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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02451943
Recruitment Status : Active, not recruiting
First Posted : May 22, 2015
Results First Posted : December 17, 2019
Last Update Posted : July 14, 2020
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: Olaratumab Drug: Doxorubicin Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 509 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : September 14, 2015
Actual Primary Completion Date : December 5, 2018
Estimated Study Completion Date : September 1, 2020


Arm Intervention/treatment
Experimental: Doxorubicin + 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.
Drug: Olaratumab
Administered IV
Other Name: LY3012207

Drug: Doxorubicin
Administered IV

Placebo Comparator: Doxorubicin + 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.
Drug: Doxorubicin
Administered IV

Drug: Placebo
Administered IV




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 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.

  2. Overall Survival (OS) Leiomyosarcoma (LMS) [ Time Frame: 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 :
  1. Progression Free Survival (PFS) [ Time Frame: 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.

  2. Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: 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.

  3. Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [ Time Frame: 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.

  4. 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 Frame: 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.

  5. Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L) [ Time Frame: 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.

  6. Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score" [ Time Frame: 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).

  7. Duration of Overall Response (DoR) [ Time Frame: 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).

  8. Duration of Disease Control (DDC) [ Time Frame: 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.

  9. Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate [ Time Frame: 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.

  10. PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate [ Time Frame: 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02451943


Locations
Show Show 118 study locations
Sponsors and Collaborators
Eli Lilly and Company
Investigators
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Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol: Study Protocol  [PDF] January 29, 2015
Study Protocol: Study Protocol (d)  [PDF] January 12, 2017
Statistical Analysis Plan  [PDF] August 23, 2018

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02451943    
Other Study ID Numbers: 15677
I5B-MC-JGDJ ( Other Identifier: Eli Lilly and Company )
2015‐000134‐30 ( EudraCT Number )
First Posted: May 22, 2015    Key Record Dates
Results First Posted: December 17, 2019
Last Update Posted: July 14, 2020
Last Verified: July 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later. Data will be indefinitely available for requesting.
Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
URL: https://vivli.org/
Keywords provided by Eli Lilly and Company:
leiomyosarcoma
soft tissue sarcoma (STS)
advanced soft tissue sarcoma
metastatic soft tissue sarcoma
liposarcoma
undifferentiated pleomorphic sarcoma
doxorubicin
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Doxorubicin
Olaratumab
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action