Phase I Study of the Combination of Trastuzumab Emtansine (T-DM1) and Capecitabine in HER2-Positive Metastatic Breast Cancer and HER2-Positive Locally Advanced/Metastatic Gastric Cancer Patients, Followed by a Randomized, Open-Label Phase II Study of Trastuzumab Emtansine and Capecitabine Versus Trastuzumab Emtansine Alone in HER2-Positive Metastatic Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 182
- 试验地点
- 40
- 主要终点
- Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This multicenter study will assess the maximum tolerated dose (MTD) of capecitabine in combination with Kadcyla (trastuzumab emtansine) in participants with HER2-positive mBC or HER2-positive LA/mGC using a Phase 1 design, followed by a randomized, open-label Phase 2 part to explore the efficacy and safety of the combination of Kadcyla and capecitabine compared with Kadcyla alone in participants with mBC. The anticipated time on study treatment is until disease progression, intolerable toxicity, withdrawal of consent, or study end.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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
- •Metastatic Breast Cancer
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •Adequate blood cell count
- •Adequate liver, renal, and cardiac function
- •Life expectancy greater than or equal to (>/=) 12 weeks
- •Histologically or cytologically confirmed breast cancer
- •Confirmed HER2-positive disease, defined as immunohistochemistry (IHC) 3+ or in situ hybridization (ISH)-positive
- •mBC with at least one measurable lesion according to RECIST v1.1
- •Disease progression on at least one prior regimen containing trastuzumab and chemotherapy either separately or in combination; participants may be eligible to receive study therapy in first-line setting if trastuzumab and chemotherapy were given in the neoadjuvant/adjuvant setting
- •Participant must have recovered from previous treatments
- •Locally Advanced/Metastatic Gastric Cancer
- •ECOG performance status of 0, 1, or 2
- •Adequate blood cell count
- •Adequate liver, renal, and cardiac function
- •Life expectancy >/= 12 weeks
- •Histologically or cytologically confirmed LA/mGC
- •HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ or IHC 2+ and ISH-positive
- •Inoperable LA/mGC
排除标准
- •Metastatic Breast Cancer
- •Prior treatments before first study treatment:
- •Investigational therapy within 28 days or 5 half-lives, whichever is longer
- •Hormonal therapy within 14 days
- •Trastuzumab within 21 days
- •Prior treatment with trastuzumab emtansine or prior enrollment in a trastuzumab emtansine-containing study, regardless of whether the patient received trastuzumab emtansine
- •Prior treatment with capecitabine
- •History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity to fluorouracil
- •Related capecitabine contraindications
- •Treatment with sorivudine or chemically-related analogues
- •Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
- •Complete absence of dihydropyrimidine dehydrogenase (DPD) activity
- •History of intolerance or hypersensitivity to trastuzumab or murine proteins or any product component
- •History of exposure to high cumulative doses of anthracyclines
- •Brain metastases that are symptomatic or require radiation, surgery, or steroid therapy to control symptoms within 28 days before study drug
- •Current peripheral neuropathy of Grade >/=3
- •History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome
- •Current unstable ventricular arrhythmia requiring treatment
- •History of symptomatic congestive heart failure (CHF)
- •History of myocardial infarction or unstable angina within 6 months prior to study drug
- •History of left ventricular ejection fraction (LVEF) less than (<) 40% or symptomatic CHF with previous trastuzumab treatment
- •Severe dyspnea at rest due to complications of advanced malignancy or currently requiring continuous oxygen therapy
- •Clinically significant malabsorption syndrome or inability to take oral medication
- •Current severe, uncontrolled systemic disease (such as clinically significant cardiovascular, pulmonary, or metabolic disease)
- •Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during study treatment
- •Current known active infection with human immunodeficiency virus (HIV) or hepatitis B or C
- •Lapatinib within 14 days before study drug
- •Locally Advanced/Metastatic Gastric Cancer
- •Same as above, with addition of previous chemotherapy for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrollment into the study)
研究组 & 干预措施
Phase 1 (mBC) Cohort 1: T-DM1 + Capecitabine
In Phase 1, Cohort 1 participants (with mBC) will receive trastuzumab emtansine (T-DM1) at a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine at de-escalating dose levels (starting from 750 milligrams per meter squared [mg/m^2]) via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, disease progression (PD), death, or study end.
干预措施: Capecitabine (Drug)
Phase 1 (mBC) Cohort 1: T-DM1 + Capecitabine
In Phase 1, Cohort 1 participants (with mBC) will receive trastuzumab emtansine (T-DM1) at a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine at de-escalating dose levels (starting from 750 milligrams per meter squared [mg/m^2]) via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, disease progression (PD), death, or study end.
干预措施: Trastuzumab emtansine (T-DM1) (Drug)
Phase 1 (LA/mGC) Cohort 2: T-DM1 + Capecitabine
In Phase 1, Cohort 2 participants (with LA/mGC) will receive trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (on Day 2 of first week) of every week along with capecitabine at MTD (determined in Cohort 1) via tablet orally twice daily on Days 1-14 followed by a 7-day rest period, in each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.
干预措施: Trastuzumab emtansine (T-DM1) (Drug)
Phase 1 (LA/mGC) Cohort 2: T-DM1 + Capecitabine
In Phase 1, Cohort 2 participants (with LA/mGC) will receive trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (on Day 2 of first week) of every week along with capecitabine at MTD (determined in Cohort 1) via tablet orally twice daily on Days 1-14 followed by a 7-day rest period, in each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.
干预措施: Capecitabine (Drug)
Phase 2 (mBC): T-DM1 + Capecitabine
In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle along with capecitabine at MTD via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.
干预措施: Trastuzumab emtansine (T-DM1) (Drug)
Phase 2 (mBC): T-DM1 + Capecitabine
In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle along with capecitabine at MTD via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.
干预措施: Capecitabine (Drug)
Phase 2 (mBC): T-DM1
In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle until investigator-assessed PD, unacceptable toxicity, withdrawal of consent, death, or study end.
干预措施: Trastuzumab emtansine (T-DM1) (Drug)
结局指标
主要结局
Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: Continuously during Cycle 1 (up to 3 weeks)
A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting more than (\>) 7 consecutive days; febrile neutropenia with absolute neutrophil count (ANC) less than (\<) 1000 cells/millimeter cube (mm\^3); Grade greater than or equal to (\>/=) 3 diarrhea or Grade 3 hand-foot syndrome (in absence of dihydropyrimidine dehydrogenase \[DPD\] deficiency only for DL 1); any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days (\>7 days for DL 1); for DL -1 only: \<14 full doses of capecitabine; Cycle 2 dose level \<100 percent (%).
Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 3 Weeks)
时间窗: Continuously during Cycle 1 (up to 3 weeks)
MTD was defined as the dose level for which the probability of DLT is equal to a protocol-specified target probability. A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting \>7 consecutive days; febrile neutropenia with ANC \<1000 cells/mm\^3; Grade \>/=3 diarrhea or Grade 3 hand-foot syndrome (in absence of DPD deficiency only for DL 1); any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days (\>7 days for DL 1); for DL -1 only: \<14 full doses of capecitabine; Cycle 2 dose level \<100%.
Phase 2 (mBC): Percentage of Participants With Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
时间窗: Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
Tumor response was assessed by the investigator according to RECIST v1.1. BOR was defined as percentage of participants with a complete response (CR) or partial response (PR) that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as the disappearance of all target lesions (TLs) and non-TLs; short axis (SA) reduction to \<10 millimeters (mm) for nodal TLs/non-TLs; and no new lesions. PR was defined as \>/=30% decrease in sum of diameters (SoD) of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. The 90% confidence Interval (CI) was computed using Clopper-Pearson approach.
Phase 1 (LA/mGC): Percentage of Participants With DLTs
时间窗: Continuously during 3 weeks
A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting \>7 consecutive days; febrile neutropenia with ANC \<1000 cells/mm\^3; Grade \>/=3 diarrhea or Grade 3 hand-foot syndrome; any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days; \<14 full doses of capecitabine; Cycle 2 dose level \<100%.
Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW)
时间窗: Continuously during 3 weeks
MTD was defined as the dose level for which the probability of DLT is equal to a protocol-specified target probability. A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting \>7 consecutive days; febrile neutropenia with ANC \<1000 cells/mm\^3; Grade \>/=3 diarrhea or Grade 3 hand-foot syndrome; any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days; \<14 full doses of capecitabine; Cycle 2 dose level \<100%.
次要结局
- Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine(Pre-trastuzumab emtansine dose (0 hour [h]) on Day 1 Cycle 2; 15-30 minutes (min) after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days))
- Phase 1 (mBC): Serum Concentration of Trastuzumab(Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days))
- Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1(Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 3.5 years overall))
- Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1(Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1(Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1(Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1(Baseline until clinical benefit response, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) of Capecitabine(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1(Baseline until first documentation of confirmed PR or CR, whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause(Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 1 (LA/mGC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1(Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 1.5 years overall))
- Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine(Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days))
- Phase 1 (LA/mGC): Cmax of Capecitabine(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (LA/mGC): t1/2 of Capecitabine(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1(From the documentation of response until PD, death, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1(Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1(Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Percentage of Participants Who Died of Any Cause(Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 2 (mBC): Overall Survival (OS)(Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall))
- Phase 1 (LA/mGC): Serum Concentration of Trastuzumab(Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days))
- Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)
- Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)(Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1)