HKI-272 for HER2-Positive Breast Cancer and Brain Metastases - Full Text View

Sponsor:	Dana-Farber Cancer Institute
Collaborator:	Translational Breast Cancer Research Consortium
Information provided by (Responsible Party):	Rachel Freedman, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT01494662

Purpose

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.

Condition	Intervention	Phase
Breast Cancer	Drug: HKI-272 Procedure: Surgical Resection	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Trial of HKI-272 (Neratinib) for Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer and Brain Metastases

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

U.S. FDA Resources

Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:

Objective Response Rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To evaluate the objective response rate in the Central Nervous System by composite response criteria in Cohort 1

Secondary Outcome Measures:

Progression-Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Progression Free Survival
Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Overall survival
CNS response by Macdonald criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]
CNS response by Macdonald criteria
First site of disease progression [ Time Frame: 2 years ] [ Designated as safety issue: No ]
First site of disease progression
Safety and Tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Safety and Tolerability of therapy - number and type and severity of adverse events related to the therapy.
Association of CTC count and OS [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Explore the association of CTC count and OS
Clinical outcomes [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Assess clinical outcomes for subjects who opt to receive trastuzumab and neratinib at the time of non-CNS progression (i.e. toxicity, CNS and non-CNS response, site of first progression, OS)

Estimated Enrollment:	45
Study Start Date:	January 2012
Estimated Primary Completion Date:	January 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Cohort 1 Patients With Progressive Brain Metastases	Drug: HKI-272 240 mg orally, once daily Other Name: Neratinib
Active Comparator: Cohort 2 Patients Who Are Candidates For Craniotomy	Drug: HKI-272 240 mg orally, once daily Other Name: Neratinib Procedure: Surgical Resection neratinib concentrations from craniotomy specimen, CSF, plasmaNeratinib Other Name: Biopsy

Detailed Description:

Subjects will receive neratinib and a drug-dosing calendar for each treatment cycle. This drug is given orally on a daily basis, continuously. Each treatment cycle will last for 4 weeks during which time the subject will be taking neratinib every day.

Physical Exams and vital signs: At the start of each cycle, you will have a physical exam. You will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking. You will also have a neurological examination to assess for neurological symptoms.
Scans (or Imaging tests): We will assess your tumor by brain MRI every other cycle (the end of cycles 2, 4, 6, 8, etc.) while on study. CT or MRI scans of your chest, abdomen, and pelvis will be performed every other cycle, at the same time points as the brain MRI. Your research doctor may ask you to have a bone scan at the same time points if this is clinically indicated.
Photographs: Photographs may be taken of your tumor to assess the response of your tumor to the treatment. Care will be taken to ensure these do not reveal your identity.
MUGA or Echo: You will have a MUGA or ECHO done every 3 treatment cycles (the end of cycles 3, 6, 9, etc.).
Blood tests: You will have blood tests done at the beginning of each treatment cycle to check your blood cell counts and how well your organs are functioning. In addition to regular blood tests, we will be collecting 2 tubes of blood for research after cycle 1.
Neurocognitive Function: If you have previously received treatment for cancer that has spread to your brain (prior to enrollment on this study), you will be asked to take a battery of tests that assess your cognition (thinking) at the start of the study, after 2 cycles of treatment, and possibly at the end of the study. With these tests, we are trying to better understand how your previous treatments and ongoing treatments affect your memory, attention, learning, and other related skills. These tests will be administered to you by a trained research assistant and may take 30-45 minutes to complete.
For preoperative patients only: If you are a patient who is planning to have an operation to remove the cancer in your brain, you will have your surgery between 7-21 days after starting neratinib. These tests will allow us to measure of how much drug (neratinib) reaches the central nervous system and will help us understand how well neratinib does this.
At surgery, a part of your tumor cerebrospinal fluid will be collected to test for levels of neratinib
You will also have a blood test on day of surgery to test for levels of neratinib
You will then resume neratinib once you have recovered from your surgery

After the final dose of the study drug:

You will have a follow-up visit one month after coming off study treatment. During that visit, you will have a physical examination, functional assessment, assessment of any toxicities and current medications, and a neurological examination. If you continue to have ongoing toxicity related to your study treatment, we will continue to follow you until this toxicity resolves. In addition, we will collect 2 additional tubes of blood for research and to measure if a marker for your particular breast cancer exists.

We would like to keep track of your medical condition for up to two years after you stop the study treatment. If you are not seen in follow-up at your participating center (where you enrolled on the study), we would like to follow you by calling you on the telephone or by sending you a letter once a year to see how you are doing. We may also contact your doctor once every 6 months to see how you are doing. Keeping in touch with you and checking your condition every year helps us look at the long-term effects of the research study. If you do not wish to be contacted after you stop the study treatment, you must notify the research study staff of your withdrawal of consent for follow-up

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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)
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
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
For cohort 1, patients must have new or progressive CNS lesions, as assessed by the patient's treating physician. This includes patients who have progressed after at least one line of standard treatment for CNS disease
In cohort 2, eligible patients will include those who have CNS disease that is amenable for surgery (typically < 3 brain metastases and with planned resection by neurosurgery). These patients may include those who have received or not received previous treatment(s) for their CNS.
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, as defined in Section 4.1.3. The location of the measurable lesion should be documented in the patient chart and case report form.
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.

Exclusion Criteria:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01494662

Contacts

Contact: Rachel Freedman, M.D., M.P.H.

6176322335

rafreedman@partners.org

Locations

United States, Massachusetts
Dana-Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02215
Contact: Nicole Ryabin, B.S. 617-623-6767 nryabin@partners.org
Massachusetts General Hosptial	Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Beverly Moy, M.D. 517-726-4920 bmoy@partners.org
Beth Israel Deaconess Medical Center	Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Christine Herold, M.D. 617-667-1970 cherold@bidmc.harvard.edu

Sponsors and Collaborators

Dana-Farber Cancer Institute

Translational Breast Cancer Research Consortium

Investigators

Principal Investigator:

Rachel Freedman, M.D., M.P.H.

Dana-Farber Cancer Institute

More Information

No publications provided

Responsible Party:	Rachel Freedman, Principle Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT01494662 History of Changes
Other Study ID Numbers:	11-344, TBCRC 022
Study First Received:	December 14, 2011
Last Updated:	February 16, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:

HER2 Positive
BrCa

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasm Metastasis
Neoplasms by Site
Neoplasms

Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes

ClinicalTrials.gov processed this record on May 23, 2012