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
ClinicalTrials.gov processed this data on April 16, 2024. Link to the current ClinicalTrials.gov record.Recruitment Status
ACTIVE, NOT RECRUITING - HAS RESULTS(See Contacts and Locations)
Verified April 2024 by Eli Lilly and Company
Sponsor
Eli Lilly and CompanyInformation Provided by (Responsible Party)
Eli Lilly and CompanyClinicaltrials.gov Identifier
NCT02451943Other Study ID Numbers: 15677
First Submitted: May 20, 2015
First Posted: May 22, 2015
Results First Posted: December 17, 2019
Last Update Posted: April 17, 2024
Last Verified: April 2024
History of Changes
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| Study Type | Interventional |
|---|---|
| Study Design | Allocation: Randomized; Interventional Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment |
| Condition(s) |
|
| Intervention(s) |
|
| Enrollment | 509 |
Participant Flow
| Pre-assignment Details | Completers include participants who died or alive and on study at conclusion, but off treatment. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Study | ||
| STARTED | 258 | 251 |
| Received at Least One Dose of Study Drug | 257 | 249 |
| Leiomyosarcoma (LMS) Population | 119 | 115 |
| COMPLETED | 238 | 227 |
| NOT COMPLETED | 20 | 24 |
| On Treatment | 4 | 4 |
| Withdrawal by Subject | 13 | 16 |
| Lost to Follow-up | 3 | 4 |
Baseline Characteristics
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo | Total |
|---|---|---|---|
| Overall Number of Baseline Participants | 258 | 251 | 509 |
| Age, Continuous | Measure Type: Mean | Unit of measure: years | |||
| Number Analyzed | 258 years | 251 years | 509 years |
| 56.7 (22%) | 57.1 (22.7%) | 56.9 (11.2%) | |
| Sex: Female, Male | Measure Type: Count of Participants | Unit of measure: Participants | |||
| Number Analyzed | 258 participants | 251 participants | 509 participants |
| Female | 144 (55.8%) | 152 (60.6%) | 296 (58.2%) |
| Male | 114 (44.2%) | 99 (39.4%) | 213 (41.8%) |
| Ethnicity (NIH/OMB) | Measure Type: Count of Participants | Unit of measure: Participants | |||
| Number Analyzed | 258 participants | 251 participants | 509 participants |
| Hispanic or Latino | 26 (10.1%) | 29 (11.6%) | 55 (10.8%) |
| Not Hispanic or Latino | 209 (81%) | 199 (79.3%) | 408 (80.2%) |
| Unknown or Not Reported | 23 (8.9%) | 23 (9.2%) | 46 (9%) |
| Race (NIH/OMB) | Measure Type: Count of Participants | Unit of measure: Participants | |||
| Number Analyzed | 258 participants | 251 participants | 509 participants |
| American Indian or Alaska Native | 3 (1.2%) | 3 (1.2%) | 6 (1.2%) |
| Asian | 50 (19.4%) | 48 (19.1%) | 98 (19.3%) |
| Native Hawaiian or Other Pacific Islander | 1 (0.4%) | 1 (0.2%) | |
| Black or African American | 12 (4.7%) | 2 (0.8%) | 14 (2.8%) |
| White | 186 (72.1%) | 193 (76.9%) | 379 (74.5%) |
| More than one race | 5 (1.9%) | 4 (1.6%) | 9 (1.8%) |
| Unknown or Not Reported | 1 (0.4%) | 1 (0.4%) | 2 (0.4%) |
| Region of Enrollment | Measure Type: Count of Participants | Unit of measure: Participants | |||
| Number Analyzed | 258 participants | 251 participants | 509 participants |
| 69 (26.7%) | 73 (29.1%) | 142 (27.9%) | |
Outcome Measures
Primary Outcome
| Title | Overall Survival (OS) |
|---|---|
| Description | 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. |
| Time Frame | Randomization to Date of Death Due to Any Cause (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants. Censored participants in Doxorubicin + Olaratumab arm = 87 and Doxorubicin + Placebo arm = 91 |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 258 | 251 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| 20.37(17.84 - 22.90) | 19.75(16.49 - 23.75) | |
Statistical Analysis 1
| Statistical Analysis Overview | |
|---|---|
| Comparison Group Selection | Doxorubicin + Olaratumab, Doxorubicin + Placebo |
| Type of Statistical Test | Superiority |
| Statistical Test of Hypothesis | |
| P-Value | 0.6945 |
| Method | Log Rank |
| Method of Estimation | |
| Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.047 |
| Estimation Comments | 2-Sided |
Primary Outcome
| Title | Overall Survival (OS) Leiomyosarcoma (LMS) |
|---|---|
| Description | 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. |
| Time Frame | Randomization to Date of Death Due to Any Cause (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants with LMS. Censored participants in Doxorubicin + Olaratumab arm = 42 and Doxorubicin + Placebo arm = 40. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 119 | 115 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| 21.55(18.63 - 27.63) | 21.88(17.54 - 25.07) | |
Statistical Analysis 1
| Statistical Analysis Overview | |
|---|---|
| Comparison Group Selection | Doxorubicin + Olaratumab, Doxorubicin + Placebo |
| Type of Statistical Test | Superiority |
| Statistical Test of Hypothesis | |
| P-Value | 0.7618 |
| Method | Log Rank |
| Method of Estimation | |
| Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.951 |
| Estimation Comments | 2-Sided |
Secondary Outcome
| Title | Progression Free Survival (PFS) |
|---|---|
| Description | 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. |
| Time Frame | Randomization to Objective Progression or Death Due to Any Cause (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants. Censored participants in the Doxorubicin + Olaratumab arm = 39 and the Doxorubicin + Placebo arm =34. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 258 | 251 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| 5.42(4.11 - 6.70) | 6.77(5.49 - 8.08) | |
Statistical Analysis 1
| Statistical Analysis Overview | |
|---|---|
| Comparison Group Selection | Doxorubicin + Olaratumab, Doxorubicin + Placebo |
| Type of Statistical Test | Superiority |
| Statistical Test of Hypothesis | |
| P-Value | 0.0422 |
| Method | Log Rank |
| Method of Estimation | |
| Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.231 |
| Estimation Comments | 2-Sided |
Secondary Outcome
| Title | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) |
|---|---|
| Description | 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. |
| Time Frame | Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 258 | 251 |
| Number (95% Confidence Interval) | Unit of Measure: percentage of participants | ||
| 14.0(9.7 - 18.2) | 18.3(13.5 - 23.1) | |
Secondary Outcome
| Title | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) |
|---|---|
| Description | 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. |
| Time Frame | Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 45 Months) |
| Analysis Population Description | All randomized participants. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 258 | 251 |
| Number (95% Confidence Interval) | Unit of Measure: percentage of participants | ||
| 67.4(61.7 - 73.2) | 75.7(70.4 - 81.0) | |
Secondary Outcome
| Title | Time to First Worsening on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores |
|---|---|
| Description | 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 Frame | Randomization (Cycle 1) through Follow-up (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants who completed at least 1 baseline assessment and at least 1 subsequent assessment during the study period. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 258 | 251 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| Global Health Status/QoL | 1.45(1.41 - 2.10) | 1.84(1.45 - 2.79) |
| Role Functional Scale | 1.41(0.99 - 1.48) | 1.41(0.95 - 2.00) |
| Physical Functional Scale | 1.81(1.45 - 2.14) | 2.79(2.07 - 3.48) |
| Emotional Functional Scale | 3.48(2.50 - 4.37) | 2.83(2.14 - 4.34) |
| Cognitive Functional Scale | 1.64(1.41 - 2.14) | 1.45(1.41 - 2.07) |
| Social Functional Scale | 1.45(1.38 - 1.64) | 1.41(1.35 - 1.45) |
| Fatigue Symptom Scale | 0.92(0.76 - 1.25) | 0.89(0.76 - 1.38) |
| Nausea and Vomiting Symptom Scale | 1.45(1.41 - 1.64) | 1.41(0.95 - 1.45) |
| Pain Symptom Scale | 1.64(1.41 - 2.10) | 2.10(1.45 - 2.76) |
| Dyspnea Symptom Scale | 2.10(1.45 - 2.76) | 2.07(1.45 - 2.79) |
| Insomnia Symptom Scale | 2.10(1.45 - 2.79) | 1.58(1.41 - 2.33) |
| Appetite Loss Symptom Scale | 1.48(1.45 - 2.04) | 1.64(1.41 - 2.14) |
| Financial Difficulties Scale | 1.48(1.41 - 2.14) | 1.45(1.41 - 2.10) |
| Constipation Symptom Scale | 1.64(1.41 - 2.10) | 1.41(1.41 - 2.10) |
| Diarrhea Symptom Scale | 2.07(1.45 - 2.79) | 2.79(2.10 - 3.52) |
Secondary Outcome
| Title | Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L) |
|---|---|
| Description | 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. |
| Time Frame | Randomization through Follow-up (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants who had a baseline and a post-baseline measurement. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 221 | 219 |
| Mean (Standard Deviation) | Unit of Measure: score on a scale | ||
| -0.163 (0.236) | -0.171 (0.235) | |
Secondary Outcome
| Title | Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score" |
|---|---|
| Description | 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). |
| Time Frame | Randomization through Follow-up (Up to 34.5 Months) |
| Analysis Population Description | All randomized participants who completed at least 1 baseline assessment and at least 1 subsequent assessment during the study period. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 211 | 206 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| 7.66(6.01 - 9.63) | 8.08(6.18 - 11.07) | |
Secondary Outcome
| Title | Duration of Overall Response (DoR) |
|---|---|
| Description | 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). |
| Time Frame | Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up to 33.4 Months) |
| Analysis Population Description | All randomized participants who have evaluable DoR data. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 36 | 46 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| 8.31(6.87 - 12.35) | 4.80(3.65 - 6.83) | |
Statistical Analysis 1
| Statistical Analysis Overview | |
|---|---|
| Comparison Group Selection | Doxorubicin + Olaratumab, Doxorubicin + Placebo |
| Type of Statistical Test | Superiority |
| Statistical Test of Hypothesis | |
| P-Value | 0.0934 |
| Method | Log Rank |
| Method of Estimation | |
| Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.616 |
| Estimation Comments | 2-Sided |
Secondary Outcome
| Title | Duration of Disease Control (DDC) |
|---|---|
| Description | 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. |
| Time Frame | Date of CR, PR, or SD to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months) |
| Analysis Population Description | All randomized participants who had evaluable DDC data. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab | Doxorubicin + Placebo |
|---|---|---|
| Overall Number of Participants Analyzed | 174 | 190 |
| Median (95% Confidence Interval) | Unit of Measure: Months | ||
| 8.28(6.93 - 9.72) | 8.34(8.08 - 9.46) | |
Statistical Analysis 1
| Statistical Analysis Overview | |
|---|---|
| Comparison Group Selection | Doxorubicin + Olaratumab, Doxorubicin + Placebo |
| Type of Statistical Test | Superiority |
| Statistical Test of Hypothesis | |
| P-Value | 0.3347 |
| Method | Log Rank |
| Method of Estimation | |
| Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.123 |
| Estimation Comments | 2-Sided |
Secondary Outcome
| Title | Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate |
|---|---|
| Description | The PK systemic clearance parameter estimates from the current analysis are listed together with the population PK model estimates. |
| Time Frame | Cycle 1- 9: Day 1 and 8, Predose, 5 minutes Post dose and then every other cycle and follow-up (30 Days) |
| Analysis Population Description | All randomized participants who received at least one dose of study drug and had evaluable PK data. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab |
|---|---|
| Overall Number of Participants Analyzed | 258 |
| Mean (95% Confidence Interval) | Unit of Measure: Liter/hour (L/h) | |
| 0.0195(0.0189 - 0.0203) | |
Secondary Outcome
| Title | PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate |
|---|---|
| Description | 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 Frame | Cycle 1- 9: Day 1 and 8; Predose, 5 Minutes Post dose and then every other cycle and follow-up (30 Days) |
| Analysis Population Description | All randomized participants who had received at least one dose of study drug and had evaluable PK data. |
|---|
| Arm/Group Title | Doxorubicin + Olaratumab |
|---|---|
| Overall Number of Participants Analyzed | 258 |
| Mean (95% Confidence Interval) | Unit of Measure: Liter (L) | |
| 5.72(5.28 - 6.17) | |
Adverse Events
| Time Frame | From Baseline to Study Completion (Up to 3 Years and 1 Month) |
|---|---|
| Adverse Event Reporting Description | All randomized participants who received at least one dose of study drug. |