Clinical Trials /

ARRY-380 + Trastuzuamab for Breast w/ Brain Mets

NCT01921335

Description:

The purpose of this study is to test the safety of different doses of ARRY-380 in combination with trastuzumab. Trastuzumab is an FDA approved drug for the treatment of HER2 metastatic breast cancer. However, the combination of ARRY-380 and trastuzumab has not yet been tested. Both agents block the HER2 receptor, which is thought to be overactive in HER2-positive breast cancer. It is thought that ARRY-380 and trastuzumab might work together because they attach to different parts of the HER2 receptor and prevent it from functioning. Because HER2 positive breast cancer contains high levels of HER2 receptor, but normal cells in your body generally do not, the drugs may be able to "target" the cancer cells. In addition, in laboratory studies, ARRY-380 appears to have some penetration into the brain.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: ARRY-380 + Trastuzuamab for Breast w/ Brain Mets
  • Official Title: Phase I Dose-escalation Trial of ARRY-380 in Combination With Trastuzumab in Participants With Brain Metastases From HER2+ Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 13-198
  • SECONDARY ID: ARRAY-380-104X
  • NCT ID: NCT01921335

Conditions

  • Brain Metastases From HER2 and Breast Cancer
  • Advanced HER2-positive Breast Cancer

Interventions

DrugSynonymsArms
ARRY-380 Twice Daily DosageARRY-380 Twice Daily Dosage
ARRY-380 Once DailyARRY-380 Once Daily
TrastuzumabHerceptinARRY-380 Twice Daily Dosage

Purpose

The purpose of this study is to test the safety of different doses of ARRY-380 in combination with trastuzumab. Trastuzumab is an FDA approved drug for the treatment of HER2 metastatic breast cancer. However, the combination of ARRY-380 and trastuzumab has not yet been tested. Both agents block the HER2 receptor, which is thought to be overactive in HER2-positive breast cancer. It is thought that ARRY-380 and trastuzumab might work together because they attach to different parts of the HER2 receptor and prevent it from functioning. Because HER2 positive breast cancer contains high levels of HER2 receptor, but normal cells in your body generally do not, the drugs may be able to "target" the cancer cells. In addition, in laboratory studies, ARRY-380 appears to have some penetration into the brain.

Detailed Description

      If a patient participates in this research study, the patient will receive ARRY-380 and a
      drug-dosing diary to record when the patient took ARRY-380 for each study treatment cycle.
      Each study treatment cycle will last for 3 weeks (21 days) during which time the patient will
      be taking ARRY-380 by mouth every day. At the time the patient enters the study, the patient
      will be assigned to either Arm A or Arm B. The difference between the two study arms includes
      ARRY-380 administered twice-daily (morning and evenings - Arm A) or once-daily (morning - Arm
      B). The patient will also be given Trastuzumab by intravenous infusion (by vein) on day 1 of
      each cycle (same dose and schedule for both study arms).

      The dose of trastuzumab will be the same for everyone on study, and will be the standard
      approved dose for this medication. In the first portion of the study, the investigators will
      examine the effects of different dose of ARRY-380 when given in combination with trastuzumab.
      Initially, 3 participants will be treated with a low dose of the ARRY-380 in combination with
      standard dose of trastuzumab. If this dose does not cause intolerable side effects, more
      participants may receive the drug combination at the same dose. The patient will be informed
      of the assigned dose when the patient enters the study. The patient will be asked to take
      ARRY-380 for as long as the study treatment is of possible benefit to the patient. After the
      patient is finished taking ARRY-380, the study doctor will ask the patient to visit the
      office for follow-up exams for at least one more visit within 4 weeks of the patient's last
      study treatment.

      At the start of each cycle the patient will have:

        -  A medical history, which includes questions about health, current medications, and any
           allergies.

        -  Performance status, which evaluates the ability to carry on with usual activities.

        -  Physical examination, the doctor will examine the patient body, including measuring
           height, weight, and vital signs (blood pressure, body temperature, pulse rate and
           breathing rate).

        -  A neurological examination to asses any neurological symptoms(for example, difficulties
           with balance)

        -  Blood tests will be drawn at the beginning of each study treatment cycle for tests to
           monitor the function of liver and kidneys and to check blood cell counts. In addition,
           blood tests will be drawn on days 4, 8, and 15 of the first cycle of study treatment to
           monitor liver function.

      Periodically the patient will undergo:

        -  The patient will have a brain MRI every two cycles. If the brain scans are stable or
           improved after the patient has been on the study for 6 months or longer, the frequency
           of your body scans will be decreased to once every 4 cycles. The patient will also have
           CT or MRI scans of the body at the end of cycle 2, cycle 4 and every 4 cycles
           thereafter. The research doctor may ask the patient to have a bone scan at the same time
           points if this is clinically indicated.

        -  Electrocardiogram (EKG), which shows the electrical activity of the heart. It will be
           performed on Day 1 of cycle 2.

        -  Echocardiogram (ECHO) (ultrasound of the heart) or MUGA scan (test of heart function
           using a small amount of a radioactive substance). This will be performed every 3-4
           months.

      Additional research procedures to be performed:

        -  On Cycle 1, Day 15 blood for ("PK") pharmacokinetic (what the body does to the drug)
           sampling will be drawn before the morning dose of ARRY-380, after 2 hours and after six
           hours.

        -  Blood tests for research, which will include about 2 tablespoons of blood collected
           before cycle 1 and after coming off study treatment. In general terms, scientists will
           study the genes, the RNA, and the proteins that are found in the blood samples.
           Scientists will also measure and characterize circulating tumor cells in the blood, if
           they are present. In addition, these specimens may be tested with new types of tests, as
           they become available. Results of the research tests on blood will not be reported back
           to the patient.

        -  Archival Tumor Tissue Sample: A sample (or samples) of the patient's tumor tissue (from
           a past surgery and/or biopsy) will be collected and used to learn more about the
           development of metastatic breast cancer. In general terms, scientists will study the
           genes, the RNA, and the proteins that are found both in breast tumors and in normal
           tissue. In addition, these specimens may be tested with new types of tests, as they
           become available. Laboratory-based investigators conducting this research will not have
           access to patient identification information such as name or medical record number.
           Results of the research tests on tissue will not be reported back to the patient.

      After the final dose of the study drug:

      The patient will have a follow-up visit one month after coming off study treatment. During
      that visit, the patient will have a physical examination, functional assessment, assessment
      of any toxicities and current medications. If the patient continues to have ongoing side
      effects related to the study treatment, the investigators will continue to follow the patient
      until these side effects resolve. If the patient withdrew from the study for another reason
      other than tumor progression, the patient will continue to be followed until tumor
      progression.

      Planned Follow-up:

      The investigators would like to keep track of the patient's medical condition indefinitely.
      The investigators would like to do this either by seeing the patient in clinic or by
      contacting the patient and the patient's primary doctor periodically to see how the patient
      is doing. Keeping in touch with the patient and checking the patient's condition periodically
      helps the investigators look at the long-term effects of the research study.
    

Trial Arms

NameTypeDescriptionInterventions
ARRY-380 Twice Daily DosageActive ComparatorARRY-380 will be 450mg orally twice-daily. Trastuzumab will be given at the standard full dose with a loading dose of 8 mg/kg on Day 1, cycle 1, followed by 6 mg/kg in subsequent cycles. Participants who are within 5 weeks of a 6 mg/kg dose or within 2 weeks of a 2 mg/kg dose of trastuzumab at the time of initial study dosing will not be required to have a re-loading dose but will begin treatment at 6 mg/kg.ARRY-380 will be escalated until MTD is defined or the maximum planned dose has been evaluated. The dose for subsequent dose levels will be determined according to the treatment-related AE observed during the cycle 1 (21 days) in the previous dose level
  • ARRY-380 Twice Daily Dosage
  • Trastuzumab
ARRY-380 Once DailyActive ComparatorARRY-380 will be 750mg orally once-daily. Trastuzumab will be given at the standard full dose with a loading dose of 8 mg/kg on Day 1, cycle 1, followed by 6 mg/kg in subsequent cycles. Participants who are within 5 weeks of a 6 mg/kg dose or within 2 weeks of a 2 mg/kg dose of trastuzumab at the time of initial study dosing will not be required to have a re-loading dose but will begin treatment at 6 mg/kg. ARRY-380 will be escalated until MTD is defined or the maximum planned dose has been evaluated. The dose for subsequent dose levels will be determined according to the treatment-related AE observed during the cycle 1 (21 days) in the previous dose level
  • ARRY-380 Once Daily
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must meet the following criteria on screening examination to be eligible
             to participate in the study. Laboratory evaluations must have been performed within 14
             days of study entry. Non-laboratory tests must have been performed within 30 days of
             study entry. Evaluation of LVEF must have been performed within 60 days of study
             entry:

          -  Participants must have histologically confirmed HER2+ (3+ by immunohistochemistry
             and/or FISH ratio >/= 2.0) invasive breast cancer. Central confirmation of HER2 status
             is not required.

          -  Participants must have measurable CNS disease, defined as at least one parenchymal
             brain lesion that can be accurately measured in at least one dimension (longest
             diameter to be recorded) as > 10 mm by local radiology review (note: measurable
             non-CNS disease is NOT required for study participation). See section 10 for the
             evaluation of measureable disease.

          -  New or progressive CNS lesions, as assessed by the patient's treating physician.

          -  It is anticipated that some participants may have multiple progressive CNS lesions,
             one or several of which are treated with SRS or surgery with residual un-treated
             lesions remaining. Such participants are eligible for enrollment on this study
             providing that at least one untreated lesion is measurable, as defined in section
             3.1.2. The location of the measurable lesion should be documented in the patient chart
             and case report form.

          -  Participants who have had prior cranial surgery are eligible, provided that there is
             evidence of measurable residual or progressive lesions. If a patient has surgical
             resection followed by WBRT, then there must be evidence of progressive CNS disease
             after the completion of WBRT.

          -  Participants who have had prior WBRT and/or SRS and then whose lesions have progressed
             thereafter are also eligible. In this case, lesions which have been treated with SRS
             may be considered as target lesions if there is unequivocal evidence, in the opinion
             of the treating physician, of progression following SRS.

          -  Participants who have not previously been treated with cranial radiation (e.g. WBRT or
             SRS) are eligible to enter the study, but such participants must be asymptomatic from
             their CNS metastases and not requiring corticosteroids.

          -  No increase in corticosteroid dose in the week prior to the baseline brain MRI.

          -  Age ≥18 years

          -  ECOG performance status 0 to 2 (see Appendix A)

          -  Participants must have normal organ and marrow function as defined below:

          -  Absolute neutrophil count ≥ 1,000/mcL

          -  Platelets ≥ 75,000/mcL

          -  Total bilirubin < 2 X institutional upper limit of normal

          -  AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal in participants
             without liver metastases and < 5 ULN in participants with documented liver metastases

          -  Left ventricular ejection fraction ≥ 50%, as determined by RVG or echocardiogram
             within 60 days prior to initiation of protocol therapy

          -  Prior therapy - Prior trastuzumab and/or lapatinib are allowed. There is no limit on
             the number of prior lines of therapy.

          -  The effects of ARRY-380 on the developing human fetus are unknown. For this reason and
             because other therapeutic agents used in this trial may 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 and for the duration
             of study participation. Should a woman become pregnant or suspect she is pregnant
             while participating in this study, she should inform her treating physician
             immediately.

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Participants who exhibit any of the following conditions at screening will not be
             eligible for admission into the study.

          -  Participants who have had chemotherapy or radiotherapy within 14 days prior to
             entering the study (with the exception of trastuzumab) or those who have not recovered
             from adverse events to ≤ grade 1 due to agents administered more than 4 weeks earlier.

          -  Participants may not be receiving any other investigational agents. Concurrent
             treatment with bisphosphonates or denosumab is allowed

          -  History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical
             or biologic composition to ARRY-380 or trastuzumab

          -  Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker,
             shrapnel, or ocular foreign body

          -  Leptomeningeal carcinomatosis as the only site of CNS involvement

          -  More than 2 seizures over the last 4 weeks prior to study entry

          -  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

          -  Pregnancy (positive pregnancy test) or lactation

          -  Individuals with a history of a different active malignancy are ineligible.
             Participants with a history of other malignancies are eligible if they have been
             disease-free for at least 2 years, not on active treatment, and deemed by the
             investigator to be at low risk for recurrence of that malignancy. Individuals with the
             following cancers are eligible if diagnosed and treated within the past 2 years:
             cervical cancer in situ, basal cell or squamous cell carcinoma of the skin.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine Maximum-tolerated dose of ARRY-380 with Trastuzumab
Time Frame:2 years
Safety Issue:
Description:To determine the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARRY-380 in combination with trastuzumab in participants with HER2+ breast cancer and central nervous system (CNS metastasis)

Secondary Outcome Measures

Measure:CNS objective response rate according to volumetric criteria
Time Frame:2 Years
Safety Issue:
Description:CNS objective response rate according to volumetric criteria
Measure:Non-CNS objective response rate according to RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:Non-CNS objective response rate according to RECIST 1.1
Measure:Proportion of participants with stable or responsive disease in both CNS and non-CNS at 16 and 24 weeks.
Time Frame:2 Years
Safety Issue:
Description:Proportion of participants with stable or responsive disease in both CNS and non-CNS at 16 and 24 weeks.
Measure:Progression-free survival
Time Frame:2 Years
Safety Issue:
Description:Progression-free survival
Measure:Clinical benefit (CR, PR, or SD>/=24 weeks)
Time Frame:2 Years
Safety Issue:
Description:Clinical benefit (CR, PR, or SD>/=24 weeks)
Measure:Overall survival
Time Frame:2 Years
Safety Issue:
Description:Overall survival
Measure:CNS Response according to modified RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • ARRY-380
  • Trastuzumab
  • Advanced HER2-positive breast cancer

Last Updated

October 2, 2017