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
- Conditions
- Colorectal CancerRectal CancerNSCLC, RecurrentNon Small Cell Lung CancerColorectal AdenocarcinomaCRCMesotheliomaPancreatic NeoplasmColon CancerOvarian Cancer
- Interventions
- Diagnostic Test: xT CDx with HLA-LOH Assay
- Registration Number
- NCT06051695
- Lead Sponsor
- A2 Biotherapeutics Inc.
- Brief Summary
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
- 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, 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 230
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description A2B694 A2B694 Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B694 intravenously on day 0 A2B694 xT CDx with HLA-LOH Assay Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B694 intravenously on day 0
- Primary Outcome Measures
Name Time Method Phase 1: Recommended Phase 2 Dose (RP2D) 21 days post A2B694 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 A2B694 infusion The ORR will be evaluated per RECIST v1.1 and assessed by independent central review.
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 A2B694 infusion Adverse Events and toxicity will be evaluated according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 (or current version). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) events will be graded according to the criteria described in the current protocol.
- Secondary Outcome Measures
Name Time Method Persistence of A2B694 up to 24 months post A2B694 infusion Number of A2B694 Tmod CAR T cells present in patients treated with A2B694 as assessed by Polymerase Chain Reaction (PCR) (or similar method) on participant blood samples
Cytokine analysis up to 24 months post A2B694 infusion Cytokine levels such as interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in patients treated with A2B694 assessed by cytokine analysis on participant blood samples
Trial Locations
- Locations (11)
Banner Health
🇺🇸Gilbert, Arizona, United States
UCSD Moores Cancer Center
🇺🇸La Jolla, California, United States
UCLA Medical Center
🇺🇸Los Angeles, California, United States
Stanford University
🇺🇸Stanford, California, United States
Mayo Clinic
🇺🇸Jacksonville, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Massachusetts General Hopsital/Dana Farber Cancer Center
🇺🇸Boston, Massachusetts, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University
🇺🇸St. Louis, Missouri, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States