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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 : October 27, 2021
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

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.

Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: Olaratumab Drug: Gemcitabine Drug: Docetaxel Drug: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 310 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 1, 2016
Actual Primary Completion Date : July 28, 2020
Actual Study Completion Date : April 27, 2021


Arm Intervention/treatment
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.
Drug: Olaratumab
Administered IV
Other Names:
  • LY3012207
  • IMC-3G3

Drug: Gemcitabine
Administered IV
Other Names:
  • LY188011
  • Gemzar

Drug: Docetaxel
Administered IV

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).
Drug: Olaratumab
Administered IV
Other Names:
  • LY3012207
  • IMC-3G3

Drug: Gemcitabine
Administered IV
Other Names:
  • LY188011
  • Gemzar

Drug: Docetaxel
Administered IV

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.
Drug: Olaratumab
Administered IV
Other Names:
  • LY3012207
  • IMC-3G3

Drug: Gemcitabine
Administered IV
Other Names:
  • LY188011
  • Gemzar

Drug: Docetaxel
Administered IV

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.
Drug: Gemcitabine
Administered IV
Other Names:
  • LY188011
  • Gemzar

Drug: Docetaxel
Administered IV

Drug: Placebo
Administered IV




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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).

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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



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

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).

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): NCT02659020


Locations
Show Show 48 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  [PDF] July 19, 2017
Statistical Analysis Plan  [PDF] September 4, 2019

Additional Information:
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02659020    
Other Study ID Numbers: 15839
I5B-MC-JGDL ( Other Identifier: Eli Lilly and Company )
2015-001316-34 ( EudraCT Number )
First Posted: January 20, 2016    Key Record Dates
Results First Posted: October 11, 2021
Last Update Posted: October 27, 2021
Last Verified: October 2021
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 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/

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Studies a U.S. FDA-regulated Drug Product: Yes
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Docetaxel
Olaratumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators