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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03190967
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : April 20, 2018
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


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 T-DMI prevents the formation of new metastases in the brain.


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


Adults at least 18 years old with a HER2-positive breast cancer that has spread to the brain and was recently treated with stereotactic radiation or surgery.


Participants will be screened with

  • Medical history
  • Physical exam
  • Heart tests
  • A scan (CT) that makes a picture of the body using a small amount of radiation
  • A scan (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.

Condition or disease Intervention/treatment Phase
Breast Cancer Brain Metastasis Brain Cancer Drug: T-DM1 Drug: TMZ Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 125 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 18, 2018
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arm Intervention/treatment
Experimental: 1 - Phase I
T-DM1 + TMZ in dose escalation
Drug: T-DM1
T-DM1 3.6 mg/kg IV every 21 days
Drug: TMZ
Phase I: TMZ 30, 40 or 50 mg/m^2 daily; Phase II: TMZ at RP2D estimated in Phase I
Active Comparator: 2A - Phase II, T-DM1 alone
Drug: T-DM1
T-DM1 3.6 mg/kg IV every 21 days
Experimental: 2B - Phase II, T-DM1 + TMZ
T-DM1 + TMZ at RP2D
Drug: T-DM1
T-DM1 3.6 mg/kg IV every 21 days
Drug: TMZ
Phase I: TMZ 30, 40 or 50 mg/m^2 daily; Phase II: TMZ at RP2D estimated in Phase I

Primary Outcome Measures :
  1. Maximum tolerated dose of temozolomide when used with TDM1 [ Time Frame: Every 21 days ]
  2. Median amount of time subject survives without disease progression after treatment [ Time Frame: At progression ]

Secondary Outcome Measures :
  1. List of adverse event frequency [ Time Frame: 30 days after treatment ]
  2. Number of patients with DLTs at each dose level [ Time Frame: 30 days after treatment ]
  3. Time to whole brain irradiation [ Time Frame: At progression ]
  4. Median amount of time subject survives after therapy [ Time Frame: Death ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
  • Patients must have histologically confirmed HER2-positive breast cancer for which standard curative measures do not exist or are no longer effective. HER2 testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity.
  • Patients must have 1-3 brain metastases, each <3cm by contrast MRI, treated within 6 weeks of study entry with SRS and/or resection. A minimum interval of 3 weeks between completion of brain SRS and/or resection and the start of treatment in this trial will be observed to allow proper healing. The presence of concomitant extracranial metastatic disease is allowed for enrollment.
  • 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 be allowed to continue in the protocol treatment if no further increase in dose is necessary. Patients that need increase in dose of corticosteroid after initial month will be taken off protocol treatment.
  • Age greater than or equal to18 years. Because breast cancer is not commonly found in pediatric population and no dosing or adverse event data are currently available on the use of temozolomide in combination with T-DM1 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
  • ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
  • Patients must have normal organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL
    • absolute neutrophil count greater than or equal to 1,000/mcL
    • platelets greater than or equal to 100,000/mcL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) <3.0 X institutional upper limit of normal
    • creatinine up to 1.5 upper institutional limits OR creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
  • Alkylating agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 7 months (women) or 4 months (men) after treatment completion. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Ability of subject to understand and the willingness to sign a written informed consent document.


  • Patients who are receiving any other investigational agents.
  • Patients unable to speak or understand English, since they cannot complete neurocognitive evaluation.
  • Patients with known leptomeningeal metastatic disease.
  • Patients previously treated with whole brain radiation therapy (WBRT).
  • Patients with major symptoms or impairments related to brain metastases, such as aphasia or severe confusion, will be excluded per PI discretion when those symptoms preclude proper neurocognitive evaluation during the study treatment.
  • Patients who have received previous treatment with T-DM1 and had systemic progression of disease while on it, are ineligible. Patients receiving treatment with T-DM1 whose only site of disease progression was brain are allowed to enroll in this trial.
  • Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin).
  • HBV (HBs Ag positive) or HCV (anti-HCV positive) patients are ineligible because of potential reactivation of hepatitis virus with temozolomide use.
  • Grade greater than or equal to 3 peripheral neuropathy according to (NCI CTCAE) version 4.0.
  • Cerebral Vascular Accident (CVA) or Transitory Ischemic Attack (TIA) in the year before enrollment, or presence of residual symptoms from CVA that happened more than a year before.
  • Pulmonary Embolism (PE) in the 3 months before enrollment. Anticoagulation is permitted as long as stable dosage for more than 3 months.
  • Impaired cardiac function or clinically significant cardiac disease including the following:

    • New York Heart Association grade III or IV congestive heart failure.
    • Myocardial infarction within the last 12 months.
    • Subjects with impaired LVEF (<50%).
  • Patients with inability to complete brain MRI studies with contrast.
  • Patients with breast tissue expanders must have those removed before enrollment.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or T-DM1.
  • Patients receiving medications that are strong CYP3A4 inhibitors or inducers are ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because temozolomide is an alkylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be discontinued if the mother is treated with either of those agents. These potential risks may also apply to other agents used in this study.
  • HIV-positive patients are excluded because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • Patients with any other concomitant or prior invasive malignancies are ineligible. However, patients with prior cancer treated with a curative intent with no evidence of recurrent disease 5 years following diagnosis and judged by the investigator to be at low risk of recurrence are eligible. Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03190967

Contact: Nicole D. Houston, R.N. (240) 760-6127

United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Alexandra S Zimmer, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI) Identifier: NCT03190967     History of Changes
Other Study ID Numbers: 170115
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: April 20, 2018
Last Verified: September 14, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Ado-trastuzumab Emtansine
Systemic Control of Disease
Maximum Tolerated Dose
Preventing the Formation of a Metastasis

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Ado-trastuzumab emtansine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic