A Study to Evaluate the Safety and Efficacy of A2B395, an Allogeneic Logic-gated CAR T, in Participants With Solid Tumors That Express EGFR and Have Lost HLA-A*02 Expression

Official title

A Seamless Phase 1/2 Study to Evaluate the Safety and Efficacy of A2B395, an Allogeneic Logic-gated Tmod™ CAR T, in Heterozygous HLA-A*02 Adults With Recurrent Unresectable, Locally Advanced, or Metastatic Solid Tumors That Express EGFR and Have Lost HLA-A*02 Expression

Overview

The goal of this study is to test A2B395, an allogeneic logic-gated Tmod™ CAR T-cell product in subjects with solid tumors including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), renal cell carcinoma (RCC) and other solid tumors that express EGFR and have lost HLA-A\*02 expression. The main questions this study aims to answer are: * Phase 1: What is the recommended dose of A2B395 that is safe for patients * Phase 2: Does the recommended dose of A2B395 kill the solid tumor cells and protect the patient's healthy cells Participants will be required to perform study procedures and assessments, and will also receive the following study treatments: * Enrollment in BASECAMP-1 (NCT04981119) * Preconditioning lymphodepletion (PCLD) regimen * A2B395 Tmod CAR T cells at the assigned dose

Detailed description

This is a seamless phase 1/2, multi-center, open-label study that enrolls adults with recurrent unresectable, locally advanced, or metastatic (considered non-curative) CRC, NSCLC, HNSCC, TNBC, RCC, or other solid tumors with EGFR expression. Subjects must be germline HLA-A\*02 heterozygous, with tumors that express EGFR and have lost HLA-A\*02 expression. The purpose of Phase 1 of this study is to determine the safety and the optimal dose of A2B395 (after PCLD) in participants with solid tumor disease. The purpose of Phase 2 of this study is to determine the further safety and efficacy (how well it treats the solid tumor disease) of A2B395.

The treatment available for these cancers and other solid tumors can be toxic, debilitating, and fatal. In the recurrent unresectable, locally advanced, or metastatic setting, the intent of standard of care treatment is typically palliative rather than curative, and has not changed significantly in several decades. A2 Bio hypothesizes that A2B395 Tmod CAR T-cell therapy will enable the killing of tumor target cells (those cells that express EGFR and have loss of heterozygosity \[LOH\] for the HLA-A\*02 protein). Additionally, normal healthy cells that maintain HLA-A\*02 expression and co-express EGFR (eg, skin tissue) will not be targeted due to the blocker portion of the Tmod CAR T cell that acts as a self-regulated safety switch that protects normal tissue from damage. Furthermore, the blocker portion of the Tmod CAR T cell will act as a safety switch to protect normal tissue from graft versus host disease (GvHD) that could be caused by an allogeneic CAR T cell. A2 Bio intends this to provide a wider therapeutic safety window compared to previous solid tumor targeting therapies. This hypothesis will be explored in the study.

Participants for this study must enroll and have confirmation of LOH in the pre-screening BASECAMP-1 study (NCT04981119). Upon disease progression the participant may screen for this study (DENALI-1). There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to DENALI-1 based on their own disease course.

Interventions

• Biological A2B395
  Allogeneic logic-gated Tmod CAR T cells
• Diagnostic test xT CDx with HLA-LOH assay
  An investigational next generation sequencing (NGS) in vitro diagnostic (IVD) medical device

Primary outcome measures

• Phase 1: Rate of adverse events and dose limiting toxicities (DLTs) by dose level [Time frame: From the time of Informed consent until 24 months (2 years) post A2B395 infusion]
• Phase 1: Recommended phase 2 dose (RP2D) [Time frame: 28 days post A2B395 infusion]
• Phase 2: The overall response rate (ORR) for patients [Time frame: 24 months post A2B395 infusion]

Secondary outcome measures (3)

• Persistence of A2B395 [Time frame: up to 24 months post A2B395 infusion]
• Cytokine analysis [Time frame: up to 24 months post A2B395 infusion]
• Cytokine analysis [Time frame: up to 24 months post A2B395 infusion]

Eligibility criteria

Inclusion criteria

Inclusion criteria

• Appropriately enrolled in the BASECAMP-1 A2 Biotherapeutics, Inc. study, with tissue demonstrating LOH of HLA-A\*02 by NGS (whenever possible from the primary site).
• Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, HNSCC, TNBC, RCC, or other solid tumors with EGFR expression. Measurable disease is required with lesions of ≥1.0 cm by CT.
• Received previous required therapy for the appropriate solid tumor disease as described in the protocol
• Has adequate organ function as described in the protocol
• ECOG performance status of 0 to 1
• Life expectancy of ≥3 months
• Willing to comply with study schedule of assessments including long-term safety follow-up

Exclusion criteria

• Has disease that is suitable for local therapy or able to receive standard of care therapy that is therapeutic and not palliative
• Prior allogeneic stem cell transplant
• Prior solid organ transplant
• Cancer therapy within 3 weeks or 3 half lives of A2B395 infusion
• Radiotherapy within 28 days of A2B395 infusion
• Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months
• Any new symptomatic pulmonary embolism (PE) or a deep vein thrombosis (DVT) within 3 months of enrollment. Therapeutic dosing of anticoagulants is allowed for history of PE or DVT if greater than 3 months from time of enrollment, and adequately treated
• History of interstitial lung disease including drug-induced interstitial lung disease and radiation pneumonitis that requires treatment with prolonged steroids or other immune suppressive agents within 1 year
• Requires supplemental home oxygen
• Females of childbearing potential who are pregnant or breastfeeding
• Subjects, both male and female, of childbearing potential who are not willing to practice birth control from the time of consent through 6 months post infusion of A2B395

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• Banner MD Anderson Cancer Center — Gilbert
• UCSD Moores Cancer Center — La Jolla
• UCLA Medical Center — Los Angeles
• Mayo Clinic — Jacksonville
• Moffitt Cancer Center — Tampa
• Mayo Clinic — Rochester
• Washington University — St Louis
• NYU Langone Health — New York
• … and 2 more centers

Publications

• DiAndreth B, Hamburger AE, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022 Aug;241:109030. doi: 10.1016/j.clim.2022.109030. Epub 2022 May 11. PMID 35561999
• Oh J, Kirsh C, Hsin JP, Radecki KC, Zampieri A, Manry D, Ando Y, Miller S, Chan J, McLeod E, Cunningham KM, Wong LM, Xu H, Kamb A. NOT gated T cells that selectively target EGFR and other widely expressed tumor antigens. iScience. 2024 May 7;27(6):109913. doi: 10.1016/j.isci.2024.109913. eCollection 2024 Jun 21. PMID 38799557
• Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, PMID 20164920
• Hwang MS, Mog BJ, Douglass J, Pearlman AH, Hsiue EH, Paul S, DiNapoli SR, Konig MF, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Vogelstein B, Zhou S, Kinzler KW. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2022410118. doi: 10.1073/pnas.2022410118. PMID 33731480
• Hamburger AE, DiAndreth B, Cui J, Daris ME, Munguia ML, Deshmukh K, Mock JY, Asuelime GE, Lim ED, Kreke MR, Tokatlian T, Kamb A. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020 Dec;128:298-310. doi: 10.1016/j.molimm.2020.09.012. Epub 2020 Oct 1. PMID 33012527

Identifiers

NCT: NCT06682793 · A2B395-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗