A Study to Evaluate the Safety and Efficacy of A2B694, a Logic-gated CAR T, in Subjects With Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression (EVEREST-2)

• ClinicalTrials.gov Identifier: NCT06051695
• Recruitment Status: Not yet recruiting
• First Posted: September 25, 2023
• Last Update Posted: November 13, 2023
• Sponsor: A2 Biotherapeutics Inc.
• Collaborator: Tempus Labs
• Information provided by (Responsible Party): A2 Biotherapeutics Inc.

Study Description

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

Condition or disease	Intervention/treatment	Phase
Solid Tumor, Adult; Colorectal Cancer; NSCLC; Non Small Cell Lung Cancer; NSCLC, Recurrent; Non-Small Cell Squamous Lung Cancer; Pancreas Cancer; Pancreatic Neoplasm; Colorectal Adenocarcinoma; CRC; Colon Cancer; Rectal Cancer; Cancer; Ovarian Cancer; Ovarian Neoplasms; Mesothelioma; Mesothelioma, Malignant; Ovary Cancer; Lung Cancer; MESOM	Biological: A2B694; Diagnostic Test: xT CDx with HLA-LOH Assay	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 230 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Seamless Phase 1/2 Study to Evaluate the Safety and Efficacy of A2B694, an Autologous Logic-gated Tmod™ CAR T, in Heterozygous HLA-A*02 Adults With Recurrent Unresectable, Locally Advanced, or Metastatic Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression
• Estimated Study Start Date: March 2024
• Estimated Primary Completion Date: June 2028
• Estimated Study Completion Date: June 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: A2B694; Patients receive Preconditioning Lymphodepletion (PCLD) Regimen followed by a single dose of A2B694 intravenously on day 0	Biological: A2B694; Autologous logic-gated Tmod CAR T cells; Other Name: Tmod CAR T-cell Therapy; Diagnostic Test: xT CDx 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 [ Time Frame: 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.
2. Phase 1: Recommended Phase 2 Dose (RP2D) [ Time Frame: 21 days post A2B694 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 [ Time Frame: 24 months post A2B694 infusion ]
   The ORR will be evaluated per RECIST v1.1 and assessed by independent central review.

Secondary Outcome Measures :

1. Persistence of A2B694 [ Time Frame: 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
2. Cytokine analysis [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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), 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, OVCA, MESO, or other solid tumors with MSLN 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. MESO with pleural involvement extending into the peritoneum
5. Cancer therapy within 3 weeks or 3 half lives of A2B694 infusion
6. Radiotherapy within 28 days of A2B694 infusion
7. Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months
8. 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
9. 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
10. Requires supplemental home oxygen
11. Females of childbearing potential who are pregnant or breastfeeding
12. 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

Contacts and Locations

Contacts

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

Locations

United States, California

City of Hope

Duarte, California, United States, 91010

UCSD Moores Cancer Center

La Jolla, California, United States, 92093

UCLA Medical Center

Los Angeles, California, United States, 90404

Stanford University

Stanford, California, United States, 94305

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33606

United States, Massachusetts

Massachusetts General Hopsital/Dana Farber Cancer Center

Boston, Massachusetts, United States, 02114

United States, Minnesota

Mayo Clinic Rochester

Rochester, Minnesota, United States, 55905

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, New York

NYU Langone Medical Center

New York, New York, United States, 10016

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

A2 Biotherapeutics Inc.

Tempus Labs

Investigators

• Study Director: John Welch, MD, PhD; A2 Biotherapeutics

More Information

Additional Information:

A2 Biotherapeutics Inc. 

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.

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.

Tokatlian T, Asuelime GE, Mock JY, DiAndreth B, Sharma S, Toledo Warshaviak D, Daris ME, Bolanos K, Luna BL, Naradikian MS, Deshmukh K, Hamburger AE, Kamb A. Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells. J Immunother Cancer. 2022 Jan;10(1):e003826. doi: 10.1136/jitc-2021-003826.

• Responsible Party: A2 Biotherapeutics Inc.
• ClinicalTrials.gov Identifier: NCT06051695
• Other Study ID Numbers: A2B694-101
• First Posted: September 25, 2023
• Last Update Posted: November 13, 2023
• Last Verified: November 2023

Individual Participant Data (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.

• 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; Mesothelin; MSLN; HLA-A2; Solid Tumors expressing MSLN; Pancreatic; Cell Therapy; Gene Therapy; blocker; Cancer; PANC; CRC; Colorectal Cancer; Lung Cancer; NSCLC; OVCA; MESOM; Ovarian Cancer; Mesothelioma

Additional relevant MeSH terms:

Neoplasms; Lung Neoplasms; Colorectal Neoplasms; Ovarian Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pancreatic Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female