A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma
- Conditions
- Soft Tissue Sarcoma
- Interventions
- Registration Number
- NCT02659020
- Lead Sponsor
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 310
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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.
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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.
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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).
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The participant has adequate hematologic, organ, and coagulation function within 2 weeks (14 days) prior to enrollment (Phase 1b) or randomization (Phase 2).
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2: Placebo + Gemcitabine + Docetaxel Placebo 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. Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel Olaratumab 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. Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel 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. Phase 1b: Cohort 1 - 15 mg/kg Olaratumab + Gemcitabine + Docetaxel Gemcitabine 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. Phase 1b: Cohort 2 overall - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel Olaratumab 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). Phase 1b: Cohort 2 overall - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel 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). Phase 2: Olaratumab + Gemcitabine + Docetaxel Olaratumab 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. Phase 1b: Cohort 2 overall - 20 mg/kg Olaratumab + Gemcitabine + Docetaxel Gemcitabine 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). Phase 2: Olaratumab + Gemcitabine + Docetaxel 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. Phase 2: Olaratumab + Gemcitabine + Docetaxel Gemcitabine 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. Phase 2: Placebo + Gemcitabine + Docetaxel Gemcitabine 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. Phase 2: Placebo + Gemcitabine + Docetaxel 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.
- Primary Outcome Measures
Name Time Method Phase 2: Overall Survival (OS) (Olaratumab-Naive) 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 1b: Number of Participants With Dose Limiting Toxicity (DLT) 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.
- Secondary Outcome Measures
Name Time Method Phase 1b: PK: Minimum Serum Concentration (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 Cmin of Olaratumab.
Phase 1b: Pharmacokinetics (PK): Maximum Serum Concentration (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 Cmax of Olaratumab.
Phase 1b/2: PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of Docetaxel 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 AUC \[0-∞\] of Docetaxel.
Phase 1b/2: PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC[0-∞]) of Gemcitabine Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) AUC\[0-∞\] of Gemcitabine
Phase 1b/2: 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 Population PK: Clearance of Olaratumab
Phase 1b: PK: Elimination Half-Life (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 T1/2 of Olaratumab.
Phase 1b/2: PK: Cmax of Docetaxel 5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8 Cmax of Docetaxel.
Phase 2: Progression Free Survival (PFS) 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]) 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) 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 1b/2: PK: Cmax of Gemcitabine Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion) Cmax of Gemcitabine.
Phase 1b/2: Population PK: Volume of Distribution at Steady State (Vss) of Olaratumab 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) 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: Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score" 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. 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: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies Baseline through Follow-Up (Up to 38 Months) Number of Participants with Treatment Emergent Anti-Olaratumab Antibodies
Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L) 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.
Trial Locations
- Locations (48)
Georgia Cancer Specialists PC
🇺🇸Atlanta, Georgia, United States
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Ohio State University Medical Center
🇺🇸Columbus, Ohio, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Medizinische Hochschule Hannover
🇩🇪Hannover, Niedersachsen, Germany
Sheba Medical Center
🇮🇱Tel Hashomer, Ramat Gan, Israel
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Utah Cancer Specialists
🇺🇸Salt Lake City, Utah, United States
Fondazione Piemonte l'Oncologia-Istituto Ricerca Cura Cancro
🇮🇹Candiolo, Torino, Italy
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
UCLA Medical Center
🇺🇸Santa Monica, California, United States
Mayo Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Washington University Medical School
🇺🇸Saint Louis, Missouri, United States
Nebraska Methodist Cancer Center
🇺🇸Omaha, Nebraska, United States
Monter Cancer Center
🇺🇸Lake Success, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
University of Texas Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Centre Oscar Lambret
🇫🇷Lille Cedex, France
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Gustave Roussy
🇫🇷Villejuif Cedex, France
Institut Bergonie
🇫🇷Bordeaux, France
Universitätsklinikum Ulm
🇩🇪Ulm, Baden-Württemberg, Germany
Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz
🇭🇺Szolnok, Hungary
HELIOS Klinikum Berlin-Buch
🇩🇪Berlin, Germany
Helios Klinikum Bad Saarow
🇩🇪Bad Saarow, Brandenburg, Germany
Klinikum der Universität München
🇩🇪München, Bayern, Germany
Universitätsklinikum Regensburg
🇩🇪Regensburg, Bayern, Germany
Rambam Medical Center
🇮🇱Haifa, Israel
Rabin Medical Center
🇮🇱Petah Tiqva, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Humanitas Gradenigo
🇮🇹Torino, Italy
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Centrum Onkologii-Instytut im Marii Sklodowskiej-Curie
🇵🇱Warszawa, Poland
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Clatterbridge Cancer Centre
🇬🇧Bebbington, Merseyside, United Kingdom
University College Hospital - London
🇬🇧London, Greater London, United Kingdom
Royal Marsden NHS Trust
🇬🇧London, Greater London, United Kingdom
Western General Hospital
🇬🇧Edinburgh, Scotland, United Kingdom
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Oklahoma Cancer Specialists & Research Institute, LLC
🇺🇸Tulsa, Oklahoma, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States