A Study to Evaluate the Safety and Efficacy of A2B694, a Logic-gated CAR T, in Participants with Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression (EVEREST-2)

A2 Biotherapeutics

Status and phase

Enrolling

Phase 2

Phase 1

Conditions

Ovarian Neoplasms

NSCLC, Recurrent

Solid Tumor, Adult

Colon Cancer

Lung Cancer

Pancreas Cancer

Mesothelioma, Malignant

Cancer

Non Small Cell Lung Cancer

Ovarian Cancer

CRC

Ovary Cancer

Colorectal Adenocarcinoma

Non-Small Cell Squamous Lung Cancer

Mesothelioma

Pancreatic Neoplasm

MESOM

Rectal Cancer

NSCLC

Colorectal Cancer

Treatments

Diagnostic Test: xT CDx with HLA-LOH Assay

Biological: A2B694

Study type

Interventional

Funder types

Industry

Identifiers

NCT06051695

A2B694-101

Details and patient eligibility

About

The goal of this study is to test A2B694, an autologous logic-gated Tmod™ CAR T-cell product in subjects with solid tumors including colorectal cancer (CRC), pancreatic cancer (PANC), non-small cell lung cancer (NSCLC), ovarian cancer (OVCA), mesothelioma (MESO), and other solid tumors that express MSLN and have lost HLA-A*02 expression.

The main questions this study aims to answer are:

Phase 1: What is the recommended dose of A2B694 that is safe for patients

Phase 2: Does the recommended dose of A2B694 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 and Apheresis in BASECAMP-1 (NCT04981119)

Preconditioning Lymphodepletion (PCLD) Regimen

A2B694 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, PANC, OVCA, MESO or other solid tumors with MSLN expression. Subjects must be germline HLA-A*02 heterozygous, with tumors that express MSLN 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 A2B694 (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 A2B694.

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 A2B694 Tmod CAR T-cell therapy will enable the killing of tumor target cells (those cells that express MSLN and have LOH for HLA-A*02 protein). Additionally, normal healthy cells that maintain HLA-A*02 expression and co-express MSLN (eg, lung 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. A2 Bio believes this will provide a 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 their T cells collected (apheresis) in the pre-screening BASECAMP-1 study (NCT04981119). T cells are collected, processed and stored for each participant. Upon disease progression the participant may screen for this study (EVEREST-2) and the participant's T cells are manufactured and then infused following PCLD regimen. There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to EVEREST-2 based on their own disease course.

Enrollment

230 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), successful apheresis and PBMC processing, and with sufficient stored cells available for Tmod CAR T-cell therapy
Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, PANC, OVCA, MESO, or other solid tumors with MSLN 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
MESO with pleural involvement extending into the peritoneum
Cancer therapy within 3 weeks or 3 half lives of A2B694 infusion
Radiotherapy within 28 days of A2B694 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 A2B694