A Randomized, Double-blind, Placebo-controlled, Active Comparator Phase 2/3 Study of Tucatinib in Combination With Trastuzumab, Ramucirumab, and Paclitaxel in Subjects With Previously Treated, Locally-advanced Unresectable or Metastatic HER2+ Gastric or Gastroesophageal Junction Adenocarcinoma (GEC)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Seagen Inc.
- 入组人数
- 17
- 试验地点
- 48
- 主要终点
- Number of Participants With Dose-limiting Toxicities (DLT) During the First Cycle of Treatment
研究概览
简要总结
This study is being done to see if tucatinib with trastuzumab, ramucirumab and paclitaxel works better than ramucirumab and paclitaxel to treat HER2-positive (HER2+) cancer of the gut (stomach or gastroesophageal cancer). This study will also look at what side effects happen when participants take this combination of drugs. A side effect is anything the drug does other than treating cancer.
Study treatment will be given in 28-day cycles.
In the Phase 2 part of the trial, participants and their doctors will know what drugs are being given (open-label). In the Phase 3 part, the study is "blinded." This means that participants, their doctor, and the study sponsor will not know which drugs are being given.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC)
- •HER2+ disease documented since progression of the most recent line of systemic therapy, as follows:
- •Phase 2 paclitaxel dose optimization stage:
- •HER2 amplification in a blood-based NGS assay performed at a central laboratory, or
- •HER2 overexpression/amplification immunohistochemistry (IHC) and in situ hybridization (ISH) (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample
- •Phase 2 dose expansion stage:
- •Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory
- •Cohort 2B: No HER2 amplification by blood-based NGS assay, but HER2 overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample
- •Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory
- •History of prior treatment with a HER2-directed antibody
- •Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC
- •Phase 2: Measurable disease according to RECIST version 1.1
- •Phase 3: Measurable or non-measurable disease according to RECIST version 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- •Life expectancy of at least 3 months, in the opinion of the investigator
排除标准
- •Subjects with squamous cell or undifferentiated GEC
- •Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic disease
- •Having received taxanes ≤12 months prior to enrollment, prior treatment with ramucirumab, or prior treatment with tucatinib, lapatinib, neratinib, afatinib, or any other investigational anti-HER2 and/or anti-EGFR tyrosine kinase inhibitor, or with T-DM1, T-Dxd, or any other HER2-directed antibody-drug conjugate
- •Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy
- •Unable to swallow pills
研究组 & 干预措施
Arm 3A
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: tucatinib (Drug)
Phase 2 Arm
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: paclitaxel (Drug)
Phase 2 Arm
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: tucatinib (Drug)
Phase 2 Arm
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: trastuzumab (Drug)
Phase 2 Arm
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: ramucirumab (Drug)
Arm 3A
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: trastuzumab (Drug)
Arm 3A
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: ramucirumab (Drug)
Arm 3A
Tucatinib + trastuzumab + ramucirumab + paclitaxel
干预措施: paclitaxel (Drug)
Arm 3B
Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
干预措施: trastuzumab placebo (Other)
Arm 3B
Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
干预措施: ramucirumab (Drug)
Arm 3B
Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
干预措施: paclitaxel (Drug)
Arm 3B
Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
干预措施: tucatinib placebo (Other)
Arm 3C
Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
干预措施: tucatinib (Drug)
Arm 3C
Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
干预措施: ramucirumab (Drug)
Arm 3C
Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
干预措施: paclitaxel (Drug)
Arm 3C
Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
干预措施: trastuzumab placebo (Other)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicities (DLT) During the First Cycle of Treatment
时间窗: Cycle 1 (28 days)
DLTs were adverse events (AEs), laboratory abnormalities, or treatment modifications that occurred during the first cycle of treatment in the Phase 2 paclitaxel dose optimization stage that were related to paclitaxel, to tucatinib, or to the combination of tucatinib, trastuzumab, ramucirumab and paclitaxel and that met any of the study protocol specified criteria. The relationship of AEs to study drugs was determined by the investigator. AEs that were attributed only to trastuzumab and/or ramucirumab, but not tucatinib or paclitaxel were not considered DLTs.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
An AE was any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. AEs were defined as treatment emergent if they were newly occurring or worsened following study treatment. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel) and up to 30 days after the last dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel, whichever was later).
Number of Participants With Treatment-emergent Laboratory Abnormalities
时间窗: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Treatment-emergent laboratory abnormalities were defined as abnormalities that are new or worsened on or after receiving the first dose of study treatment up to 30 days after the last dose of study treatment. Laboratory abnormalities included: 1) Blood chemistry: alanine aminotransferase increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase increased, calcium corrected for albumin decreased, calcium corrected for albumin increased, creatinine increased, glomerular filtration rate estimated decreased, glucose decreased, lactate dehydrogenase increased, magnesium decreased, magnesium increased, potassium decreased, potassium increased, sodium decreased, sodium increased, and total bilirubin increased; 2) Hematological: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased, and platelets decreased.
Number of Participants With Clinically Significant Vital Signs Values
时间窗: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Vital sign examinations included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate. Criteria: SBP greater than or equal to (\>=) 120 millimeters of mercury (mm Hg) or DBP \>= 80 mm Hg; SBP \>= 140 mm Hg or DBP \>= 90 mm Hg; SBP \>= 160 mm Hg or DBP \>= 100 mm Hg), heart rate greater than (\>) 100 beats per minute (min). Clinical significance in vital signs abnormalities was judged by investigator. In this outcome measure number of participants with at least 1 clinically significant abnormality in any vital sign are reported.
Maximum Percentage Change From Baseline in Weight
时间窗: From Baseline (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Maximum percentage decrease from baseline in weight is reported in this outcome measure.
Number of Participants With Any Dose Modifications
时间窗: From first dose of the study treatment (Day 1) up to the last dose of study treatment (maximum treatment duration up to 19.8 months)
Dose modification included dose hold, dose reduction, dose error and unplanned dose adjustments. Number of participants with any dose treatment modifications for paclitaxel, ramucirumab, trastuzumab, and tucatinib are reported in this outcome measure.
次要结局
- Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 By Investigator Assessment(From the first dose of study treatment until the first documented CR or PR on or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 19.8 months))
- Confirmed ORR Per RECIST v1.1 By Investigator Assessment(From the first dose of study treatment until the first documented confirmed CR or PR or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 19.8 months))
- Progression-Free Survival (PFS) Per RECIST v1.1 By Investigator Assessment(From the date of first dose until the first documentation of PD or death or censoring date, whichever occurred first (up to 19.8 months))
- Duration of Response (DOR) Per RECIST v1.1 By Investigator Assessment(From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (up to 19.8 months))
- Disease Control Rate (DCR) Per RECIST v1.1 By Investigator Assessment(From the first dose study treatment until PD or death, whichever occurred first (up to 19.8 months))
- Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites(Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose; Paclitaxel and its metabolites- Cycle 1 Days 1 and 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days))
- Maximum Observed Plasma Concentration (Cmax)(Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days))
- Time to Maximum Observed Plasma Concentration (Tmax)(Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days))
- Trough Concentration (Ctrough)(Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Predose (each cycle length=28 days))
- Metabolite Ratio Based on AUClast (MRAUClast)(Paclitaxel and its metabolites- Cycle 1 Days 1 and 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days))