BATs in Patients With Breast Cancer and Leptomeningeal Metastases

A Phase I Study of Anti-CD3 x Anti-Her2/Neu (Her2Bi) Armed Activated T Cells (ATC) in Patients With Breast Cancer Leptomeningeal Metastases

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer Female; Leptomeningeal Metastases
• Intervention / Treatment: Drug: HER2 BATs

Detailed Description

Once subjects are determined eligible, white blood cells (lymphocytes) are collected via leukapheresis procedure approximately 3 to 4 weeks prior to the first BATs infusion. The white blood cells, specifically T cells, are then mixed with two proteins in order to activate 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 leukapheresis, 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 leukapheresis 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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Test dose then 8 doses HER2 Bi-armed activated T-cells (BATs); Approximately 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.

Drug: HER2 BATs; A test dose (1 million cells) of HER2 BATs (at one of the two dose levels: 5 million cells or 10 million cells per infusion) followed by 8 weekly infusions of Her2 BATs delivered into the ventricle of the brain. Infusions are delivered weekly over 8 weeks with brain MRIs prior to first infusion and following the eighth infusion. Blood will be drawn for immune evaluation before during and after study treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Types of adverse events (AEs)	Types of any adverse events or abnormalities of laboratory tests	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.
Frequency of adverse events (AEs)	Frequency of any adverse events or abnormalities of laboratory tests	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.
Severity of adverse events (AEs)	Severity of any adverse events or abnormalities of laboratory tests	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.
Timing of onset of adverse events	Timing of onset of any adverse events or abnormalities of laboratory tests	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.
Duration of adverse events	Duration of any adverse events or abnormalities of laboratory tests	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.
Relationship to study therapy of any adverse events or abnormalities of laboratory tests as determined by CTCAE v5.0 will be assessed based on protocol-defined relationships of definitely, probably, possibly, unlikely and unrelated to study therapy.	Relationship to study therapy of any adverse events or abnormalities of laboratory tests	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.
Number of participants achieving at least 80% of the planned HER2 BATs dose.	If at least 80% of the planned dose of cells cannot be produced for 3 consecutive participants at a designated dose level, that dose level will be considered not feasible.	An average of 4 weeks following blood draw to collect cells for HER2 BATs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune shift: in vitro cytotoxicity assays and/or IFN-y EliSpots against breast cancer cell lines	Immune shift induced by Her2 BATs as detected by in vitro cytotoxicity assays and/or IFN-γ EliSpots against breast cancer cell lines	Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Immune shift: Phenotyping of activating and regulatory immune cells	Immune shift induced by Her2 BATs as detected by phenotyping of activating and regulatory immune cells	Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Immune shift: Measurement of cytokine patterns	Immune shift induced by Her2 BATs as detected by measurement of cytokine patterns	Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Immune shift: Determination of anti-Her2 antibodies	Immune shift induced by Her2 BATs as detected by determination of anti-Her2 antibodies	Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
Correlation of clinical and immune response characteristics to progression-free survival	Correlation individually and by heatmap analysis of imaging, pathology, clinical, and immune response characteristics to progression free survival (PFS)	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
Correlation of clinical and immune response characteristics to overall survival	Correlation individually and by heatmap analysis of imaging, pathology, clinical, and immune response characteristics to overall survival (OS).	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
Objective response rate (ORR)	Proportion of participants with complete or partial response according to brain and spine MRI	Assessed on MRI studies done 9 weeks after first BATs infusion
Progression-free survival (PFS)	Length of time from study participation initiation through disease progression for each participant	From date of first BATs infusion (approximately 4 weeks following eligibility confirmation) until the date of confirmed progression, assessed up to 28 months
Overall survival (OS)	Length of time from study participation initiation through death or for 2 years following study treatment for each participant	Through each participant's death or for 2 years following study treatment
MD Anderson Symptom Inventory for Spinal Tumors (MDASI - SP)	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.	Prior to test dose of study treatment, prior to the 5th and 8th weekly infusions, and 30 days following last infusion
MD Anderson Symptom Inventory for Brain Tumors (MDASI- BT)	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.	Prior to test dose of study treatment, prior to the 5th and 8th weekly infusions, and 30 days following last infusion

Collaborators and Investigators

• Sponsor: University of Virginia
• Investigators: Principal Investigator: Camilo Fadul, MD, University of Virginia

Publications and helpful links

General Publications

• Lum LG, Thakur A, Al-Kadhimi Z, Colvin GA, Cummings FJ, Legare RD, Dizon DS, Kouttab N, Maizel A, Colaiace W, Liu Q, Rathore R. Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clin Cancer Res. 2015 May 15;21(10):2305-14. doi: 10.1158/1078-0432.CCR-14-2280. Epub 2015 Feb 16.
• Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG. Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer. 2015;2015:285193. doi: 10.1155/2015/285193. Epub 2015 Feb 23.

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2019
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: September 4, 2018
• First Posted (Actual): September 7, 2018

Study Record Updates

• Last Update Posted (Estimate): December 20, 2022
• Last Update Submitted That Met QC Criteria: December 15, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Immunotherapy; Metastatic Breast Cancer; Adoptive Cell Therapy; Armed Activated T-cells; Bispecific Antibodies
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Meningeal Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Meningeal Carcinomatosis
• Other Study ID Numbers: 20805

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No