Study of ACTR T Cell Product in Combination With Trastuzumab in Subjects With HER2-Positive Advanced Solid Tumor Cancers

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1, open-label, multi-center study to assess safety and determine the recommended phase 2 dose (RP2D) of ACTR T cell product (ACTR707 or ACTR087) in combination with trastuzumab, following lymphodepleting chemotherapy in subjects with HER2-positive advanced malignancies.

Official Title
-----------------
A Phase 1 Study of an Autologous ACTR T Cell Product in Combination With Trastuzumab, a Monoclonal Antibody, in Subjects With HER2-Positive Advanced Malignancies

Conditions
-----------------
Solid Tumor, HER-2 Protein Overexpression

Intervention / Treatment
-----------------
* Biological: ACTR T Cell Product
* Drug: Trastuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed written informed consent obtained prior to study procedures Histologically-confirmed Her2 positive advanced solid tumor malignancy with documented disease progression during or immediately following the immediate prior therapy, or within 6 months of completing adjuvant therapy for subjects with breast cancer Subjects must have previously received adequate standard therapy for treatment of their malignancy For those with metastatic breast cancer, must have received HER2-directed therapy including trastuzumab, pertuzumab and ado-trastuzumab in any breast cancer disease setting For those with advanced gastric cancer, adequate prior treatment with HER2-directed chemotherapy is required At least 1 measurable lesion by iRECIST Able to provide fresh tumor biopsy or archived block specimen taken since time of most recent anti-HER2 mAb-directed therapy ECOG of 0 or 1 Life expectancy ≥ 6 months LVEF ≥ 50% by MUGA or ECHO Absolute neutrophil (ANC) count ≥ 1500/ µL Platelet count ≥ 100,000/µL Hemoglobin ≥ 9g/dL Estimated GFR >30mL/min/1.73m2 Exclusion Criteria: glioblastoma multiforme or other primary CNS tumors are excluded clinically significant cardiac disease clinically significant active infection clinical history, prior diagnosis, or overt evidence of autoimmune disease current use of more than 5mg/day of prednisone (or an equivalent glucocorticoid) Prior treatment as follows: prior cumulative doxorubicin dose greater than or equal to 300 mg/m^2 or equivalent chemotherapy within 2 weeks of enrollment external beam radiation within 2 weeks of enrollment (28 days if CNS-directed therapy) any monoclonal antibody (mAb) or other protein therapeutic containing Fc-domains within 4 weeks of enrollment pertuzumab within 4 months of enrollment Experimental agents within 3 half-lives or 28 days prior to enrollment, whichever is shorter allogeneic hematopoietic stem cell transplant (HSCT) prior infusion of a genetically modified therapy Pregnant or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACTR T cell product in combination with trastuzumab<br> | Biological: ACTR T Cell Product<br>* Autologous Antibody-Coupled T Cell Receptor (ACTR) T Cell Product (ACTR707 or ACTR087)<br>Drug: Trastuzumab<br>* monoclonal antibody targeting HER2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of ACTR T cell product with trastuzumab as assessed by committee review of dose limiting toxicities (DLTs), incidence and severity of adverse events (AEs) and clinically significant abnormalities of laboratory values |  | 42 days | 
| Determination of recommended phase 2 dose (RP2D) regimen | Review of DLTs, maximum tolerated dose (MTD), incidence and severity of AEs and clinically significant abnormalities of laboratory values | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity as measured by overall response rate (ORR) per iRECIST |  | 52 weeks | 
| Anti-tumor activity as measured best overall response (BOR) |  | 52 weeks | 
| Anti-tumor activity as measured by duration of response (DOR) |  | 52 weeks | 
| Anti-tumor activity as measured by progression-free survival (PFS) |  | 52 weeks | 
| Anti-tumor activity as measured by overall survival (OS) |  | 52 weeks | 
| Assessment of persistence of ACTR as measured by flow cytometry |  | 52 weeks | 
| Assessment of persistence of ACTR as measured by quantitative polymerase chain reaction (qPCR) |  | 52 weeks | 
| Assessment of ACTR phenotype and function as measured by flow cytometry |  | 52 weeks | 
| Assessment of induction of inflammatory markers and cytokines/chemokines after ACTR T cell product administration | Levels of inflammatory markers, cytokines/chemokines in blood | 52 weeks | 
| Trastuzumab pharmacokinetics (PK) | trastuzumab serum concentration, Area Under the Curve (AUC), trough levels | 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HER2, ACTR, ACTR087, ACTR707, T cell, T cell product, adoptive T cells, gene therapy, breast cancer, gastric cancer, gastro esophageal cancer, immunotherapy, solid tumor, adenoid cystic carcinoma