Clinical trial NCT06682793: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumor, Adult
Colorectal Cancer
Non-Small Cell Lung
NSCLC (Non-small Cell Lung Cancer)
Cancer
Colon Cancer
Rectal Cancer
Lung Cancer
CRC
Head and Neck Squamous Cell Cancer
HNSCC
Renal Cell Carcinoma
RCC
Kidney Cancer
Triple Negative Breast Cancer
TNBC
Colorectal Adenocarcinoma
Keywords: CAR T Cell
Solid Tumors
Allogeneic
T Cell
EGFR
HLA-A2
Solid tumors expressing EGFR
CRC
Colorectal
Cell Therapy
Gene Therapy
Blocker
Cancer
NSCLC
Non small Cell Lung Cancer
Lung Cancer
renal cell carcinoma
RCC
Kidney Cancer
Renal cell cancer
Triple negative breast cancer
TNBC
Lead sponsor: A2 Biotherapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2024-11-12
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1: Rate of adverse events and dose limiting toxicities (DLTs) by dose level
timeFrame: From the time of Informed consent until 24 months (2 years) post A2B395 infusion
measure: Phase 1: Recommended phase 2 dose (RP2D)
timeFrame: 28 days post A2B395 infusion
measure: Phase 2: The overall response rate (ORR) for patients
timeFrame: 24 months post A2B395 infusion
Secondary outcomes:
measure: Persistence of A2B395
timeFrame: up to 24 months post A2B395 infusion
measure: Cytokine analysis
timeFrame: up to 24 months post A2B395 infusion
measure: Cytokine analysis
timeFrame: up to 24 months post A2B395 infusion
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: NYU Langone Health
state: New York
Study officials:
affiliation: A2 Biotherapeutics
name: John Welch, MD, PhD
role: STUDY_DIRECTOR
References:
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