A Study to Evaluate the Safety and Efficacy of A2B530, a Logic-gated CAR T, in Subjects With Solid Tumors That Express CEA and Have Lost HLA-A*02 Expression (EVEREST-1)

• ClinicalTrials.gov Identifier: NCT05736731
• Recruitment Status: Recruiting
• First Posted: February 21, 2023
• Last Update Posted: April 9, 2024
• Sponsor: A2 Biotherapeutics Inc.
• Collaborator: Tempus AI
• Information provided by (Responsible Party): A2 Biotherapeutics Inc.

Tracking Information

• First Submitted Date: January 30, 2023
• First Posted Date: February 21, 2023
• Last Update Posted Date: April 9, 2024
• Actual Study Start Date: April 28, 2023
• Estimated Primary Completion Date: December 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2023)

• 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 A2B530 infusion. ]
  Adverse Events and toxicity will be evaluated according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events version 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.
• Phase 1: Recommended Phase 2 Dose (RP2D) [ Time Frame: 21 days post A2B530 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 [ Time Frame: 24 months post A2B530 infusion ]
  The ORR will be evaluated per RECIST v1.1 and assessed by independent central review.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2023)

• Persistence of A2B530 [ Time Frame: up to 24 months post A2B530 infusion ]
  Number of A2B530 Tmod CAR T cells present in patients treated with A2B530 as assessed by Polymerase Chain Reaction (PCR) (or similar method) on participant blood samples
• Cytokine analysis [ Time Frame: up to 24 months post A2B530 infusion ]
  Cytokine levels in patients treated with A2B530 assessed by cytokine analysis on participant blood samples

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Safety and Efficacy of A2B530, a Logic-gated CAR T, in Subjects With Solid Tumors That Express CEA and Have Lost HLA-A*02 Expression
• Official Title: A Phase 1/2 Study to Evaluate the Safety and Efficacy of A2B530, an Autologous Logic-gated Tmod™ Chimeric Antigen Receptor T Cell (CAR T), in Heterozygous HLA-A*02 Adult Subjects With Recurrent Unresectable, Locally Advanced, or Metastatic Solid Tumors That Express CEA and Have Lost HLA-A*02 Expression

Brief Summary

The goal of this study is to test A2B530,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), and other solid tumors that express CEA and have lost HLA-A*02 expression.

The main questions this study aims to answer are:

• Phase 1: What is the maximum or recommended dose of A2B530 that is safe for patients
• Phase 2: Does the recommended dose of A2B530 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
• A2B530 Tmod CAR T cells at the assigned dose

Detailed Description

This is a phase 1/2, multi-center, open-label study that enrolls adult subjects with recurrent unresectable, locally advanced, or metastatic (considered non-curative) CRC, NSCLC, PANC, or other solid tumors with CEA expression. Subjects must be germline HLA-A*02 heterozygous, with tumors that express CEA and somatic loss of HLA-A*02. The purpose of Phase 1 of this study is to determine the safety and the optimal dose of A2B530 (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 A2B530.

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 A2B530 Tmod CAR T-cell therapy will enable the killing of tumor target cells (those cells that express CEA and have LOH for HLA-A*02 protein). Additionally, normal healthy cells that maintain HLA-A*02 expression and co-express CEA (eg, gut mucosal 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-1) and the participant's T cells are then manufactured and infused following PCLD regimen. There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to EVEREST-1 based on their own disease course.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor, Adult
• Solid Tumor
• Pancreatic Cancer
• Pancreatic Neoplasms
• Pancreas Cancer
• Non Small Cell Lung Cancer
• Non Small Cell Lung Cancer Recurrent
• Non-Small Cell Squamous Lung Cancer
• NSCLC
• NSCLC, Recurrent
• Colorectal Cancer
• Colorectal Neoplasms
• Colorectal Adenocarcinoma
• CRC
• Colorectal Cancer Metastatic
• Cancer

Intervention

• Biological: A2B530
  Autologous logic-gated Tmod CAR T-cells
  Other Name: Tmod CAR T-cell Therapy
• Diagnostic Test: xT-Onco with HLA-LOH Assay
  An investigational next generation sequencing (NGS) in vitro diagnostic (IVD) medical device

Study Arms

Experimental: A2530

Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B530 intravenously on day 0

Interventions:

• Biological: A2B530
• Diagnostic Test: xT-Onco with HLA-LOH Assay

Publications *

• Hamburger AE, DiAndreth B, Cui J, Daris ME, Munguia ML, Deshmukh K, Mock JY, Asuelime GE, Lim ED, Kreke MR, Tokatlian T, Kamb A. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020 Dec;128:298-310. doi: 10.1016/j.molimm.2020.09.012. Epub 2020 Oct 1.
• Hwang MS, Mog BJ, Douglass J, Pearlman AH, Hsiue EH, Paul S, DiNapoli SR, Konig MF, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Vogelstein B, Zhou S, Kinzler KW. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2022410118. doi: 10.1073/pnas.2022410118.
• Perera J, Mapes B, Lau D, et al. Detection of human leukocyte antigen class I loss of heterozygosity in solid tumor types by next-generation DNA sequencing. J Immunother Cancer. 2019, 7(Suppl 1):P103
• Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M. The landscape of somatic copy-number alteration across human cancers. Nature. 2010 Feb 18;463(7283):899-905. doi: 10.1038/nature08822.
• Sandberg ML, Wang X, Martin AD, Nampe DP, Gabrelow GB, Li CZ, McElvain ME, Lee WH, Shafaattalab S, Martire S, Fisher FA, Ando Y, Liu E, Ju D, Wong LM, Xu H, Kamb A. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. Sci Transl Med. 2022 Mar 2;14(634):eabm0306. doi: 10.1126/scitranslmed.abm0306. Epub 2022 Mar 2.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 10, 2023): 160
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2028
• Estimated Primary Completion Date: December 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

1. Appropriately enrolled in the BASECAMP-1 A2 Biotherapeutics, Inc. study, with tissue demonstrating LOH of HLA-A*02:01 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
2. Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, PANC, or other solid tumors associated with CEA expression. Measurable disease is required with lesions of >1.0 cm by computed tomography (CT). (Soluble CEA is not acceptable as the sole measure of disease).
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 A2B530 infusion
5. Radiotherapy within 28 days of A2B530 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. Requires supplemental home oxygen
9. Females of childbearing potential who are pregnant or breastfeeding
10. 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 A2B530

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Clinical Trials; 310-431-9180; ClinicalTrials@a2bio.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05736731
• Other Study ID Numbers: A2B530-101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Study data will be shared within 1 year of study completion.
• Supporting Materials: Clinical Study Report (CSR)
• 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.

• Current Responsible Party: A2 Biotherapeutics Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: A2 Biotherapeutics Inc.
• Original Study Sponsor: Same as current
• Collaborators: Tempus AI

Investigators

• Study Director: Eric Ng, MD; Sr. Medical Director, Safety, A2 Biotherapeutics, Inc.

• PRS Account: A2 Biotherapeutics Inc.
• Verification Date: April 2024