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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 310
- 试验地点
- 48
- 主要终点
- Phase 2: Overall Survival (OS) (Olaratumab-Naive)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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).
研究组 & 干预措施
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.
干预措施: Olaratumab (Drug)
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.
干预措施: Gemcitabine (Drug)
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.
干预措施: Docetaxel (Drug)
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).
干预措施: Olaratumab (Drug)
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).
干预措施: Gemcitabine (Drug)
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).
干预措施: Docetaxel (Drug)
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.
干预措施: Olaratumab (Drug)
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.
干预措施: Gemcitabine (Drug)
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.
干预措施: Docetaxel (Drug)
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.
干预措施: Gemcitabine (Drug)
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.
干预措施: Docetaxel (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Phase 2: Overall Survival (OS) (Olaratumab-Naive)
时间窗: 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)
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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))
- 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)
- 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)
- Phase 1b/2: PK: Cmax of Docetaxel(5 min, 1, 3, 24, 48 h post-dose on Cycle 1 Day 8)
- Phase 2: Progression Free Survival (PFS)(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])(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)(Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 38 Months))
- Phase 1b/2: PK: Cmax of Gemcitabine(Day 8 of Cycle 1 (end of infusion, 1, 2, 4, 24 hours post-infusion))
- 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)
- Phase 2: Overall Survival (Olaratumab Pre-Treated)(Baseline to Date of Death Due to Any Cause (Up To 38 Months))
- 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))
- 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))
- Phase 2: Number of Participants With Treatment Emergent Anti-Olaratumab Antibodies(Baseline through Follow-Up (Up to 38 Months))
- Phase 2: Health Status on the EuroQol 5-Dimension 5 Level (EQ-5D-5L)(Cycle 1 (Day 1), Follow-up (Up to 38 Months))