A Phase 1b, Multicenter, Two-Part, Open-Label Study of Trastuzumab Deruxtecan, an Anti-Human Epidermal Growth Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), in Combination With Nivolumab, an Anti-PD-1 Antibody, for Subjects With HER2-expressing Advanced Breast and Urothelial Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 86
- 试验地点
- 29
- 主要终点
- Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation
研究概览
简要总结
This is a study of trastuzumab deruxtecan for the treatment of HER2-positive unresectable or metastatic breast cancer following two or more prior anti-HER2 based regimens.
Participants will receive this study drug along with a cancer drug, an immune checkpoint inhibitor, anti-PD1, called nivolumab.
The study will be done in two parts:
- Part 1 is to identify the recommended dose to use for treatment.
- Part 2 is to find out how well the combination works, and how safe and tolerable it is.
详细描述
The purpose of this phase 1b (Part 1, Part 2) study is to assess the combination of a test drug (trastuzumab deruxtecan) with nivolumab in participants with HER2-expressing breast and urothelial cancer who had disease progression during or after prior therapies, did not respond to standard therapies, or for whom no standard therapy is available.
The study will be performed in 2 parts.
- Part 1 is to test different doses of trastuzumab deruxtecan when given along with a fixed dose of nivolumab, and establish the maximum tolerated dose/recommended dose for expansion, when used in combination with nivolumab
- Part 2 is to assess the efficacy and safety of this dose combination.
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
- •Is the age of majority (adulthood) in their country
- •Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1
- •Has pathologically documented breast cancer or urothelial cancer that is unresectable or metastatic, and refractory to or intolerant of existing therapy(ies) known to provide clinical benefit, and as specified in each study cohort
- •Has an adequate archival tumor sample available for the central laboratory to determine eligibility to participate
- •Has at least 1 measurable lesion per RECIST version 1.1
- •Has cardiac, bone marrow, kidney, liver, blood and clotting test results required per protocol
- •Has had an adequate washout period before enrollment since previous surgery and other treatment
- •If reproduction is possible, agrees to use protocol-defined methods of contraception (or completely abstain from heterosexual intercourse) from screening to at least 7 months for females and males after the last dose of study drug
- •Agrees to avoid harvesting sperm or ova for any reason from screening to at least 7 months for females and males after the last dose of study drug
- •Has a life expectancy of at least 3 months
排除标准
- •Has received prior treatment with nivolumab or trastuzumab deruxtecan
- •Has medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association classes II-IV). Troponin levels above upper limit of normal (ULN) at screening (as defined by the manufacturer) and without any MI-related symptoms should have a cardiologic consultation before enrollment to rule out MI.
- •Has a corrected QT interval by Fredericia (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on an average of the screening triplicate 12-lead electrocardiogram
- •Has history of non-infectious interstitial lung disease (ILD/pneumonitis) (that required steroids), has ILD/pneumonitis currently, or it cannot be ruled out by imaging at screening
- •Has a condition (other than active autoimmune disease) that requires systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of starting study treatment
- •Is pregnant or breastfeeding, or planning to become pregnant
研究组 & 干预措施
Dose Escalation (3.2 mg/kg)
Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).
Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle.
The DLT observation period will be the first 2 cycles.
干预措施: Trastuzumab deruxtecan (Drug)
Dose Escalation (3.2 mg/kg)
Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).
Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle.
The DLT observation period will be the first 2 cycles.
干预措施: Nivolumab (Drug)
Dose Escalation (5.4 mg/kg)
Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).
Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle.
The DLT observation period will be the first 2 cycles.
干预措施: Trastuzumab deruxtecan (Drug)
Dose Escalation (5.4 mg/kg)
Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).
Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle.
The DLT observation period will be the first 2 cycles.
干预措施: Nivolumab (Drug)
Dose Expansion - Cohort 1
Cohort 1: Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined positive HER2 expression (IHC 3+ or IHC 2+/ISH+) [as defined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines]. These participants received prior ado-trastuzumab emtansine (T-DM1).
Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Trastuzumab deruxtecan (Drug)
Dose Expansion - Cohort 1
Cohort 1: Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined positive HER2 expression (IHC 3+ or IHC 2+/ISH+) [as defined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines]. These participants received prior ado-trastuzumab emtansine (T-DM1).
Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Nivolumab (Drug)
Dose Expansion - Cohort 2
Cohort 2: Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined low HER2 expression (IHC 1+ or IHC 2+/ISH-), who have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for patients who are hormone receptor positive).
Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Trastuzumab deruxtecan (Drug)
Dose Expansion - Cohort 2
Cohort 2: Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined low HER2 expression (IHC 1+ or IHC 2+/ISH-), who have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for patients who are hormone receptor positive).
Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Nivolumab (Drug)
Dose Expansion - Cohort 3
Cohort 3: Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 2+ or 3+, who received prior platinum-based therapy with documented progression.
Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Trastuzumab deruxtecan (Drug)
Dose Expansion - Cohort 3
Cohort 3: Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 2+ or 3+, who received prior platinum-based therapy with documented progression.
Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Nivolumab (Drug)
Dose Expansion - Cohort 4
Cohort 4: Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 1+, who received prior platinum-based therapy with documented progression.
Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Trastuzumab deruxtecan (Drug)
Dose Expansion - Cohort 4
Cohort 4: Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 1+, who received prior platinum-based therapy with documented progression.
Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.
干预措施: Nivolumab (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicities at 3.2 mg/kg and 5.4 mg/kg Dose Level in Participants With HER2-expressing Advanced Breast Cancer in Dose Escalation
时间窗: Cycles 1 and 2 (each cycle is 21 days)
A Dose-Limiting Toxicity (DLT) is defined as any Treatment Emergent Adverse Event not attributable to disease or disease-related processes that occurs during the DLT evaluation period (2 complete cycles during Part 1) and is Grade 3 or above according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Each cycle is 21 days. Low dose was set at 3.2 mg/kg and high dose was set at 5.4 mg/kg.
Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer
时间窗: Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 2 years 11.5 months (each cycle is 21 days)
The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by independent central review (ICR) committee based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR based on ICR is reported. As prespecified in the protocol, participants enrolled in Part 1 were pooled according to their trastuzumab deruxtecan dose and HER2 expressing levels (HER2 positive or HER2 low) for efficacy analyses. Participants who were dosed at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC score 3+ or IHC score 2+/ISH+) in Part 1 were pooled with the same participants from Part 2 (in this case, participants enrolled in Cohort 1).
次要结局
- Duration of Response (DoR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer(Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days))
- Percentage of Participants With Disease Control Rate (DCR) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer(Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days))
- Progression-Free Survival (PFS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer(Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days))
- Time to Response (TTR) Based on Independent Central Review in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer(Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days))
- Overall Survival (OS) in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer(Date of first dose of study drug to the date of death due to any cause, up to 5 years)
- Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment in Participants With HER2-expressing Advanced Breast Cancer or Urothelial Cancer(Every 6 weeks in the first year after Day 1 of Cycle 1 and thereafter every 12 weeks until disease progression or initiation of additional anticancer therapy and survival, up to 5 years (each cycle is 21 days))
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(Date of signing the informed consent form up to 100 days after last dose of study drug or start of a new anticancer drug (whichever occurs first), up to 5 years)