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

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

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.

Study Overview

• Status: Completed
• Conditions: Soft Tissue Sarcoma
• Intervention / Treatment: Drug: Docetaxel; Drug: Placebo; Drug: Olaratumab; Drug: Gemcitabine

• Study Type: Interventional
• Enrollment (Actual): 310
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Lille Cedex, France, 59020
    • Centre Oscar Lambret
  • Villejuif Cedex, France, 94805
    • Gustave Roussy
• Germany
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin-Buch
  • Baden-Württemberg
    • Ulm, Baden-Württemberg, Germany, 89081
      • Universitätsklinikum Ulm
  • Bayern
    • München, Bayern, Germany, 81377
      • Klinikum der Universität München
    • Regensburg, Bayern, Germany, 93053
      • Universitätsklinikum Regensburg
  • Brandenburg
    • Bad Saarow, Brandenburg, Germany, 15526
      • Helios Klinikum Bad Saarow
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover
• Hungary
  • Szolnok, Hungary, 5000
    • Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház
• Israel
  • Haifa, Israel, 3525408
    • Rambam Medical Center
  • Petah Tiqva, Israel, 4941492
    • Rabin Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
  • Ramat Gan
    • Tel Hashomer, Ramat Gan, Israel, 5265601
      • Sheba Medical Center
• Italy
  • Torino, Italy, 10153
    • Humanitas Gradenigo
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Fondazione Piemonte l'Oncologia-Istituto Ricerca Cura Cancro
• Poland
  • Warszawa, Poland, 02-781
    • Centrum Onkologii-Instytut im Marii Sklodowskiej-Curie
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, NW1 2BU
      • University College Hospital - London
    • London, Greater London, United Kingdom, SW3 6JJ
      • Royal Marsden NHS Trust
  • Merseyside
    • Bebbington, Merseyside, United Kingdom, CH63 4JY
      • Clatterbridge Cancer Centre
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Western General Hospital
• United States
  • California
    • Santa Monica, California, United States, 90404
      • UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic-Jacksonville
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Georgia Cancer Specialists PC
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical School
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Cancer Center
  • New York
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists & Research Institute, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6307
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University Of Texas Southwestern Medical Center At Dallas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / 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: Docetaxel; Administered IV; Drug: Olaratumab; Administered IV; Other Names: LY3012207; IMC-3G3; Drug: Gemcitabine; Administered IV; Other Names: Gemzar; LY188011
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: Docetaxel; Administered IV; Drug: Olaratumab; Administered IV; Other Names: LY3012207; IMC-3G3; Drug: Gemcitabine; Administered IV; Other Names: Gemzar; LY188011
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: Docetaxel; Administered IV; Drug: Olaratumab; Administered IV; Other Names: LY3012207; IMC-3G3; Drug: Gemcitabine; Administered IV; Other Names: Gemzar; LY188011
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: Docetaxel; Administered IV; Drug: Placebo; Administered IV; Drug: Gemcitabine; Administered IV; Other Names: Gemzar; LY188011

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Number of Participants With Dose Limiting Toxicity (DLT)	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: Febrile neutropenia with documented Grade ≥3 infection or sepsis; Grade 4 neutropenia lasting 7 days or longer.; Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage.; 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.	Cycle 1 (Up To 21 Days)
Phase 2: Overall Survival (OS) (Olaratumab-Naive)	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.	Baseline to Date of Death Due to Any Cause (Up To 38 Months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Olaratumab	Cmax of Olaratumab.	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
Phase 1b: PK: Minimum Serum Concentration (Cmin) of Olaratumab	Cmin of Olaratumab.	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
Phase 1b: PK: Elimination Half-Life (T1/2) of Olaratumab	T1/2 of Olaratumab.	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
Phase 1b/2: PK: Cmax of Gemcitabine	Cmax of Gemcitabine.	Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion)
Phase 1b/2: PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC[0-∞]) of Gemcitabine	AUC[0-∞] of Gemcitabine	Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion)
Phase 1b/2: PK: Cmax of Docetaxel	Cmax of Docetaxel.	5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8
Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel	AUC [0-∞] of Docetaxel.	5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8
Phase 1b/2: Population PK: Clearance of Olaratumab	Population PK: Clearance of Olaratumab	Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8
Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab	The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2).	Cycle 1-19: Pre-dose, 5 min, 1, 4, 4.5, 24, 96, 168, 336 h post-dose on days 1, 8
Phase 2: Overall Survival (Olaratumab Pre-Treated)	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.	Baseline to Date of Death Due to Any Cause (Up To 38 Months)
Phase 2: Progression Free Survival (PFS)	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.	Baseline to Objective Disease Progression or Death from Any Cause (Up To 38 Months)
Phase 2: Percentage of Participants With a Complete or Partial Response (Objective Response Rate [ORR])	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.	Baseline to Objective Disease Progression or Start of New Anti-Cancer Therapy (Up To 38 Months)
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)	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.	Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 38 Months)
Phase 2: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score"	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.	Baseline to Follow-up (Up To 24 Months)
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.	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.	Baseline to Follow-up (Up to 33 months)
Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L)	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.	Cycle 1 (Day 1), Follow-up (Up to 38 Months)
Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies	Number of Participants with Treatment Emergent Anti-Olaratumab Antibodies	Baseline through Follow-Up (Up to 38 Months)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): July 28, 2020
• Study Completion (Actual): April 27, 2021

Study Registration Dates

• First Submitted: January 15, 2016
• First Submitted That Met QC Criteria: January 15, 2016
• First Posted (Estimate): January 20, 2016

Study Record Updates

• Last Update Posted (Actual): May 9, 2022
• Last Update Submitted That Met QC Criteria: April 15, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gemcitabine; Docetaxel; Olaratumab
• Other Study ID Numbers: 15839; I5B-MC-JGDL (Other Identifier: Eli Lilly and Company); 2015-001316-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing 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.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes