Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
- Conditions
- Breast Neoplasms
- Interventions
- Procedure: Tumor biopsyProcedure: Research blood sample
- Registration Number
- NCT01670877
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 56
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part I: Neratinib Only Tumor biopsy -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. Part I: Neratinib Only Research blood sample -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. Part II: Neratinib Only (ER-) Tumor biopsy -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. Part II: Neratinib Only (ER-) Research blood sample -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. Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive) Tumor biopsy -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. Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive) Research blood sample -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. Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx) Neratinib -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. Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx) Tumor biopsy -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. Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx) Research blood sample -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. Crossover: Neratinib + Trastuzumab Tumor biopsy -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. Crossover: Neratinib + Trastuzumab Research blood sample -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. Crossover: Neratinib + Fulvestrant + Trastuzumab Tumor biopsy -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. Crossover: Neratinib + Fulvestrant + Trastuzumab Research blood sample -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. Part I: Neratinib Only Neratinib -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. Part II: Neratinib Only (ER-) Neratinib -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. Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive) Neratinib -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. Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive) Fulvestrant -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. Crossover: Neratinib + Trastuzumab Neratinib -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. Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx) Fulvestrant -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. Crossover: Neratinib + Fulvestrant + Trastuzumab Neratinib -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. Crossover: Neratinib + Fulvestrant + Trastuzumab Fulvestrant -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. Crossover: Neratinib + Trastuzumab 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. Crossover: Neratinib + Fulvestrant + Trastuzumab 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.
- Primary Outcome Measures
Name Time Method Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone 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 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 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 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.
- Secondary Outcome Measures
Name Time Method 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) * Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.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) -CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.
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) * RR is defined as number of participants with complete response or partial response as best response.
* 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.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) * Participants were followed for progressive disease from start of treatment until completion of follow-up.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.Number of Participants With HER2 Mutation Subtype and Tumor Grade A time of enrollment -Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.
* A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.
* An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.
* A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis At time of enrollment * Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.
* Stage I has a better outcome than Stage IV.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) * Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.Part II ER-cohort Only: Progression-free Survival (PFS) Through completion of treatment (median treatment time of 62 days, full range 56-413 days) * Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.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) * Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.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) * RR is defined as number of participants with complete response or partial response as best response.
* 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.
Trial Locations
- Locations (17)
BC Cancer Agency
🇨🇦Vancouver, British Columbia, Canada
University of Southern California Keck School of Medicine
🇺🇸Los Angeles, California, United States
University of Miami Hospital and Clinics
🇺🇸Miami, Florida, United States
Northwestern University - Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
Dana-Farber Cancer Institute, Harvard University
🇺🇸Boston, Massachusetts, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of Alabama Cancer Center
🇺🇸Birmingham, Alabama, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mayo Clinic
🇺🇸Phoenix, Arizona, United States
Stanford Medicine Cancer Institute
🇺🇸Stanford, California, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
St. Luke's Cancer Institute
🇺🇸Kansas City, Missouri, United States
University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center)
🇺🇸Chapel Hill, North Carolina, United States
Avera Cancer Institute
🇺🇸Sioux Falls, South Dakota, United States
Duke Cancer Institute at Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada