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)

September 3, 2025 updated by: A2 Biotherapeutics Inc.

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

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

240

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Gilbert, Arizona, United States, 85234
        • Recruiting
        • Banner MD Anderson Cancer Center
        • Principal Investigator:
          • Matthew Ulrickson, MD
        • Contact:
    • California
      • La Jolla, California, United States, 92093
      • Los Angeles, California, United States, 90404
        • Recruiting
        • UCLA Medical Center
        • Principal Investigator:
          • Deborah Wong, MD
        • Contact:
    • Florida
      • Jacksonville, Florida, United States, 32224
        • Recruiting
        • Mayo Clinic
        • Contact:
          • Clinical Trials Referral Office
          • Phone Number: 855-776-0015
        • Principal Investigator:
          • Yanyan Lou, MD
      • Tampa, Florida, United States, 33606
        • Recruiting
        • Moffitt Cancer Center
        • Principal Investigator:
          • Kedar Kirtane, MD
        • Contact:
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic
        • Contact:
          • Clinical Trials Referral Office
          • Phone Number: 855-776-0015
        • Principal Investigator:
          • Harry E. Fuentes Bayne, MD
    • Missouri
      • St Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University
        • Principal Investigator:
          • Patrick Grierson, M.D., Ph.D.
        • Contact:
    • New York
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Recruiting
        • The Ohio State University
        • Principal Investigator:
          • Kai He, MD, PhD
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98109
        • Recruiting
        • Fred Hutch Cancer Center
        • Principal Investigator:
          • Jennifer Specht, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Key Inclusion Criteria:

  1. 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).
  2. 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.
  3. Received previous required therapy for the appropriate solid tumor disease as described in the protocol
  4. Has adequate organ function as described in the protocol
  5. ECOG performance status of 0 to 1
  6. Life expectancy of ≥3 months
  7. Willing to comply with study schedule of assessments including long-term safety follow-up

Key Exclusion Criteria:

  1. Has disease that is suitable for local therapy or able to receive standard of care therapy that is therapeutic and not palliative
  2. Prior allogeneic stem cell transplant
  3. Prior solid organ transplant
  4. Cancer therapy within 3 weeks or 3 half lives of A2B395 infusion
  5. Radiotherapy within 28 days of A2B395 infusion
  6. Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months
  7. 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
  8. 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
  9. Requires supplemental home oxygen
  10. Females of childbearing potential who are pregnant or breastfeeding
  11. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A2B395
Participants receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B395 intravenously on day 0
Biological: A2B395
Allogeneic logic-gated Tmod CAR T cells
Other Names:
  • Tmod CAR T-cell Therapy
Diagnostic test: xT CDx with HLA-LOH assay
An investigational next generation sequencing (NGS) in vitro diagnostic (IVD) medical device

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Adverse events and toxicity will be evaluated according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (or current version). Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and graft versus host disease (GvHD) events will be graded according to the criteria described in the current protocol.
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
The RP2D will be identified utilizing a BOIN study design in addition to considering safety and biomarker analysis.
28 days post A2B395 infusion
Phase 2: The overall response rate (ORR) for patients
Time Frame: 24 months post A2B395 infusion
The ORR will be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and assessed by independent central review.
24 months post A2B395 infusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Persistence of A2B395
Time Frame: up to 24 months post A2B395 infusion
Number of A2B395 Tmod CAR T cells present in participants treated with A2B395 as assessed by polymerase chain reaction (PCR) (or similar method) on participant blood samples
up to 24 months post A2B395 infusion
Cytokine analysis
Time Frame: up to 24 months post A2B395 infusion
Cytokine levels such as interferon-gamma (IFN-γ) in participants treated with A2B395 assessed by cytokine analysis on participant blood samples
up to 24 months post A2B395 infusion
Cytokine analysis
Time Frame: up to 24 months post A2B395 infusion
Cytokine levels such as interleukin-6 (IL-6) in participants treated with A2B395 assessed by cytokine analysis on participant blood samples
up to 24 months post A2B395 infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

A2 Biotherapeutics Inc.

Investigators

  • Study Director: John Welch, MD, PhD, A2 Biotherapeutics

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 22, 2025

Primary Completion (Estimated)

March 31, 2029

Study Completion (Estimated)

March 31, 2030

Study Registration Dates

First Submitted

November 7, 2024

First Submitted That Met QC Criteria

November 7, 2024

First Posted (Actual)

November 12, 2024

Study Record Updates

Last Update Posted (Estimated)

September 9, 2025

Last Update Submitted That Met QC Criteria

September 3, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • A2B395-101

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Study data will be shared within 1 year of study completion.

IPD Sharing Time Frame

Data will be available within 1 year of the completion of the study, the length of time of availability is to be determined.

IPD Sharing Supporting Information Type

  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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