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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)

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ClinicalTrials.gov Identifier: NCT06051695
Recruitment Status : Recruiting
First Posted : September 25, 2023
Last Update Posted : April 9, 2024
Sponsor:
Collaborator:
Tempus AI
Information provided by (Responsible Party):
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


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.

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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
Actual Study Start Date : April 3, 2024
Estimated Primary Completion Date : June 2028
Estimated Study Completion Date : June 2029


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06051695


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

Locations
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United States, California
UCSD Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Jona Plevin       jplevin@health.ucsd.edu   
Principal Investigator: Sandip Patel, MD         
UCLA Medical Center Recruiting
Los Angeles, California, United States, 90404
Contact: Christopher Hannigan       channigan@mednet.ucla.edu   
Principal Investigator: J. Randolph Hecht, MD         
Stanford University Not yet recruiting
Stanford, California, United States, 94305
United States, Florida
Mayo Clinic Recruiting
Jacksonville, Florida, United States, 32224
Contact: Jawad Khan       khan.jawad@mayo.edu   
Principal Investigator: Yanyan Lou, MD         
Moffitt Cancer Center Not yet recruiting
Tampa, Florida, United States, 33606
United States, Massachusetts
Massachusetts General Hopsital/Dana Farber Cancer Center Not yet recruiting
Boston, Massachusetts, United States, 02114
United States, Minnesota
Mayo Clinic Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Mohammed Elhaj       elhaj.mohammed@mayo.edu   
Principal Investigator: Julian Molina, MD, PhD         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Amberly Scott         
Contact       amberly@wustl.edu   
United States, New York
NYU Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Salman Punekar, MD       salman.punekar@nyulangone.org   
Contact: Peter Warren       Peter.Warren@nyulangone.org   
Sponsors and Collaborators
A2 Biotherapeutics Inc.
Tempus AI
Investigators
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Study Director: John Welch, MD, PhD A2 Biotherapeutics
Additional Information:
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.

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Responsible Party: A2 Biotherapeutics Inc.
ClinicalTrials.gov Identifier: NCT06051695    
Other Study ID Numbers: A2B694-101
First Posted: September 25, 2023    Key Record Dates
Last Update Posted: April 9, 2024
Last Verified: April 2024
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.

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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:
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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