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A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma (ANNOUNCE 2)

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: NCT02659020
Recruitment Status : Completed
First Posted : January 20, 2016
Results First Posted : October 11, 2021
Last Update Posted : May 9, 2022
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Tracking Information
First Submitted Date  ICMJE January 15, 2016
First Posted Date  ICMJE January 20, 2016
Results First Submitted Date  ICMJE July 26, 2021
Results First Posted Date  ICMJE October 11, 2021
Last Update Posted Date May 9, 2022
Actual Study Start Date  ICMJE March 1, 2016
Actual Primary Completion Date July 28, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 14, 2021)
  • Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 (Up To 21 Days) ]
    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:
    1. Febrile neutropenia with documented Grade ≥3 infection or sepsis
    2. Grade 4 neutropenia lasting 7 days or longer.
    3. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage.
    4. 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.
  • Phase 2: Overall Survival (OS) (Olaratumab-Naive) [ Time Frame: Baseline to Date of Death Due to Any Cause (Up To 38 Months) ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 15, 2016)
  • Recommended Phase 2 Dose of Olaratumab: Number of Participants with Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 (21 Days) ]
  • Overall Survival (OS) [ Time Frame: Baseline to Date of Death Due to Any Cause (Approximately 15 Months) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2021)
  • Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab [ Time Frame: 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 ]
    Cmax of Olaratumab.
  • Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab [ Time Frame: 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 ]
    Cmin of Olaratumab.
  • Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab [ Time Frame: 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 ]
    T1/2 of Olaratumab.
  • Phase 1b/2: PK: Cmax of Gemcitabine [ Time Frame: Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) ]
    Cmax of Gemcitabine.
  • Phase 1b/2: PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC[0-∞]) of Gemcitabine [ Time Frame: Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) ]
    AUC[0-∞] of Gemcitabine
  • Phase 1b/2: PK: Cmax of Docetaxel [ Time Frame: 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 ]
    Cmax of Docetaxel.
  • Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel [ Time Frame: 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 ]
    AUC [0-∞] of Docetaxel.
  • Phase 1b/2: Population PK: Clearance of Olaratumab [ Time Frame: Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8 ]
    Population PK: Clearance of Olaratumab
  • Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab [ Time Frame: Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8 ]
    The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2).
  • Phase 2: Overall Survival (Olaratumab Pre-Treated) [ Time Frame: Baseline to Date of Death Due to Any Cause (Up To 38 Months) ]
    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.
  • Phase 2: Progression Free Survival (PFS) [ Time Frame: Baseline to Objective Disease Progression or Death from Any Cause (Up To 38 Months) ]
    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.
  • Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) [ Time Frame: Baseline to Objective Disease Progression or Start of New Anti-Cancer Therapy (Up To 38 Months) ]
    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.
  • 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) [ Time Frame: Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 38 Months) ]
    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.
  • Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score" [ Time Frame: Baseline to Follow-up (Up To 24 Months) ]
    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.
  • 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. [ Time Frame: Baseline to Follow-up (Up to 33 months) ]
    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.
  • Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) [ Time Frame: Cycle 1 (Day 1), Follow-up (Up to 38 Months) ]
    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.
  • Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies [ Time Frame: Baseline through Follow-Up (Up to 38 Months) ]
    Number of Participants with Treatment Emergent Anti-Olaratumab Antibodies
Original Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2016)
  • Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab [ Time Frame: Post-dose on Days 1 and 8 of Cycles 1 and 3 (21 day cycles) ]
  • PK: Minimum Serum Concentration (Cmin) of Olaratumab [ Time Frame: Pre-dose on Day 8 of Cycles 1 and 3, and on Day 1 of Cycles 2 and 4 ]
  • PK: Elimination Half-Life (T1/2) of Olaratumab [ Time Frame: Days 8 to 21 of Cycles 1 and 3 ]
  • Progression Free Survival (PFS) [ Time Frame: Baseline to Objective Progression or Death from Any Cause (Approximately 6 Months) ]
  • Proportion of Participants With a Complete or Partial Response (Objective Response Rate [ORR]) [ Time Frame: Baseline to Objective Progression or Start of New Anti-Cancer Therapy (Approximately 6 Months) ]
  • Disease Control Rate (DCR): Defined as Proportion of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) [ Time Frame: Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Approximately 6 Months) ]
  • Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score" [ Time Frame: Baseline through Follow-up (Approximately 6 Months) ]
  • Time to Sustained Worsening of Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Scores [ Time Frame: Baseline through Follow-up (Approximately 6 Months) ]
  • Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) [ Time Frame: Baseline through Follow-up (Approximately 6 Months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Soft Tissue Sarcoma
Intervention  ICMJE
  • Drug: Olaratumab
    Administered IV
    Other Names:
    • LY3012207
    • IMC-3G3
  • Drug: Gemcitabine
    Administered IV
    Other Names:
    • LY188011
    • Gemzar
  • Drug: Docetaxel
    Administered IV
  • Drug: Placebo
    Administered IV
Study Arms  ICMJE
  • Experimental: Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel
    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.
    Interventions:
    • Drug: Olaratumab
    • Drug: Gemcitabine
    • Drug: Docetaxel
  • Experimental: Phase 1b: Cohort 2 overall - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel
    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).
    Interventions:
    • Drug: Olaratumab
    • Drug: Gemcitabine
    • Drug: Docetaxel
  • Experimental: Phase 2: Olaratumab + Gemcitabine + Docetaxel
    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.
    Interventions:
    • Drug: Olaratumab
    • Drug: Gemcitabine
    • Drug: Docetaxel
  • Placebo Comparator: Phase 2: Placebo + Gemcitabine + Docetaxel
    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.
    Interventions:
    • Drug: Gemcitabine
    • Drug: Docetaxel
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 21, 2018)
310
Original Estimated Enrollment  ICMJE
 (submitted: January 15, 2016)
196
Actual Study Completion Date  ICMJE April 27, 2021
Actual Primary Completion Date July 28, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   France,   Germany,   Hungary,   Israel,   Italy,   Poland,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02659020
Other Study ID Numbers  ICMJE 15839
I5B-MC-JGDL ( Other Identifier: Eli Lilly and Company )
2015-001316-34 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: 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 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/
Current Responsible Party Eli Lilly and Company
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Eli Lilly and Company
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Eli Lilly and Company
Verification Date April 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP