Clinical trial NCT03661424: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Breast Cancer Female
Leptomeningeal Metastases
Keywords: Metastatic Breast Cancer
Adoptive Cell Therapy
Armed Activated T-cells
Bispecific Antibodies
Immunotherapy
Lead sponsor: University of Virginia
Sponsor class: OTHER
First posted: 2018-09-07
Enrollment: 3
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Types of adverse events (AEs)
timeFrame: 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.
measure: Frequency of adverse events (AEs)
timeFrame: 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.
measure: Severity of adverse events (AEs)
timeFrame: 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.
measure: Timing of onset of adverse events
timeFrame: 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.
measure: Duration of adverse events
timeFrame: 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.
measure: 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.
timeFrame: 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.
measure: Number of participants achieving at least 80% of the planned HER2 BATs dose.
timeFrame: An average of 4 weeks following blood draw to collect cells for HER2 BATs
Secondary outcomes:
measure: Immune shift: in vitro cytotoxicity assays and/or IFN-y EliSpots against breast cancer cell lines
timeFrame: Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
measure: Immune shift: Phenotyping of activating and regulatory immune cells
timeFrame: Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
measure: Immune shift: Measurement of cytokine patterns
timeFrame: Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
measure: Immune shift: Determination of anti-Her2 antibodies
timeFrame: Blood for immune analysis collected prior to, during and following study treatment (tx) (up to 6 months following study tx).
measure: Correlation of clinical and immune response characteristics to progression-free survival
timeFrame: 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
measure: Correlation of clinical and immune response characteristics to overall survival
timeFrame: 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
measure: Objective response rate (ORR)
timeFrame: Assessed on MRI studies done 9 weeks after first BATs infusion
measure: Progression-free survival (PFS)
timeFrame: From date of first BATs infusion (approximately 4 weeks following eligibility confirmation) until the date of confirmed progression, assessed up to 28 months
measure: Overall survival (OS)
timeFrame: Through each participant's death or for 2 years following study treatment
measure: MD Anderson Symptom Inventory for Spinal Tumors (MDASI - SP)
timeFrame: Prior to test dose of study treatment, prior to the 5th and 8th weekly infusions, and 30 days following last infusion
measure: MD Anderson Symptom Inventory for Brain Tumors (MDASI- BT)
timeFrame: Prior to test dose of study treatment, prior to the 5th and 8th weekly infusions, and 30 days following last infusion
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Virginia
name: Camilo Fadul, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.