EVEREST-1: 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

• Sponsor: A2 Biotherapeutics Inc. (Industry)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05736731
• Collaborator: Tempus Labs (Industry)
• Enrollment: 160
• Locations: 7
• Arm: 1
• Anticipated Duration (Months): 68
• Patients Per Site: 22.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
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	Biological: A2B530; Diagnostic Test: xT-Onco with HLA-LOH Assay	Phase 1/Phase 2

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-A02 heterozygous, with tumors that express CEA and somatic loss of HLA-A02. 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-A02 protein). Additionally, normal healthy cells that maintain HLA-A02 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 Design

• Study Type: Interventional
• Anticipated Enrollment: 160 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Anticipated Study Start Date: Apr 1, 2023
• Anticipated Primary Completion Date: Dec 1, 2026
• Anticipated Study Completion Date: Dec 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A2530 Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B530 intravenously on day 0	Biological: A2B530; Autologous logic-gated Tmod CAR T-cells; Other Names: 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

Outcome Measures

Primary Outcome Measures

1. 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 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.

2. Phase 1: Recommended Phase 2 Dose (RP2D) [21 days post A2B530 infusion]

   The RP2D will be identified utilizing a BOIN study design in addition to considering safety and biomarker analysis.

3. Phase 2: The Overall Response Rate (ORR) for patients [24 months post A2B530 infusion]

   The ORR will be evaluated per RECIST v1.1 and assessed by independent central review.

Secondary Outcome Measures

1. Persistence of A2B530 [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

2. Cytokine analysis [up to 24 months post A2B530 infusion]

   Cytokine levels in patients treated with A2B530 assessed by cytokine analysis on participant blood samples

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	90101
2	UCLA Medical Center	Los Angeles	California	United States	90404
3	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
4	Moffitt Cancer Center	Tampa	Florida	United States	33136
5	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
6	NYU Langone Medical Center	New York	New York	United States	10016
7	MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• A2 Biotherapeutics Inc.
• Tempus Labs

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A2 Biotherapeutics Inc.
• BASECAMP-1 Study

Publications

• 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.
• 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

• Responsible Party: A2 Biotherapeutics Inc.
• ClinicalTrials.gov Identifier: NCT05736731
• Other Study ID Numbers: A2B530-101
• First Posted: Feb 21, 2023
• Last Update Posted: Feb 21, 2023
• Last Verified: Feb 1, 2023

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by A2 Biotherapeutics Inc.: CAR T Cell; Solid Tumors; autologous; T cell; Carcinoembryonic Antigen; CEA; HLA-A2; Solid Tumors Expressing CEA; Pancreatic Cancer; PANC; CRC; Colorectal Cancer; NSCLC; Non-Small Cell Lung Cancer
• Additional relevant MeSH terms: Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Pancreatic Neoplasms; Recurrence

Study Results

No Results Posted as of Feb 21, 2023