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
- Conditions
- Solid Tumor, AdultLung CancerCRCColorectal CancerNon-Small Cell LungCancerColon CancerNSCLC (Non-small Cell Lung Cancer)Rectal CancerHead and Neck Squamous Cell Cancer
- Interventions
- Diagnostic Test: xT CDx with HLA-LOH assay
- Registration Number
- NCT06682793
- Lead Sponsor
- A2 Biotherapeutics Inc.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 240
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description A2B395 A2B395 Participants receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B395 intravenously on day 0 A2B395 xT CDx with HLA-LOH assay Participants receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B395 intravenously on day 0
- Primary Outcome Measures
Name Time Method Phase 1: Rate of adverse events and dose limiting toxicities (DLTs) by dose level 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.
Phase 1: Recommended phase 2 dose (RP2D) 28 days post A2B395 infusion The RP2D will be identified utilizing a BOIN study design in addition to considering safety and biomarker analysis.
Phase 2: The overall response rate (ORR) for patients 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.
- Secondary Outcome Measures
Name Time Method Persistence of A2B395 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
Cytokine analysis 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
Trial Locations
- Locations (6)
UCSD Moores Cancer Center
🇺🇸La Jolla, California, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
UCLA Medical Center
🇺🇸Los Angeles, California, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Washington Unversity
🇺🇸Saint Louis, Missouri, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States