Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Rare Diseases

Breast Neoplasms

Neoplasm Metastasis

Brain Neoplasms

Breast Diseases

Skin Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Myotonic Dystrophy Type 1

Antineoplastic Agents

All Drugs and Chemicals

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Trastuzumab

Temozolomide

Ado-Trastuzumab Emtansine

Adenosine

Antineoplastic Agents, Immunological

Antineoplastic Agents, Alkylating

Alkylating Agents

T-DM1 + TMZ at recommended phase 2 dose (RP2D)

T-DM1 3.6 mg/kg intravenous (IV) every 21 days

T-DM1

Phase I: TMZ 30, 40 or 50 mg/m\^2 daily Phase II: TMZ at recommended phase 2 dose (RP2D) estimated in Phase I dose escalation part of the study.

Stanley Lipkowitz, M.D.

Background:

Sometimes breast cancer spreads (metastasizes) to the brain. Researchers want to study new treatments for brain metastases. The drug Temozolomide is approved to treat brain tumors. Researchers want to see if combining it with the drug trastuzumab emtansine (T-DMI) prevents the formation of new metastases in the brain.

Objective:

To study if Temozolomide with T-DM1 lowers the chance of having new metastases in the brain.

Eligibility:

Adults at least 18 years old with a human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to the brain and was recently treated with stereotactic radiation or surgery.

Design:

Participants will be screened with

* Medical history
* Physical exam
* Heart tests
* A scan (computed tomography (CT) that makes a picture of the body using a small amount of radiation
* A scan (magnetic resonance imaging (MRI) that uses a magnetic field to make an image of the brain
* Blood tests.
* Pregnancy test.

The study will be done in 3-week cycles.

All participants will get T-DM1 on Day 1 of every cycle through a small plastic tube inserted in an arm vein.

Some participants will also take Temozolomide capsules by mouth every day.

Participants will keep a medication diary.

During the study, participants will also:

* Repeat most of the screening tests.
* Answer questions about their general well-being and functioning.

Participants will have lumbar puncture at least 2 times. A needle is inserted into the spinal canal low in the back and cerebrospinal fluid is collected. This will be done with local anesthesia and with the help of images.

Participants will be asked to provide tumor samples when available.

Participants will have a follow-up visit about 1 month after stopping the study drug. They will be contacted by telephone or email every 3 months after that.

Background:

* Breast cancer is the most common cancer in women. In the human epidermal growth factor receptor 2 (HER2+) subtype, brain metastases can occur in up to 25-40% of patients.
* The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).
* Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients.
* Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion.
* Our group has shown in vitro and in vivo in animal models injected with a brain tropic O6-methylguanine DNA methyltransferase (MGMT) + cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases.
* We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease.

Objectives:

* Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1.
* Phase II: to determine if the combination regimen of trastuzumab emtansine (T-DM1) and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement.

Eligibility:

Phase I:

* Histologically confirmed HER2+ breast cancer.
* Eastern Cooperative Oncology (ECOG) performance status 0-2 and adequate organ and marrow function.
* Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT.
* Patients with leptomeningeal metastatic disease are ineligible.
* Patients that are unable to complete a brain MRI with contrast are ineligible.
* Patients with breast tissue expanders must have those removed before enrollment.
* Hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV)-positive patients are ineligible.
* Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
* Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period and will be taken off protocol.

Phase II:

* Histologically confirmed HER2+ breast cancer.
* ECOG performance status 0-2 and adequate organ and marrow function.
* 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS and/or resection.
* Patients with leptomeningeal metastatic disease are ineligible.
* Patients with history of WBRT are ineligible.
* Patients that are unable to complete a brain MRI with contrast are ineligible.
* Patients with breast tissue expanders must have those removed before enrollment.
* HBV, HCV or HIV-positive patients are ineligible.
* Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
* Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period and will be taken off protocol.

Design:

* This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in prevention of new brain metastases in patients with limited brain metastases from HER2+ breast cancer, previously treated with SRS or surgical resection of brain metastases.
* All patients will receive the standard second-line therapy for HER2+ metastatic breast cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus T-DM1 alone.
* Phase I run in: T-DM1 3.6 mg/kg intravenous (IV) every 21 days plus TMZ 30, 40 or 50 mg/m\^2 daily.
* Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D).
* Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients may be included in the initial safety evaluation.
* In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98 total) will need to be randomized over a 3-year period and followed for an additional 2 years from the date of entry of the last patient, with occurrence of 79 total relapses in both arms combined, in order to have 80% power to compare the curves.

T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery

Phase I/II Study of T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Maximum tolerated dose of TMZ when used in combination with T-DM1. MTD is defined as the dose level at which 0 or 1 participant in 6 has a dose limiting toxicity (DLT). A DLT is defined as grade 3 or higher non-hematologic adverse events excluding grade 3 hypertension controlled with anti-hypertensive therapy; or grade 3 asymptomatic electrolytes imbalance; grade 3 endocrinopathy; grade 3 asymptomatic increase in aspartate aminotransferase or alanine aminotransferase; and transient (lasting less than \<48 hours) nausea, emesis, or diarrhea if corrected with conservative measures within 24-48 hours. A hematologic grade 4 neutropenia of ≥ 7 days duration, grade ≥ 3 thrombocytopenia, and all other grade 4 hematologic toxicities excluding grade 4 lymphopenia, or leukopenia in the absence of grade 3 or higher neutropenia. Grade 3 is severe. Grade 4 is life-threatening.

Median time to progression. Progression was assessed using the Response Assessment in Neuro-oncology Brain Metastases (RANO-BM) Criteria for evaluation of brain lesions, and the Response Evaluation Criteria in Solid Tumors (RECIST) for systemic evaluation. Progression is a 25% increase in the sum of products of all measurable lesions observed over baseline if no decrease. Or appearance of new lesions, or failure to return for evaluation due to death or deteriorating condition.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe. Grade 4 is life-threatening.

Number of participants with DLTs at each dose level 30 days after treatment. A DLT is defined as grade 3 or higher non-hematologic adverse events excluding grade 3 hypertension controlled with anti-hypertensive therapy; or grade 3 asymptomatic electrolytes imbalance; grade 3 endocrinopathy; grade 3 asymptomatic increase in aspartate aminotransferase or alanine aminotransferase; and transient (lasting less than \<48 hours) nausea, emesis, or diarrhea if corrected with conservative measures within 24-48 hours. A hematologic grade 4 neutropenia of ≥ 7 days duration, grade ≥ 3 thrombocytopenia, and all other grade 4 hematologic toxicities excluding grade 4 lymphopenia, or leukopenia in the absence of grade 3 or higher neutropenia. Grade 3 is severe. Grade 4 is life-threatening.

Time to whole brain irradiation compared between the two arms and Kaplan-Meier curves constructed with a two-tailed log-rank test used to compare the arms.

Median amount of time participants survives after therapy. Survival compared between the two arms and Kaplan-Meier curves constructed with a two-tailed log-rank test used to compare the arms.

TTP is the time between the first day of treatment to the day of disease progression. Progression was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 25% increase in the sum of products of all measurable lesions over smallest sum observed, clear worsening of any evaluable disease, appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition.

National Cancer Institute (NCI)

Principal Investigator

Level 1: T-DM1 3.6 mg/kg intravenous (IV) every 21 days; Temozolomide 30 mg/m\^2 by mouth (PO) daily

Level 1 Phase I: Ado-trastuzumab (T-DMI) 3.6 mg/kg + Temozolomide (TMZ) 30 mg/m^2

Level 2: T-DM1 3.6 mg/kg intravenous (IV) every 21 days; Temozolomide 40 mg/ m\^2 by mouth (PO) daily

Level 2 Phase I: Ado-trastuzumab (T-DMI) 3.6 mg/kg + Temozolomide (TMZ) 40 mg/m^2

Level 3: T-DM1 3.6 mg/kg intravenous (IV) every 21 days; Temozolomide 50 mg/ m\^2 by mouth (PO) daily

Level 3 Phase I: Ado-trastuzumab (T-DMI) 3.6 mg/kg + Temozolomide (TMZ) 50 mg/m^2

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Stanley Lipkowitz, PhD

All participants who received at least one dose of Temozolomide at 30, 40 or 50 mg/m\^2 by mouth (PO) daily.

All Participants

Phase I: Maximum Tolerated Dose (MTD) of Temozolomide (TMZ) When Used With T-DM1 (Ado-trastuzumab)

Phase II Arm A: Ado-trastuzumab (T-DMI) Alone

Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)

Phase II Arm B: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)

This outcome measure was not done because the trial was terminated early due to withdrawal of drug support for the planned randomized phase II cohorts. Data was never collected.

Phase II: Median Amount of Time Participant Survives Without New Brain Lesions After Starting Treatment

Grade 3 Anemia

Grade 3 Aspartate aminotransferase increased

Grade 3 CD4 lymphocytes decreased

Grade 3 Dysphasia

Grade 3 Hypokalemia

Grade 3 Lymphocyte count decreased

Grade 3 Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Malignant Neoplasm-CML

Grade 3 Neutrophil count decreased

Grade 3 Platelet count decreased

Grade 3 Surgical and medical procedures - Other, Lap Cholecystectomy/Hernia Repair

Grade 3 White blood cell decreased

Grade 4 White blood cell decreased

Grade 4 CD4 lymphocytes decreased

Grade 4 Lymphocyte count decreased

Grade 5

Level 3 Phase I:Ado-trastuzumab (T-DMI) 3.6 mg/kg + Temozolomide (TMZ) 50 mg/m^2

Phase I: Number of Participants With Grade 3 and/or Grade 4 Adverse Events

Phase I: Number of Participants With Dose Limiting Toxicity (DLTs) at Each Dose Level

Phase II: Time to Whole Brain Irradiation

Phase I: Median Survival

Level 2 Phase I:Ado-trastuzumab (T-DMI) 3.6 mg/kg + Temozolomide (TMZ) 40 mg/m^2

TTP was not reached for 1 participant in dose level 1, and 1 participant in dose level 3.

Phase I: Standard Time to Progression (TTP)

Phase II: Median Survival

Phase I: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Spots Global Cancer Trial Database for preventing the formation of a metastasis