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 (DENALI-1)

A2 Biotherapeutics

Status and phase

Begins enrollment in 3 months

Phase 2

Phase 1

Conditions

Solid Tumor, Adult

HNSCC

Colon Cancer

Head and Neck Squamous Cell Cancer

Lung Cancer

Cancer

CRC

Colorectal Adenocarcinoma

Non-Small Cell Lung

TNBC

Kidney Cancer

RCC

Triple Negative Breast Cancer

Renal Cell Carcinoma

NSCLC (non-small Cell Lung Cancer)

Rectal Cancer

Colorectal Cancer

Treatments

Biological: A2B395

Diagnostic Test: xT CDx with HLA-LOH assay

Study type

Interventional

Funder types

Industry

Identifiers

NCT06682793

A2B395-101

Details and patient eligibility

About

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
A2B395 Tmod CAR T cells at the assigned dose

Full 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.

Enrollment

240 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Key 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

Key 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