A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 17
- 主要终点
- Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone
研究概览
简要总结
This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.
详细描述
Overexpression of HER2 due to gene amplification is an established therapeutic target in breast cancer for which multiple HER2 targeted drugs are now available. However, the majority of breast cancers are without HER2 overexpression/non-amplified and not currently eligible to receive HER2 targeted drugs. Advances in tumor genome sequencing technology led to the identification of recurrent HER2 mutations (HER2mut) in approximately 2% of HER2 non-amplified primary breast cancers, and 3-5% of metastatic tumors. Importantly, tumor cells harboring HER2mut are sensitive to the anti-tumor effects of HER2-targeted agents in preclinical models, especially neratinib, a potent irreversible pan-HER inhibitor. However, neratinib monotherapy has demonstrated only modest single agent activity in HER2mut,, non-amplified metastatic breast cancer (MBC). Based on the hypothesis that the combination of neratinib and fulvestrant will be more effective than neratinib alone in ER+/HER2mut, non-amplified MBC the investigators conducted a single arm phase II study of neratinib plus fulvestrant with 2 cohorts, fulvestrant (FUL)-treated and FUL-naïve, for patients with ER+/HER2mut, non-amplified MBC to assess the anti-tumor effects of this combination. An exploratory ER-negative (ER-) HER2mut cohort was also included for the efficacy of neratinib monotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part I: Neratinib Only
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Neratinib (Drug)
Part I: Neratinib Only
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Tumor biopsy (Procedure)
Part I: Neratinib Only
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Research blood sample (Procedure)
Part II: Neratinib Only (ER-)
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Neratinib (Drug)
Part II: Neratinib Only (ER-)
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Tumor biopsy (Procedure)
Part II: Neratinib Only (ER-)
-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Research blood sample (Procedure)
Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Neratinib (Drug)
Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fulvestrant (Drug)
Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Tumor biopsy (Procedure)
Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Research blood sample (Procedure)
Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Neratinib (Drug)
Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fulvestrant (Drug)
Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Tumor biopsy (Procedure)
Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Research blood sample (Procedure)
Crossover: Neratinib + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
干预措施: Neratinib (Drug)
Crossover: Neratinib + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
干预措施: Trastuzumab (Drug)
Crossover: Neratinib + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
干预措施: Tumor biopsy (Procedure)
Crossover: Neratinib + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
干预措施: Research blood sample (Procedure)
Crossover: Neratinib + Fulvestrant + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
干预措施: Neratinib (Drug)
Crossover: Neratinib + Fulvestrant + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
干预措施: Fulvestrant (Drug)
Crossover: Neratinib + Fulvestrant + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
干预措施: Trastuzumab (Drug)
Crossover: Neratinib + Fulvestrant + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
干预措施: Tumor biopsy (Procedure)
Crossover: Neratinib + Fulvestrant + Trastuzumab
-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
干预措施: Research blood sample (Procedure)
结局指标
主要结局
Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone
时间窗: Through completion of treatment (median treatment time of 90 days, full range 54-716 days)
* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation
时间窗: Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation
时间窗: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation
时间窗: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
次要结局
- Number of Participants With HER2 Mutation Subtype and Histology Subtype(At the time of enrollment)
- Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)(Through completion of treatment (median treatment time of 168 days, full range 28-671 days))
- Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events(Through completion of follow-up; follow-up was through 28 days following completion of treatment (median follow-up of 140 days, full range 52-798 days))
- Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)(Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days))
- Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)(Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 92 days, full range 86 days-443 days))
- Number of Participants With HER2 Mutation Subtype and Tumor Grade(A time of enrollment)
- Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis(At time of enrollment)
- Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival(Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 142 days, full range 54-800 days))
- Part II ER-cohort Only: Progression-free Survival (PFS)(Through completion of treatment (median treatment time of 62 days, full range 56-413 days))
- Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)(Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days))
- Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)(Through completion of treatment (median treatment time of 168 days, full range 28-671 days))