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

Phase 3

Completed

Conditions: Soft Tissue Sarcoma

Interventions: Drug: Olaratumab
Drug: Placebo
Drug: Doxorubicin

Registration Number: NCT02451943

Lead Sponsor: Eli Lilly and Company

Brief Summary: The main purpose of this study is to evaluate the efficacy of the combination of doxorubicin plus the study drug known as olaratumab versus doxorubicin plus placebo in participants with advanced or metastatic soft tissue sarcoma.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 509

Inclusion Criteria

Histologically confirmed diagnosis of advanced unresectable or metastatic soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy. Participants with Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded. Note: Evidence of disease progression is required for participants that are not newly diagnosed.
Presence of measurable or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1, Eisenhauer et al. 2009).
Performance status 0-1 on the Eastern Cooperative Oncology Group (ECOG) scale.
The participant has not received any previous treatment with anthracyclines.
The participant may have had any number of prior systemic cytotoxic therapies for advanced/metastatic disease and are considered appropriate candidates for anthracycline therapy. All previous anticancer treatments must be completed ≥ 3 weeks (21 days) prior to first dose of study drug.
Availability of tumor tissue is required for study eligibility. The participant must have consented to provide archived formalin-fixed paraffin embedded (FFPE) 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).
Adequate hematologic, organ, and coagulation within 2 weeks (14 days) prior to randomization.
Left ventricular ejection fraction (LVEF) ≥50% assessed within 28 days prior to randomization.
Females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
Females of child-bearing potential and males must agree to use highly effective contraceptive precautions during the trial and up to 3 months following the last dose of study drug.
The participant has, in the opinion of the investigator, a life expectancy of at least 3 months.

Exclusion Criteria

Diagnosis of GIST or Kaposi sarcoma.
Active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of randomization. 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 randomization to rule out brain metastasis.
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.
Prior radiotherapy of the mediastinal/pericardial area or whole pelvis radiation.
The participant has symptomatic congestive heart failure (CHF), left ventricular dysfunction (LVEF < 50%), severe myocardial insufficiency, cardiac arrhythmia, or cardiomyopathy.
The participant has unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction within 6 months of randomization.
The participant has a QT interval calculated using Bazett's formula (QTcB) interval of >450 milliseconds (msec) for males and >470 msec for females on screening electrocardiogram (ECG).
Females who are pregnant or breastfeeding.
Known allergy to any of the treatment components including a history of allergic reactions attributed to compounds of chemical or biological composition similar to olaratumab.
The participant has a known active fungal, bacterial, or viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Doxorubicin + Placebo	Placebo	75 mg/m\^2 doxorubicin administered IV on day 1 of each 21-day cycle for 8 cycles plus placebo (equivalent volume) administered IV on day 1 and day 8 for 8 cycles. Beginning with cycle 9, placebo (equivalent volume) administered on days 1 and 8 of each subsequent 21-day cycle until PD or discontinuation for any other reason.
Doxorubicin + Olaratumab	Olaratumab	75 milligrams per meter squared (mg/m\^2) doxorubicin administered intravenously (IV) on day 1 of each 21-day cycle for 8 cycles plus 20 milligrams per kilogram (mg/kg) dose of olaratumab administered IV on day 1 and day 8 of cycle 1 and 15 mg/kg olaratumab administered IV on day 1 and day 8 of cycles 2-8. Beginning with cycle 9, 15 mg/kg olaratumab administered IV on day 1 and day 8 of each subsequent 21-day cycle until documented progressive disease (PD) or discontinuation for any other reason.
Doxorubicin + Olaratumab	Doxorubicin	75 milligrams per meter squared (mg/m\^2) doxorubicin administered intravenously (IV) on day 1 of each 21-day cycle for 8 cycles plus 20 milligrams per kilogram (mg/kg) dose of olaratumab administered IV on day 1 and day 8 of cycle 1 and 15 mg/kg olaratumab administered IV on day 1 and day 8 of cycles 2-8. Beginning with cycle 9, 15 mg/kg olaratumab administered IV on day 1 and day 8 of each subsequent 21-day cycle until documented progressive disease (PD) or discontinuation for any other reason.
Doxorubicin + Placebo	Doxorubicin	75 mg/m\^2 doxorubicin administered IV on day 1 of each 21-day cycle for 8 cycles plus placebo (equivalent volume) administered IV on day 1 and day 8 for 8 cycles. Beginning with cycle 9, placebo (equivalent volume) administered on days 1 and 8 of each subsequent 21-day cycle until PD or discontinuation for any other reason.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Randomization to Date of Death Due to Any Cause (Up to 35.8 Months)	Overall survival was defined as the time from the date of randomization to the date of death due to any cause. For each participant, prior to data analysis, a reasonable effort was made to obtain the most up-to-date status (date of death or last date known to be alive). For any participant not known to have died as of the data cutoff date, OS was censored at the date the participant was last known to be alive. For any participant who withdrew consent for survival follow-up, OS was censored at the last date for which the participant provided consent for follow-up contact. The Kaplan-Meier method was used to estimate median parameters.
Overall Survival (OS) Leiomyosarcoma (LMS)	Randomization to Date of Death Due to Any Cause (Up to 35.8 Months)	Overall survival was defined as the time from the date of randomization to the date of death due to any cause. For each participant, prior to data analysis, a reasonable effort was made to obtain the most up-to-date status (date of death or last date known to be alive). For any participant not known to have died as of the data cutoff date, OS was censored at the date the participant was last known to be alive. For any participant who withdrew consent for survival follow-up, OS was censored at the last date for which the participant provided consent for follow-up contact. The Kaplan-Meier method was used to estimate median parameters.

Secondary Outcome Measures

Name	Time	Method
Duration of Disease Control (DDC)	Date of CR, PR, or SD to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months)	Duration of disease control was defined for each participant with a best response of CR, PR, or stable disease (SD) as the time from randomization to the first date of disease progression or death due to any cause.
Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)	Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months)	ORR was defined as the percentage of participants achieving a best overall response of complete response (CR) + partial response (PR). CR is the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to RECIST v1.1.
Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L)	Randomization through Follow-up (Up to 35.8 Months)	The EQ-5D-5L is a standardized measure of health status used to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of a descriptive system of the respondent's health which comprises the following 5 dimensions: (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Health status was calculated from a set of item weights to derive a score of 0 to 1, with 1 representing the best health status. United Kingdom (UK) weights were applied. The analysis includes all cycles for which at least 25% of participants in each arm have an assessment. For each participant a change from baseline was calculated for every post-baseline assessment by subtracting the baseline assessment result from the current assessment result. Maximum improvement (over baseline) was determined from the set of all post-baseline change scores.
PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate	Cycle 1- 9: Day 1 and 8; Predose, 5 Minutes Post dose and then every other cycle and follow-up (30 Days)	The PK parameter estimates from the current analysis are listed together with the population PK model estimates. The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2).
Time to First Worsening on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores	Randomization (Cycle 1) through Follow-up (Up to 35.8 Months)	Time to first worsening was calculated as the time from the first study drug dose to the first observation of worsening according to the EORTC QLQ-C30 Scoring Manual (Fayers et al. 2001). The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 total items covered by 1 of 3 dimensions (1 global health status/QoL total score, 5 functional subscales \[physical, role, cognitive, emotional, and social\]), and 9 symptom subscales \[fatigue/nausea/vomiting/pain/dyspnea/insomnia/appetite loss/constipation/diarrhea\]). There are 28 questions answered on a 4-point scale where 1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). A linear transformation was used to obtain total score ranging from 0 to 100 where "worsening" was defined as an increase of at least 10 points for the symptom scales or a decrease of at least 10 points for the functional scales and the global health status/QoL scale.
Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score"	Randomization through Follow-up (Up to 34.5 Months)	Time to first worsening of the brief pain inventory short form modified (mBPI-sf) "worst pain score" was defined as the time from the date of the first study drug dose (baseline date) to the first date of a "worst pain" score increase of greater than or equal to (≥) 2 points from baseline. The mBPI-sf is an 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).
Progression Free Survival (PFS)	Randomization to Objective Progression or Death Due to Any Cause (Up to 35.8 Months)	PFS was defined by (Response Evaluation Criteria In Solid Tumors RECIST v.1.1) as the time from the date of randomization to the first date of radiologic disease progression or death due to any cause. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 millimeter (mm), or unequivocal progression of non-target lesions, or 1 or more new lesions. Censoring for death or PD due to increase sum of target lesions is defined for each participant as the time from the date of randomization to the first date of radiographic documentation of 1 or more lesions. Censoring for death without progression is defined as the date of death if there is no prior or concurrent radiologic disease progression.
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)	Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 45 Months)	DCR was defined as the percentage of randomized participants achieving a best overall response of CR, PR, or SD per RECIST v.1.1. CR is the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Tumor marker results must have normalized. PD is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Duration of Overall Response (DoR)	Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up to 33.4 Months)	The duration of overall response was defined for each participant with a best response of CR or PR and measured from the time measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective disease progression or death due to any cause is observed (taking as reference for PD the smallest measurements recorded on study).
Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate	Cycle 1- 9: Day 1 and 8, Predose, 5 minutes Post dose and then every other cycle and follow-up (30 Days)	The PK systemic clearance parameter estimates from the current analysis are listed together with the population PK model estimates.

Trial Locations

Locations (109): University of Pittsburgh Medical Center
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Pittsburgh, Pennsylvania, United States
Georgia Cancer Specialists PC
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Atlanta, Georgia, United States
Chris O'Brien Lifehouse
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Camperdown, New South Wales, Australia
Pennsylvania Oncology Hematology Associates
🇺🇸
Philadelphia, Pennsylvania, United States
UCLA Medical Center
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Los Angeles, California, United States
The Clatterbridge Cancer Centre
🇬🇧
Bebbington, Merseyside, United Kingdom
Centre Georges François Leclerc
🇫🇷
Dijon, Côte-d'Or, France
Centro de Atención E Investigación Clínica En Oncología
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Merida, Yucatán, Mexico
The West Clinic
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Germantown, Tennessee, United States
Japanese Foundation for Cancer Research
🇯🇵
Koto-ku, Tokyo, Japan
Alexander Fleming
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Caba, BS, Argentina
Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
🇧🇪
Leuven, Belgium
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Hospital Provincial del Centenario
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Rosario, Santa Fe, Argentina
Universitair Ziekenhuis Gent
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Gent, Oost-Vlaanderen, Belgium
Sheba Medical Center
🇮🇱
Tel Hashomer, Ramat Gan, Israel
Tel Aviv Sourasky Medical Center
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Tel Aviv Jaffa, Israel
National Hospital Organization Osaka National Hospital
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Osaka, Japan
Universitätsklinikum Tübingen
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Tubingen, Baden-Württemberg, Germany
Tampereen yliopistollinen sairaala
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Tampere, Pirkanmaa, Finland
Icesp - Instituto Do Câncer Do Estado de São Paulo
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Sao Paulo, São Paulo, Brazil
National Cancer Center Hospital
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Chuo-Ku, Tokyo, Japan
Universitair Medisch Centrum St Radboud Nijmegen
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Nijmegen, Netherlands
Erasmus Medisch Centrum
🇳🇱
Rotterdam, Netherlands
Taipei Veterans General Hospital
🇨🇳
Taipei City, Taiwan
National Hospital Organization Hokkaido Cancer Center
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Sapporo, Hokkaido, Japan
Consultorio Dr. Reinoso
🇲🇽
Monterrey, Nuevo Leon, Mexico
Hospital Civil Fray Antonio Alcalde
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Guadalajara, Jalisco, Mexico
Cantonal Hospital St.Gallen
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St Gallen, Sankt Gallen, Switzerland
Maastricht UMC+
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Maastricht, Limburg, Netherlands
National Hospital Organization Kyushu Cancer Center
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Fukuoka, Japan
University Medical Center Groningen
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Groningen, Netherlands
Kazan Oncology Dispensary
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Kazan, Tatarstan Republic, Russian Federation
Inselspital Bern
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Bern, Switzerland
National Cancer Center
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Goyang-si, Gyeonggi-do, Korea, Republic of
City of Hope National Medical Center
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Duarte, California, United States
Mayo Clinic in Florida
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Jacksonville, Florida, United States
Moffitt Cancer Center & Research Institute
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Tampa, Florida, United States
Washington University Medical School
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Saint Louis, Missouri, United States
University of New Mexico Cancer Center
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Albuquerque, New Mexico, United States
Columbia University Medical Center
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New York, New York, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
Fairfax Northern Virginia Hematology Oncology, PC
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Fairfax, Virginia, United States
CENIT Centro de Neurociencias, Investigación y Tratamiento
🇦🇷
Caba, Buenos Aires, Argentina
AKH
🇦🇹
Wien, Austria
Cliniques universitaires Saint-Luc
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Bruxelles, Brussel, Belgium
INCA Hospital do Câncer III
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Rio de Janeiro, RJ, Brazil
Princess Margaret Hospital (Ontario)
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Lai Chi Kok, Kowloon, Canada
BC Cancer Vancouver
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Vancouver, British Columbia, Canada
Turku University Central Hospital
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Turku, Finland
Royal Victoria Hospital-Montreal
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Montreal, Quebec, Canada
Tom Baker Cancer Center
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Calgary, Alberta, Canada
Herlev and Gentofte Hospital
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Herlev, Denmark
Institut Curie
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Paris, France
Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest
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Bordeaux, France
Centre Leon Berard
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Lyon, Rhône-Alpes, France
CHU Hopital d'enfants de la Timone
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Marseille CEDEX 05, France
Institut Claudius Regaud
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Toulouse cedex 9, France
Gustave Roussy
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Villejuif Cedex, France
Klinikum Mannheim gGmbH Universitätsmedizin
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Mannheim, Baden-Württemberg, Germany
Klinikum der Universität München Großhadern
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Munchen, Bayern, Germany
Universitaetsklinikum Essen
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Essen, Nordrhein-Westfalen, Germany
Magyar Honvedseg Egeszsegugyi Kozpont
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Budapest, Hungary
HELIOS Klinikum Berlin-Buch
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Berlin, Germany
Hadassah Medical Center
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Jerusalem, Israel
Istituto Nazionale dei Tumori
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Milano, Lombardie, Italy
Istituto Clinico Humanitas
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Rozzano, Milano, Italy
Istituto di Candiolo IRCCS - Fondazione del Piemonte per l'Oncologia
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Candiolo, Torino, Italy
Università degli Studi di Catania - Azienda Policlinico
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Catania, Sicilia, Italy
National Cancer Center Hospital East
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Kashiwa, Chiba, Japan
Nagoya University Hospital
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Nagoya, Aichi, Japan
Osaka University Hospital
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Suita, Osaka, Japan
Saitama Medical University International Medical Center
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Hidaka, Saitama, Japan
Okayama University Hospital
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Okayama, Japan
Osaka International Cancer Institute
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Osaka, Japan
Severance Hospital, Yonsei University Health System
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Seoul, Korea, Republic of
Asan Medical Center
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Seoul, Korea, Korea, Republic of
Seoul St. Mary's Hospital
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Seoul, Korea, Korea, Republic of
Samsung Medical Center
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Seoul, Korea, Republic of
Hospital Angeles
🇲🇽
Tijuana, Baja California, Mexico
Centro de Alta Especialidad Reumatologia Inv del Potosi SC
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San Luis Potosi, Mexico
Leids Universitair Medisch Centrum
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Leiden, Netherlands
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
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Warszawa, Poland
Hospital Universitario Virgen Del Rocio
🇪🇸
Sevilla, Andalucía, Spain
Blokhin Cancer Research Center
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Moscow, Russian Federation
Hospital Universitari Vall d'Hebron
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Barcelona, Spain
St-Petersburg scientifical practical cente spec medical care
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St. Petersburg, Russian Federation
Hospital Duran I Reynals
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Barcelona, Spain
Hospital Universitario La Fe de Valencia
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Valencia, Spain
Skånes universitetssjukhus Lund
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Lund, Sweden
Chang Gung Memorial Hospital - Linkou
🇨🇳
Taoyuan Hsien, Taiwan
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
University College Hospital - London
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London, Greater London, United Kingdom
Royal Marsden NHS Trust
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London, Greater London, United Kingdom
The Christie NHS Foundation Trust
🇬🇧
Manchester, Greater Manchester, United Kingdom
Weston Park Hospital
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Sheffield, South Yorkshire, United Kingdom
University of Utah School of Medicine
🇺🇸
Salt Lake City, Utah, United States
University of Colorado Cancer Center
🇺🇸
Aurora, Colorado, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Nebraska Methodist Cancer Center
🇺🇸
Omaha, Nebraska, United States
Oncology Hematology Care Inc
🇺🇸
Nashville, Tennessee, United States
Duke Cancer Institute
🇺🇸
Durham, North Carolina, United States
Tennessee Oncology PLLC
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Nashville, Tennessee, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Utah Cancer Specialists
🇺🇸
Salt Lake City, Utah, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Stanford University
🇺🇸
Stanford, California, United States
Hospital Clinico San Carlos
🇪🇸
Madrid, Spain
Hospital Universitario 12 de Octubre
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Madrid, Spain