HKI-272 for HER2-Positive Breast Cancer and Brain Metastases

NCT01494662 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 11-344TBCRC 022
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 18

Brief Summary

The purpose of this research study is to determine how well neratinib works in treating breast cancer that has spread to the brain. Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2). In this research study, the investigators are looking to see how well neratinib works to decrease the size of or stabilize breast cancer that has spread to the brain. The investigators are also looking at how previous treatments have affected your thinking (or cognition) and how much neratinib reaches the central nervous system.

Conditions

Breast Cancer

Keywords

HER2 Positive; BrCa

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate Per Composite Response Criteria

  Defined as the percentage of patients achieving a complete response (CR) or partial response (PR) of Central Nervous System (CNS) lesions based on composite criteria, reported separately in Cohorts 1, 3A, 3B. For the volumetric criteria, an objective CR will be defined as the following: Disappearance of all CNS target and non-target lesions sustained for at least 4 weeks; no new lesions; stable or decreasing steroid dose; stable or improved neurological symptoms. An objective PR by volumetric criteria will be defined as the following: At least a 50% decrease in the sum volume of CNS target lesions, taking as reference the baseline sum volume sustained for at least 4 weeks; no new lesions; stable or decreasing steroid dose; stable or improved neurological symptoms.

  2 years

• Objective Response Rate Per RANO-BM Criteria

  Defined as the percentage of patients achieving a complete response (CR) or partial response (PR) of Central Nervous System (CNS) lesions based on RANO-BM criteria, reported separately in Cohorts 4A, 4B, and 4C. For the RANO-BM criteria, an objective CR will be defined as the following: Disappearance of all CNS target and non-target lesions sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. An objective PR by RANO-BM criteria will be defined as the following: At least a 30% decrease in the sum LD of CNS target lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically.

  2 years

Secondary Outcomes (6)

• Progression-Free Survival

  Assessed from date of first treatment until the date of first documented progression or date of death from any cause, whichever came first, up to 3 years

• Overall Survival

  Assessed from date of trial registration until the date of death from any cause, up to 5 years

• CNS Response by Macdonald Criteria (Bidirectional Criteria)

  2 years

• Reason for Subject Being Taken Off Study Treatment

  2 years

• Objective Response Based on CNS Composite Criteria for Extension Subgroup of Cohort 1

  2 years

Study Arms (4)

Cohort 1

ACTIVE COMPARATOR

Patients With Progressive Brain Metastases Intervention: HKI-272 (Neratinib)340 mg orally, once daily.

Drug: HKI-272

Cohort 2

ACTIVE COMPARATOR

Patients Who Are Candidates For Craniotomy. Intervention: HKI-272 (Neratinib) 240 mg orally, once daily. Surgical resection (biopsy). Neratinib concentrations from craniotomy specimen, CSF, plasma Neratinib.

Procedure: Surgical Resection

Cohort 3a/3b

ACTIVE COMPARATOR

Cohort 3a will be made up of participants with No Prior Lapatinib Treatment. They will receive Neratinib 240mg Orally daily and 750mg/m2 Capecitabine twice per day for 14 days followed by 7 days rest. Cohort 3b will be made of of participants with Prior Lapatinib Treatment. Cohort 3b participants will receive Neratinib 240mg Orally daily and 750mg/m2 Capecitabine twice per day for 14 days followed by 7 days rest.

Drug: Capecitabine

Cohort 4a/4b/4c

ACTIVE COMPARATOR

Cohort 4a will be made up of participants with previously untreated brain metastases. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks. Cohort 4b will be made up of participants with progressive brain metastases. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks. Cohort 4c will be made up of participants with progressive brain metastases and prior T-DM1. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks.

Drug: HKI-272; Drug: Ado-Trastuzumab Emtansine

Interventions

Capecitabine DRUG

750 mg/m2 orally, twice daily (1,500 mg/m2 daily) for 14 days followed by 7 days off

Also known as: Xeloda

Cohort 3a/3b

Ado-Trastuzumab Emtansine DRUG

3.6 mg/kg IV every 3 weeks

Also known as: T-DM1

Cohort 4a/4b/4c

HKI-272 DRUG

240 mg orally, once daily

Also known as: Neratinib

Cohort 1

Surgical Resection PROCEDURE

Neratinib concentrations from craniotomy specimen, CSF, plasma Neratinib.

Also known as: Biopsy

Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients (men or women) must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study.
• Invasive primary tumor or metastatic tissue confirmation of HER2-positive status
• Over-expression by immunohistochemistry (IHC) with score of 3+ (in \> 30% of invasive tumor cells) AND/OR HER2 gene amplification (\> 6 HER2 gene copies per nucleus or a FISH ratio \[HER2 gene copies to chromosome 17 signals\] of ≥ 2.0)
• Note: Patients with a negative or equivocal overall result (FISH ratio of \< 2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment
• No increase in corticosteroid dose in the week prior to baseline brain MRI
• Prior trastuzumab and lapatinib therapy are allowed.
• There is no limit to the number of previous lines of therapy (including chemotherapy, trastuzumab, and endocrine therapies)
• No prior therapy with neratinib is allowed
• At least 2 weeks washout period post chemotherapy, any prior protocol therapy, lapatinib, other targeted or biologic therapy, or radiation therapy is required prior to study entry
• No washout is required for hormonal therapy but concurrent hormonal therapy is not allowed for patients on study
• Patients with progressive disease (Cohort 1):
• For cohort 1, patients must have new or progressive CNS lesions, as assessed by the patient's treating physician.
• In cohort 1, patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension ≥10 mm by local radiology review. Note: measurable non-CNS disease is NOT required for study participation
• It is anticipated that some patients may have multiple progressive CNS lesions, one or several of which are treated with SRS or surgery with residual untreated lesions remaining. Such patients are eligible for enrollment on this study providing that at least one residual (i.e. non-SRS-treated or non-resected) lesion is measurable (≥10 mm).
• Patients who have had prior cranial surgery are eligible, provided that there is evidence of measurable residual or progressive lesions, and at least 2 weeks have passed since surgery. If a patient has surgical resection followed by WBRT, then there must be evidence of progressive CNS disease after the completion of WBRT.

You may not qualify if:

• Not pregnant or breastfeeding
• Participants who have had chemotherapy or radiotherapy (including investigational agents) within 2 weeks prior to entering the study or those who have not recovered adequately from adverse events due to agents administered more than 4 weeks earlier (excluding alopecia). Washout from trastuzumab is not required.
• Participants who are currently receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib
• Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone
• Patients who are receiving any cancer-directed concurrent therapy, such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment with bisphosphonates is allowed but should be started before the first dose of neratinib.
• 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
• More than two seizures over the last 4 weeks prior to study entry
• Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body
• Those with leptomeningeal metastases as the only site of CNS disease
• Significant malabsorption syndrome or inability to tolerate oral medications
• Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea
• Patient Cohort 4:
• \- In cohort 4, eligible patients must have measurable Central Nervous System disease. Cohort 4a will have participants with previously untreated brain metastases. Cohort 4b will have participants with progressive brain metastases. Cohort 4c will have participants will have progressive brain metastases and prior T-DM1
• Participants who are currently receiving any other investigational agents.

Sponsors & Collaborators

• Puma Biotechnology, Inc.: collaborator
• Dana-Farber Cancer Institute: lead
• Translational Breast Cancer Research Consortium: collaborator

Study Sites (18)

University of California, San Francisco Medical Center

San Francisco, California, 94115, United States

Location

MedStar Georgetown Univeristy Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hosptial

Boston, Massachusetts, 02215, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

University of North Carolina at Chapel Hill - Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

UPMC Passavant Cranberry

Cranberry Township, Pennsylvania, 16066, United States

Location

Arnold Palmer Cancer Center-Greensburg

Greensburg, Pennsylvania, 15601, United States

Location

UPMC Pinnacle Harrisburg

Harrisburg, Pennsylvania, 17101, United States

Location

UPMC Ortenzio Cancer Center

Mechanicsburg, Pennsylvania, 17050, United States

Location

UPMC Cancer Centers - Magee-Womens Hospital of UPMC

Pittsburgh, Pennsylvania, 15213, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Baylor College of Medicine Lester and Sue Smith Breast Center

Houston, Texas, 77030, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (3)

• Freedman RA, Gelman RS, Agar NYR, Santagata S, Randall EC, Gimenez-Cassina Lopez B, Connolly RM, Dunn IF, Van Poznak CH, Anders CK, Melisko ME, Silvestri K, Cotter CM, Componeschi KP, Marte JM, Moy B, Blackwell KL, Puhalla SL, Ibrahim N, Moynihan TJ, Nangia J, Tung N, Burns R, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU; Translational Breast Cancer Research Consortium (TBCRC). Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022. Clin Breast Cancer. 2020 Apr;20(2):145-151.e2. doi: 10.1016/j.clbc.2019.07.011. Epub 2019 Aug 22.

  PMID: 31558424 DERIVED

• Freedman RA, Gelman RS, Anders CK, Melisko ME, Parsons HA, Cropp AM, Silvestri K, Cotter CM, Componeschi KP, Marte JM, Connolly RM, Moy B, Van Poznak CH, Blackwell KL, Puhalla SL, Jankowitz RC, Smith KL, Ibrahim N, Moynihan TJ, O'Sullivan CC, Nangia J, Niravath P, Tung N, Pohlmann PR, Burns R, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU; Translational Breast Cancer Research Consortium. TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases. J Clin Oncol. 2019 May 1;37(13):1081-1089. doi: 10.1200/JCO.18.01511. Epub 2019 Mar 12.

  PMID: 30860945 DERIVED

• Freedman RA, Gelman RS, Wefel JS, Melisko ME, Hess KR, Connolly RM, Van Poznak CH, Niravath PA, Puhalla SL, Ibrahim N, Blackwell KL, Moy B, Herold C, Liu MC, Lowe A, Agar NY, Ryabin N, Farooq S, Lawler E, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU. Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases. J Clin Oncol. 2016 Mar 20;34(9):945-52. doi: 10.1200/JCO.2015.63.0343. Epub 2016 Feb 1.

  PMID: 26834058 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

neratinib; Biopsy; Capecitabine; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Rachel Freedman, MD
• Organization: Dana-Farber Cancer Institute

Rachel_Freedman@dfci.harvard.edu

617-632-3800

Study Officials

• Rachel Freedman, M.D., M.P.H.

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: December 14, 2011
• First Posted: December 19, 2011
• Study Start: February 1, 2012
• Primary Completion: February 1, 2023
• Study Completion: April 19, 2024
• Last Updated: January 23, 2026
• Results First Posted: May 22, 2024

Record last verified: 2026-01

Locations

US (18)