Clinical Trials /

BATs in Patients With Breast Cancer and Leptomeningeal Metastases

NCT03661424

Description:

This study uses bi-specific antibody (HER2Bi) armed activated T-cells (HER2 BATs) to target breast cancer cells that have metastasized to the membranes surrounding the brain and spinal cord. This is known as leptomeningeal metastases. Two doses will be evaluated in order to determine a safe dose. Study treatment includes a test dose of HER2 BATs followed by 8 weekly infusions of HER2 BATs at the assigned dose level. Before, during and after study treatment, participants will be monitored objectively by brain MRIs and clinically through physical and neurological exams, and blood and cerebrospinal fluid will be collected to evaluate immune responses.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: BATs in Patients With Breast Cancer and Leptomeningeal Metastases
  • Official Title: A Phase I Study of Anti-CD3 x Anti-Her2/Neu (Her2Bi) Armed Activated T Cells (ATC) in Patients With Breast Cancer Leptomeningeal Metastases

Clinical Trial IDs

  • ORG STUDY ID: 20805
  • NCT ID: NCT03661424

Conditions

  • Breast Cancer Female
  • Leptomeningeal Metastases

Interventions

DrugSynonymsArms
HER2 BATsTest dose then 8 doses HER2 Bi-armed activated T-cells (BATs)

Purpose

This study uses bi-specific antibody (HER2Bi) armed activated T-cells (HER2 BATs) to target breast cancer cells that have metastasized to the membranes surrounding the brain and spinal cord. This is known as leptomeningeal metastases. Two doses will be evaluated in order to determine a safe dose. Study treatment includes a test dose of HER2 BATs followed by 8 weekly infusions of HER2 BATs at the assigned dose level. Before, during and after study treatment, participants will be monitored objectively by brain MRIs and clinically through physical and neurological exams, and blood and cerebrospinal fluid will be collected to evaluate immune responses.

Detailed Description

      Once subjects are determined eligible, blood will be collected in order to make the HER2
      BATs. For HER2 BATs, the white blood cells, specifically T cells, are then mixed with two
      proteins - OKT3 and IL-2 -- which activates the cells to multiply. After approximately 14
      days in culture, the activated T cells are coated with OKT3 and trastuzumab/Herceptin
      (HER2Bi), and washed to remove excess Herceptin in order to produce bispecific antibody armed
      T cells (BATs). Cells are then frozen and stored until scheduled to be infused. Up to 2 weeks
      following blood collection, participants will undergo surgery to place the catheter/reservoir
      into the lateral ventricle of the brain to allow intraventricular administration of HER2 BATs
      and a chemotherapy agent methotrexate. A few weeks later, participants will receive the
      intraventricular methotrexate in order to control disease while the BATs product is being
      manufactured. About 4-5 weeks following the initial blood collection and at least 7 days
      after receiving methotrexate, study treatment will begin with a test dose of HER2 BATs. If
      this dose is well tolerated by the participant, she will then receive 8 weekly doses of HER2
      BATs at the assigned dose level.
    

Trial Arms

NameTypeDescriptionInterventions
Test dose then 8 doses HER2 Bi-armed activated T-cells (BATs)ExperimentalApproximately 4 weeks following registration and blood collection, participants are given a test dose of HER2 BATs followed by 8 weekly infusions. Infusions are given intraventricularly.
  • HER2 BATs

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the trial.

          2. Participants must be female.

          3. Histologically confirmed breast cancer (any Her2, estrogen receptor (ER), or
             progesterone receptor (PR) expression) with leptomeningeal metastasis (LM) as
             determined by imaging and/or cerebrospinal fluid (CSF) cytology.

          4. 18 years of age or older.

          5. Women of reproductive potential must agree to use an effective method of contraception
             during therapy. Effective methods include intrauterine device (IUD), vasectomy of the
             male partner, diaphragm with spermicide, cervical cap with spermicide, contraceptive
             sponge, male or female condom, or hormonal contraceptive.

          6. Karnofsky Performance Status (KPS) of ≥60.

          7. Eligible for intraventricular (IVENT) catheter/reservoir placement as determined by
             neurosurgery.

          8. Demonstrate adequate organ function as defined below. All screening labs should be
             performed within 10 days of confirmation of eligibility.

        Absolute lymphocyte count ≥ 500/mm3 Absolute neutrophil count ≥ 1000/mcL Platelets ≥
        100,000 / mnL Hemoglobin ≥ 8 g/dL BUN ≤ 1.5 x upper limit of normal (ULN) Serum creatinine
        within the normal limits OR measured or calculated creatinine clearance ≥ 60 mL/min 1.73m2
        Serum total bilirubin ≤ 2 x ULN OR AST (SGOT) and ALT (SGPT) ≤ 5 x ULN Albumin ≥ 2.5 mg/dL

        Exclusion Criteria:

          1. Current severe increased intracranial pressure with clinical or imaging findings
             suggestive of herniation, status epilepticus, or other serious complications requiring
             emergency or urgent intervention.

          2. Patients who cannot have MRI studies for any reason (intolerance, medical
             contraindication, etc.).

          3. Patients with a history of another malignancy within 1 year of study enrollment with
             the following exceptions: patients with history of ductal carcinoma in situ (DCIS),
             squamous cell skin cancers, or other in situ carcinomas are not excluded.

          4. Patients with unresolved autoimmune toxicity.

          5. Patients with a known disorder that increases the risk of bleeding (e.g., Hemophilia,
             von Willebrands disease, or clinically significant clotting factor deficiency).

          6. 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.

          7. Administration of any investigational agents, immunomodulating agents, radiation
             therapy or chemotherapy for MBC within the 7 days before the 80 mL blood draw to
             collect cells for study treatment.

          8. Has Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known active Hepatitis
             B (e.g. HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

          9. Pregnancy or lactation at the time of registration.

         10. Psychiatric or addictive disorders or other conditions that in the opinion of the
             investigator would preclude the patient from complying with the study protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Types of adverse events (AEs)
Time Frame:For each participant, AEs will be collected from the time of the first protocol-related procedure through 30 days following last infusion of BATs. SAEs considered related to study treatment will also be collected following this period.
Safety Issue:
Description:Types of any adverse events or abnormalities of laboratory tests

Secondary Outcome Measures

Measure:Immune shift: in vitro cytotoxicity assays and/or IFN-y EliSpots against breast cancer cell lines
Time Frame:Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Safety Issue:
Description:Immune shift induced by Her2 BATs as detected by in vitro cytotoxicity assays and/or IFN-γ EliSpots against breast cancer cell lines
Measure:Immune shift: Phenotyping of activating and regulatory immune cells
Time Frame:Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Safety Issue:
Description:Immune shift induced by Her2 BATs as detected by phenotyping of activating and regulatory immune cells
Measure:Immune shift: Measurement of cytokine patterns
Time Frame:Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Safety Issue:
Description:Immune shift induced by Her2 BATs as detected by measurement of cytokine patterns
Measure:Immune shift: Determination of anti-Her2 antibodies
Time Frame:Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Safety Issue:
Description:Immune shift induced by Her2 BATs as detected by determination of anti-Her2 antibodies
Measure:Correlation of clinical and immune response characteristics to progression-free survival
Time Frame:Blood collected prior to, during and following study treatment (tx) (up to 6 months following study tx). Clinical characteristics and imaging prior to and after study tx through 1st progression
Safety Issue:
Description:Correlation individually and by heatmap analysis of imaging, pathology, clinical, and immune response characteristics to progression free survival (PFS)
Measure:Correlation of clinical and immune response characteristics to overall survival
Time Frame:Blood for immune analysis collected prior to, during and after study treatment (tx) (up to 6 months following study tx). Clinical characteristics and imaging prior to and after study tx through 1st progression
Safety Issue:
Description:Correlation individually and by heatmap analysis of imaging, pathology, clinical, and immune response characteristics to overall survival (OS).
Measure:Objective response rate (ORR)
Time Frame:Assessed on MRI studies done 9 weeks after first BATs infusion
Safety Issue:
Description:Proportion of participants with complete or partial response according to brain and spine MRI
Measure:Progression-free survival (PFS)
Time Frame:From date of first BATs infusion (approximately 4 weeks following eligibility confirmation) until the date of confirmed progression, assessed up to 28 months
Safety Issue:
Description:Length of time from study participation initiation through disease progression for each participant
Measure:Overall survival (OS)
Time Frame:Through each participant's death or for 2 years following study treatment
Safety Issue:
Description:Length of time from study participation initiation through death or for 2 years following study treatment for each participant
Measure:MD Anderson Symptom Inventory for Spinal Tumors (MDASI - SP)
Time Frame:Prior to test dose of study treatment, prior to the 5th and 8th weekly infusions, and 30 days following last infusion
Safety Issue:
Description:The MDASI- SP is a 24 item questionnaire that focuses on symptoms related to spinal tumors. For each potential symptom, there is an eleven-point scale where 0 is "Not Present" and 10 is "As Bad As You Can Imagine" so the minimum score would be 0 and the maximum score would be 240. For a subset of questions, the scale measures how much the symptoms interfered with other parts of life and the scale ranges from symptoms that "Did Not Interfere" (0) to those that "Interfered Completely" (10). Lower scores indicate fewer/less severe/less interfering symptoms and higher scores indicate more/more severe/more interfering symptoms.
Measure:MD Anderson Symptom Inventory for Brain Tumors (MDASI- BT)
Time Frame:Prior to test dose of study treatment, prior to the 5th and 8th weekly infusions, and 30 days following last infusion
Safety Issue:
Description:The MDASI- BT is a 28 item questionnaire that focuses on symptoms related to brain tumors. For each potential symptom, there is an eleven-point scale where 0 is "Not Present" and 10 is "As Bad As You Can Imagine" so the minimum score would be 0 and the maximum score would be 280. For a subset of questions, the scale measures how much the symptoms interfered with other parts of life and the scale ranges from symptoms that "Did Not Interfere" (0) to those that "Interfered Completely" (10). Lower scores indicate fewer/less severe/less interfering symptoms and higher scores indicate more/more severe/more interfering symptoms.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Virginia

Trial Keywords

  • Metastatic Breast Cancer
  • Adoptive Cell Therapy
  • Armed Activated T-cells
  • Bispecific Antibodies
  • Immunotherapy

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