BATs in Patients With Breast Cancer and Leptomeningeal Metastases

NCT ID: NCT03661424

Last Updated: 2022-12-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-26
• Study Completion Date: 2021-12-14

Brief Summary

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, 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.

Conditions

Breast Cancer Female; Leptomeningeal Metastases

Keywords

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

HER2 BATs

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Camilo E. Fadul, MD

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Camilo Fadul, MD

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Locations

University of Virginia

Charlottesville, Virginia, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 25688159 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25802762 (View on PubMed)

Other Identifiers

20805

Identifier Type: -

Identifier Source: org_study_id