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Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer

NCT02598427

Description:

The purpose of this research study is to determine how well pertuzumab and trastuzumab works in treating breast cancer that has spread to the brain. Pertuzumab and trastuzumab are treatments that 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). Pertuzumab and trastuzumab have been found to be very effective for HER2-positive breast cancer and are FDA approved for treatment of metastatic breast cancer outside of the brain when given through the vein. This suggests that pertuzumab and trastuzumab may help shrink or stabilize HER2-positive breast cancer that has spread to the brain in this research study. In this research study, the investigators are looking to see whether pertuzumab and trastuzumab will work to decrease the size of or stabilize breast cancer that has spread to the brain.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer
  • Official Title: Phase I Dose Escalation Trial of Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis

Clinical Trial IDs

  • ORG STUDY ID: Pro00061309
  • NCT ID: NCT02598427

Conditions

  • HER2 Positive Untreated Metastatic Breast Cancer
  • Asymptomatic or Low Symptomatic Brain Metastasis in Breast Cancer

Interventions

DrugSynonymsArms
PertuzumabPerjetaIntrathecal Pertuzumab and Trastuzumab
TrastuzumabHerceptinIntrathecal Pertuzumab and Trastuzumab

Purpose

The purpose of this research study is to determine how well pertuzumab and trastuzumab works in treating breast cancer that has spread to the brain. Pertuzumab and trastuzumab are treatments that 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). Pertuzumab and trastuzumab have been found to be very effective for HER2-positive breast cancer and are FDA approved for treatment of metastatic breast cancer outside of the brain when given through the vein. This suggests that pertuzumab and trastuzumab may help shrink or stabilize HER2-positive breast cancer that has spread to the brain in this research study. In this research study, the investigators are looking to see whether pertuzumab and trastuzumab will work to decrease the size of or stabilize breast cancer that has spread to the brain.

Detailed Description

      Intrathecal administration of pertuzumab and trastuzumab will occur via lumbar puncture
      (spinal tap) under fluoroscopic guidance by interventional radiology at Duke University
      Medical Center. The spinal needle will be inserted into the spinal column and 7 mL of
      cerebrospinal fluid (CSF) will be collected. Once the CSF is removed, the intrathecal
      pertuzumab and trastuzumab will be administered using aseptic technique. At certain time
      points the CSF will be analyzed for free cell DNA. If subjects consent, the CSF fluid will
      also be stored for additional future research.

      Patients will be treated using a 3+3 dose-escalation design. Patients will not be accrued to
      the next cohort (dose escalation) until at least one patient on the previous cohort has been
      followed for six weeks. If a dose limiting toxicity (DLT) is seen in a patient then the
      cohort will be expanded by an additional 3 patients to allow for 1 in 6 patients per cohort
      to have a DLT before dose escalation. Dose limiting toxicity will be assessed weekly during
      the first six weeks of the treatment.

      Patients will be treated weekly for the first six weeks and then every 3 weeks (q21 days).
      Once the maximum tolerated dose is reached, an additional 12 patients will be enrolled in the
      cohort at the maximum tolerated dose. The maximum number of enrolled patients is 36. Dosing
      is as follows: Cohort 1 - 80mg IT trastuzumab, 10mg IT pertuzumab, cohort 2 - 80mg IT
      trastuzumab, 20mg IT pertuzumab, cohort 3 - 80mg IT trastuzumab, 40mg IT pertuzumab, cohort 4
      - 80mg IT trastuzumab, 80mg IT pertuzumab. If the lowest dose level is found to be too toxic,
      the trial will stop without finding a maximum tolerated dose.
    

Trial Arms

NameTypeDescriptionInterventions
Intrathecal Pertuzumab and TrastuzumabExperimentalFour cohorts will enroll in a dose escalation of pertuzumab and a consistent dose of trastuzumab. The cohorts will be assigned as follows: Cohort: Intrathecal Dose: 10mg pertuzumab, 80mg trastuzumab 20mg pertuzumab, 80mg trastuzumab 40mg pertuzumab, 80mg trastuzumab 80mg pertuzumab, 80mg trastuzumab
  • Pertuzumab
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  HER2 positive by 2013 ASCO-CAP guidelines (IHC 3+ and/or FISH positive; IHC 2+ HER2
             patients are eligible with reflex FISH positive testing with the ratio ≥ 2.0) breast
             cancer patients with untreated asymptomatic or minimally symptomatic brain metastasis
             by MRI. There is no upper or lower limit to the size or number of brain metastases.

          -  Patients can have previous brain metastasis that was completely surgically resected if
             the previously resected lesion is at least 1 cm from target lesion(s) for this study.
             The location of the previous resection cavity is determined by the post-resection MRI.

          -  Patients can have previous brain metastasis that was treated with stereotactic
             radiosurgery (SRS) if the previously treated lesion is at least 1cm from the target
             lesion(s) for this study. The location of the previous SRS treatment location is
             determined by the SRS MRI.

          -  Patients can be on steroids as long as the dose has been stable for ≥ 7 days

          -  No limitations on prior systemic or intrathecal therapies.

          -  There are no restrictions on systemic therapy at enrollment.

          -  Negative serum pregnancy test for pre-menopausal women and women within 12 months from
             the onset of menopause.

          -  Sexually active women of childbearing potential must commit to 2 methods of
             contraception while enrolled on the trial and continue using contraceptives for at
             least 7 months post study drug administration. Sexually active men must commit to 1
             method of contraception while enrolled and for 7 months after. Hormonal contraceptives
             such as birth control pills, patches, implants or injections are not allowed in
             patients who are HR+.

          -  Life expectancy ≥ 8 weeks

          -  Laboratory criteria: normal renal function: creatinine < 1.5 x upper limit of normal
             (ULN)), liver function: bilirubin ≤ 1.5 x ULN, transaminases ≤ 2 x ULN, except in
             known hepatic disease, wherein may be ≤ 5 x ULN, and blood counts: WBC ≥ 2.0,
             Neutrophils ≥1500, platelets ≥100,000, Hemoglobin ≥ 10.

          -  LVEF (left ventricular ejection fraction) ≥ 50%

          -  Karnofsky performance status (KPS) ≥ 50

          -  Age ≥ 18 years

          -  Patients must have the ability to give informed consent.

          -  Patients must sign an informed consent form.

        Exclusion Criteria:

          -  No seizures, focal weakness of any extremity (by neurologic exam), or stroke symptoms
             in the past month.

          -  No history of prior whole brain radiation.

          -  No history of lumbar surgery or other pre-existing spinal conditions that would
             preclude frequent, safe, reliable lumbar punctures.

          -  No history of serious cardiac arrhythmia or EF < 50%.

          -  Systemic sites of disease need to be stable on systemic therapy based on the most
             recent (within 12 weeks) staging scans.

          -  Radiation while on study is not allowed EXCEPT to a localized region for pain control.

          -  No history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ
             of the cervix) unless the patient has been in remission and off all other cancer
             therapy for at least 3 years.

          -  Patients should have no significant psychiatric illness or medical illness that would
             preclude the ability to comply with the protocol.

          -  Patients may not be pregnant or breastfeeding.

          -  No known hypersensitivity to trastuzumab or pertuzumab.

          -  Symptomatic intrinsic lung disease or extensive tumor involvement in the lungs
             resulting in dyspnea at rest.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety as measured by adverse events
Time Frame:Baseline up to 36 weeks
Safety Issue:
Description:Adverse events will be closely monitored and assessed for all subjects on study treatment. The main observational portion of study will be complete at 36 weeks. However, subjects will be allowed to continue on treatment for as long as they are receiving clinical benefit and any adverse events occurring during this time will be assessed. Following discontinuation of study treatment, patient follow-up will take place every 3 months.

Secondary Outcome Measures

Measure:Response rate as measured by brain MRI
Time Frame:Every 6 weeks from Baseline up to 36 weeks
Safety Issue:
Description:Response assessed: Complete Response (CR): Radiographic complete response (RCR), 100% reduction in tumor, with complete clearing of MRI scan evidence of disease on 2 consecutive scans 6 weeks apart with stable or improved clinical function. Partial Response (PR): Radiographic stability of disease (RSD), > 50% but < 100% reduction in tumor, with improved clinical function. Stable Disease (SD): Radiographic stability of disease (RSD), < 50% reduction in tumor or < 25% increase in size of tumor, with stable clinical function. Progressive Disease (PD): Radiographic progressive disease (RPD), > 25% increase in size of tumor, and/or the presence of declining clinical function attributable to the CNS metastasis. Other indications of progression include development of new CNS metastases or increase in size of previous CNS metastasis. Changes in size of previous CNS metastasis must measure > 25% increase in the largest unidimensional measurement in the absence of new neurologic symptoms.
Measure:Changes in cell-free circulating tumor DNA (ctDNA) in response to treatment
Time Frame:Baseline up to 36 weeks
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Kimberly Blackwell

Trial Keywords

  • Breast Cancer
  • HER2 Positive
  • HER2+
  • Brain Metastases
  • Metastatic Breast Cancer
  • Intrathecal Treatment
  • Lumbar Puncture
  • Pertuzumab
  • Trastuzumab
  • Advanced Breast Cancer
  • Duke University

Last Updated

February 28, 2018