Clinical Trials /

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

NCT03190967

Description:

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 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 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 (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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 170115
  • SECONDARY ID: 17-C-0115
  • NCT ID: NCT03190967

Conditions

  • Breast Cancer
  • Brain Metastasis
  • Brain Cancer

Interventions

DrugSynonymsArms
T-DM11 - Phase I
TMZ1 - Phase I

Purpose

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 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 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 (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.

Detailed Description

      Background:

        -  Breast cancer is the most common cancer in women. In the 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
           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 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 at one year as
           compated to T-DM1 alone.

      Eligibility:

        -  Histologically confirmed HER2+ breast cancer.

        -  ECOG performance status 0-2 and adequate organ and marrow function.

        -  1-3 brain metastases, each < 3 cm by contrast MRI, treated within 6 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 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
1 - Phase IExperimentalT-DM1 + TMZ in dose escalation
  • T-DM1
  • TMZ
2A - Phase II, T-DM1 aloneActive ComparatorT-DM1
  • T-DM1
2B - Phase II, T-DM1 + TMZExperimentalT-DM1 + TMZ at RP2D
  • T-DM1
  • TMZ

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  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.

        EXCLUSION CRITERIA:

          -  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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of temozolomide when used with TDM1
Time Frame:Every 21 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:List of adverse event frequency
Time Frame:30 days after treatment
Safety Issue:
Description:
Measure:Number of patients with DLTs at each dose level
Time Frame:30 days after treatment
Safety Issue:
Description:
Measure:Time to whole brain irradiation
Time Frame:At progression
Safety Issue:
Description:
Measure:Median amount of time subject survives after therapy
Time Frame:Death
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Ado-trastuzumab Emtansine
  • Systemic Control of Disease
  • Maximum Tolerated Dose
  • Preventing the Formation of a Metastasis

Last Updated

February 8, 2018