Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

Study Description

Brief Summary

Detailed Description

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms	Drug: Neratinib Other Names PF-05208767 Drug: Fulvestrant Other Names Faslodex Drug: Trastuzumab Other Names Herceptin Procedure: Tumor biopsy Other Names Procedure: Research blood sample Other Names	Phase 2

Tracking Information

First Submitted Date	August 17, 2012
Last Update Posted Date	February 08, 2018
Actual Start Date	December 11, 2012
Anticipated Completion Date	November 30, 2020
Actual Primary Completion Date	December 31, 2018
Results First Submitted Date	N/A
Received Results Disposit Date	N/A

Current Primary Outcome Measures

• Part II ER-cohort only: Overall clinical activity (CR+PR+SD≥6months) of neratinib in patients with metastatic HER2-, ER- breast cancer that carry HER2 mutation [Time Frame: 6 months]

  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eighty percent confidence interval (CI) will be calculated.

• Part II fulvestrant-treated ER+ cohort only: Overall clinical activity (CR+PR+SD≥6months) of neratinib + fulvestrant in patients with metastatic HER2- ER+ fulvestrant-treated breast cancer that carry HER2 mutation [Time Frame: 6 months]

  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eighty percent confidence interval (CI) will be calculated.

• 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 [Time Frame: 6 months]

  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eighty percent confidence interval (CI) will be calculated.

• Part I only: Overall clinical activity (CR+PR+SD≥6months) of neratinib alone in patients with metastatic HER2- breast cancer that carry HER2 mutation [Time Frame: 6 months]

  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eighty percent confidence interval (CI) will be calculated.

Original Primary Outcome Measures

Current Secondary Outcome Measures

• PFS of patients with HER2- but HER2 mutated breast cancer treated with neratinib alone [Time Frame: 2 years]

  The time to progression or death will be listed, and the progression-free survival (PFS) will be estimated using Kaplan-Meier product limit method. For all the enrolled patients, the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and metastatic sites will be described using contingency tables and assess by McNemar test. The association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and progression-free survival (PFS) will be assessed using Fisher's exact test, Mann-Whitney rank sum test, or log-rank test as appropriate.

• Correlate the presence of HER2 mutation with histology subtype (invasive lobular vs. invasive ductal cancer), tumor grade (grade 1-2 vs 3), tumor staging at initial diagnosis (I vs. II or III vs. IV), disease free survival in HER2- breast cancer. [Time Frame: 2 years]

• PFS of patients with HER2- ER+ HER2 mutated breast cancer who are fulvestrant-naive treated with neratinib + fulvestrant [Time Frame: 2 years]

  The time to progression or death will be listed, and the progression-free survival (PFS) will be estimated using Kaplan-Meier product limit method. For all the enrolled patients, the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and metastatic sites will be described using contingency tables and assess by McNemar test. The association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and progression-free survival (PFS) will be assessed using Fisher's exact test, Mann-Whitney rank sum test, or log-rank test as appropriate.

• PFS of patients with HER2- ER+ HER2 mutated breast cancer who are fulvestrant-treated treated with neratinib + fulvestrant [Time Frame: 2 years]

  The time to progression or death will be listed, and the progression-free survival (PFS) will be estimated using Kaplan-Meier product limit method. For all the enrolled patients, the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and metastatic sites will be described using contingency tables and assess by McNemar test. The association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and progression-free survival (PFS) will be assessed using Fisher's exact test, Mann-Whitney rank sum test, or log-rank test as appropriate.

• Safety and tolerability of neratinib in combination with fulvestrant in patients with HER2- ER+ HER2 mutated breast cancer as measured by grade and frequency of adverse events [Time Frame: 5 months]

  CTCAE v 4.0 will be used to record AEs

• Response rate of neratinib in combination with fulvestrant in patients with fulvestrant-naïve metastatic ER+ HER2- breast cancer carrying activating HER2 mutations [Time Frame: 2 years]

  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eighty percent confidence interval (CI) will be calculated.

• Response rate of neratinib in combination with fulvestrant in patients with metastatic ER+ HER2- breast cancer carrying activating HER2 mutations previously treated with fulvestrant [Time Frame: 2 years]

  Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Eighty percent confidence interval (CI) will be calculated.

Original Secondary Outcome Measures

Study Design

Brief Title	Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
Official Title	A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer
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
Study Type	Interventional
Study Phase	Phase 2
Estimated Enrollment	70
Allocation	Non-Randomized
Interventional Model	Parallel Assignment
Masking	None (Open Label)
Primary Purpose	Treatment
Conditions	Breast Neoplasms
Target Follow-Up Duration	N/A
Biospecimen:	N/A
Sampling Method	N/A
Study Population	N/A
Intervention	Drug: Neratinib Other Names PF-05208767 Drug: Fulvestrant Other Names Faslodex Drug: Trastuzumab Other Names Herceptin Procedure: Tumor biopsy -Optional at baseline and disease progression Other Names Procedure: Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression) Other Names
Study Groups/Cohorts	Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.
Study Arms	Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Neratinib Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Trastuzumab Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Tumor biopsy -Optional at baseline and disease progression Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression) Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Tumor biopsy -Optional at baseline and disease progression Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Trastuzumab Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Fulvestrant Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Neratinib Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression) Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression) Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Neratinib Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Fulvestrant Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Trastuzumab Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Tumor biopsy -Optional at baseline and disease progression Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression) Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Procedure : Tumor biopsy -Optional at baseline and disease progression Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Trastuzumab Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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. Drug : Neratinib

Arm	Intervention/Treatment
Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Neratinib
Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Trastuzumab
Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Tumor biopsy -Optional at baseline and disease progression
Experimental Part I: met HER2- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Tumor biopsy -Optional at baseline and disease progression
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Trastuzumab
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Fulvestrant
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Neratinib
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Neratinib
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Fulvestrant
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Trastuzumab
Experimental Part II: met HER2- ER+ BC w/HER2 mutations, 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Tumor biopsy -Optional at baseline and disease progression
Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Research blood sample -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)
Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Procedure : Tumor biopsy -Optional at baseline and disease progression
Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Trastuzumab
Experimental Part II: met HER2- ER- BC w/HER2 mutations 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. If a participant experiences disease progression following neratinib, trastuzumab 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.	Drug : Neratinib

Recruitment Information

Recruitment Status:	Recruiting
Enrollment	70
Completion Date	November 30, 2020
Eligibility Criteria:	Inclusion Criteria for Pre-registration: - Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-amplified by FISH) breast cancer that is stage IV. - There is no limitation on the number of prior lines of systemic therapy. - Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except to be eligible for the Part II fulvestrant-naive ER+ cohort, at least one measurable disease by RECIST 1.1 is required. - At least 18 years of age. - ECOG performance status ≤ 2 - Adequate organ function as defined below within 8 weeks of pre-registration: - Serum creatinine ≤1.5 x ULN - Total bilirubin ≤1.5 × ULN (in case of known Gilbert's syndrome, < 2 x ULN is allowed) - AST and ALT ≤3× ULN or < 5 ULN for patients with liver metastases - Able to understand and willing to sign an IRB approved written informed consent document. Note: HER2 mutation testing may be performed while the patient is receiving active systemic therapy for metastatic breast cancer so that the result can be used to determine eligibility for study drug therapy in the future. Exclusion Criteria for Pre-registration: - Testing for LVEF is not required for pre-registration, but patient must not have a recent LVEF < LLN or have symptoms of congestive heart failure. - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. - Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment). - History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias. - Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest. Inclusion Criteria for Registration - Tumor tissue tested positive for HER2 mutation. HER2 mutations detected by Guardant360 are also eligible. - ECOG performance status ≤2 - Adequate organ function as defined below within 2 weeks of registration: - ANC ≥1.5 x 10^9/L - Platelet count ≥100 x 10^9/L - Serum creatinine ≤1.5 x ULN - Total bilirubin ≤1.5 x ULN (in case of known Gilbert's syndrome, < 2 x ULN is allowed) - AST and ALT ≤3× ULN or ≤ 5 x ULN for patients with liver metastases. - The patient must have completed radiation therapy and be at least 1 week from the last systemic chemotherapy administration, with adequate recovery of bone marrow and organ functions, before starting neratinib. - Presence of disease progression on the most recent disease evaluation. - Patients with known brain metastasis are eligible, but must have received radiation and be off steroids and stable (without evidence of disease progression by imaging or exam) for 3 months. - QTc interval ≤450 msec for men or < or ≤ 470 msec for women within 2 weeks of registration. - LVEF > or = institutional ILLN within 4 weeks of registration. - Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product. - Able to understand and willing to sign an IRB approved written informed consent document. - There is no limitation on the number of prior lines of systemic therapy. - To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required. - To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required. In addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology form an earlier time point could be used and a discussion with the study chair is required. Exclusion Criteria for Registration: - Currently receiving any other investigational agents or systemic cancer therapy. - Currently taking medications and herbal or dietary supplements that are strong cytochrome P450 (CYP) 3A4 inducers or inhibitors. The washout period must have been completed prior to the start of neratinib if the patient was taking any of these agents. If unavoidable, patients taking CYP3A4 inhibitors should be monitored closely. - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. - Acute or currently active/requiring antiviral therapy hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment). - Pregnant and/or breastfeeding. - History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias. - Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest. - Experiencing grade 2 or greater diarrhea.
Gender	All
Age	18 Years to N/A
Accepts Healthy Volunteers	No
Contacts	Cynthia Ma, M.D., Ph.D. 314-362-9383 [email protected]
Listed Location Countries	Canada United States

Administrative Information

NCT Number:	NCT01670877
Other Study ID Numbers	201209135
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement	Not Available
Responsible Party	,
Study Sponsor	Washington University School of Medicine
Collaborators	Not Available
Investigators	Principal Investigator Cynthia Ma, M.D., Ph.D Washington University School of Medicine