of all subsequent cycles in combination with gemcitabine 900 mg/m^2 on days 1, 8 and docetaxel 75 mg/m^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. This cohort is a combination of participants who never received olaratumab (olaratumab-naive) and who received commercially available olaratumab (olaratumab pre-treated) prior to enrollment. | Drug: Olaratumab<br>* Administered IV<br>* Other names: IMC-3G3;Drug: Gemcitabine<br>* Administered IV<br>* Other names: Gemzar;Drug: Docetaxel<br>* Administered IV<br>|
| Placebo Comparator: Phase 2: Placebo + Gemcitabine + Docetaxel<br>Participants received intravenous infusions of placebo on days 1, 8 in combination with gemcitabine 900 mg/m^2 on days 1, 8 and docetaxel 75 mg/m^2 on day 8 of a 21-day cycle until disease progression, unacceptable toxicity, death, or other discontinuation criteria were met. This cohort is a combination of participants who never received olaratumab (olaratumab-naive) and who received commercially available olaratumab (olaratumab pre-treated) prior to enrollment. | Drug: Gemcitabine<br>* Administered IV<br>* Other names: Gemzar;Drug: Docetaxel<br>* Administered IV<br>Drug: Placebo<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT) | A Dose Limiting Toxicity is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: Febrile neutropenia with documented Grade ≥3 infection or sepsis 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. | Cycle 1 (Up To 21 Days) | 
| Phase 2: Overall Survival (OS) (Olaratumab-Naive) | OS was 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 38 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab | Cmax of Olaratumab. | Pre-dose, 5 minutes (min), 1, 4, 4.5, 24, 96, 168, 336 hours (h) post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 8 | 
| Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab | Cmin of Olaratumab. | Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1 | 
| Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab | T1/2 of Olaratumab. | Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 8 | 
| Phase 1b/2: PK: Cmax of Gemcitabine | Cmax of Gemcitabine. | Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) | 
| Phase 1b/2: PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC[0-∞]) of Gemcitabine | AUC[0-∞] of Gemcitabine | Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) | 
| Phase 1b/2: PK: Cmax of Docetaxel | Cmax of Docetaxel. | 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 | 
| Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel | AUC [0-∞] of Docetaxel. | 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 | 
| Phase 1b/2: Population PK: Clearance of Olaratumab | Population PK: Clearance of Olaratumab | Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8 | 
| Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab | The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2). | Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8 | 
| Phase 2: Overall Survival (Olaratumab Pre-Treated) | OS was 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 38 Months) | 
| Phase 2: Progression Free Survival (PFS) | PFS was defined as the time from randomization to the first date of radiologic disease progression (as defined by Response Evaluation Criteria In Solid Tumors, Version 1.1 [RECIST v.1.1]) or death due to any cause. Progressive disease (PD) was 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 from Any Cause (Up To 38 Months) | 
| Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) | ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator 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 to Objective Disease Progression or Start of New Anti-Cancer Therapy (Up To 38 Months) | 
| Phase 2: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 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 to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 38 Months) | 
| Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) Worst Pain Score | The mBPI-sf is a 11-item instrument used as a multiple-item measure of cancer pain intensity ranging from 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can imagine or completely interferes). Time to first worsening of the mBPI-sf worst pain score (TWP) was defined as the time from the date of randomization to the first date of either a worst pain score increase of greater than or equal to (≥) 2 points from baseline or an analgesic drug class increase of ≥1 level. If the patient has not worsened by either of these criteria, TWP was censored for analysis on the last date the mBPI-sf was administered. | Baseline to Follow-up (Up To 24 Months) | 
| Phase 2: Time to First Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Symptom Scales. | The EORTC QLQ-C30 is a self-reported general cancer instrument consisting of 30 items covered by 1 of 3 dimensions: global health status/quality of life (2 items), functional scales (15 total items addressing either physical, role, emotional, cognitive, or social functioning), symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, or financial impact). Time to first worsening of Symptom Burden was defined as the time from randomization to the first observation of worsening on symptom scales (i.e.,) increase of at least 10 points from baseline. For symptom scales, a linear transformation was used to obtain total score ranging from 0 to 100, a high score represents a high level of symptomatology or problems. | Baseline to Follow-up (Up to 33 months) | 
| Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) | The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) of health status are each assessed with 5 response options (1=no problem, 2=slight, 3=moderate, 4=severe, and 5=extreme problem) and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status. Additionally, current health status was assessed on a visual analogue scale (VAS) ranging from 0 to 100 with a higher score representing better health status. | Cycle 1 (Day 1), Follow-up (Up to 38 Months) | 
| Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies | Number of Participants with Treatment Emergent Anti-Olaratumab Antibodies | Baseline through Follow-Up (Up to 38 Months) |