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

Soft Tissue Sarcoma Clinical Trial

— ANNOUNCE  

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Doxorubicin Plus Olaratumab Versus Doxorubicin Plus Placebo in Patients With Advanced or Metastatic Soft Tissue Sarcoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02451943
• Other study ID #: 15677
• Secondary ID: I5B-MC-JGDJ2015-
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 14, 2015
• Est. completion date: July 31, 2024

Study information

• Verified date: April 2024
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 509
• Est. completion date: July 31, 2024
• Est. primary completion date: December 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Sarcoma
• Soft Tissue Sarcoma

Intervention

Drug:
• Olaratumab
Administered IV
• Doxorubicin
Administered IV
• Placebo
Administered IV

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Denmark,  Finland,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	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.	Randomization to Date of Death Due to Any Cause (Up to 35.8 Months)
Primary	Overall Survival (OS) Leiomyosarcoma (LMS)	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.	Randomization to Date of Death Due to Any Cause (Up to 35.8 Months)
Secondary	Progression Free Survival (PFS)	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.	Randomization to Objective Progression or Death Due to Any Cause (Up to 35.8 Months)
Secondary	Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)	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.	Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months)
Secondary	Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)	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.	Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 45 Months)
Secondary	Time to First Worsening on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores	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.	Randomization (Cycle 1) through Follow-up (Up to 35.8 Months)
Secondary	Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L)	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.	Randomization through Follow-up (Up to 35.8 Months)
Secondary	Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score"	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).	Randomization through Follow-up (Up to 34.5 Months)
Secondary	Duration of Overall Response (DoR)	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).	Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up to 33.4 Months)
Secondary	Duration of Disease Control (DDC)	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.	Date of CR, PR, or SD to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months)
Secondary	Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate	The PK systemic clearance parameter estimates from the current analysis are listed together with the population PK model estimates.	Cycle 1- 9: Day 1 and 8, Predose, 5 minutes Post dose and then every other cycle and follow-up (30 Days)
Secondary	PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate	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).	Cycle 1- 9: Day 1 and 8; Predose, 5 Minutes Post dose and then every other cycle and follow-up (30 Days)

External Links

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