EVEREST-2: 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
Study Details
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 |
|---|---|---|
|
|
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-A02 heterozygous, with tumors that express MSLN and have lost HLA-A02 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-A02 protein). Additionally, normal healthy cells that maintain HLA-A02 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
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 Names:
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
- 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.
- 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.
Secondary Outcome Measures
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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.
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Received previous required therapy for the appropriate solid tumor disease as described in the protocol
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Has adequate organ function as described in the protocol
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ECOG performance status of 0 to 1
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Life expectancy of ≥3 months
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Willing to comply with study schedule of assessments including long term safety follow up
Key Exclusion Criteria:
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Has disease that is suitable for local therapy or able to receive standard of care therapy that is therapeutic and not palliative
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Prior allogeneic stem cell transplant
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Prior solid organ transplant
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MESO with pleural involvement extending into the peritoneum
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Cancer therapy within 3 weeks or 3 half lives of A2B694 infusion
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Radiotherapy within 28 days of A2B694 infusion
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Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months
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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
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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
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Requires supplemental home oxygen
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Females of childbearing potential who are pregnant or breastfeeding
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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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope | Duarte | California | United States | 91010 |
| 2 | UCSD Moores Cancer Center | La Jolla | California | United States | 92093 |
| 3 | UCLA Medical Center | Los Angeles | California | United States | 90404 |
| 4 | Stanford University | Stanford | California | United States | 94305 |
| 5 | Moffitt Cancer Center | Tampa | Florida | United States | 33606 |
| 6 | Massachusetts General Hopsital/Dana Farber Cancer Center | Boston | Massachusetts | United States | 02114 |
| 7 | Mayo Clinic Rochester | Rochester | Minnesota | United States | 55905 |
| 8 | Washington University | Saint Louis | Missouri | United States | 63110 |
| 9 | NYU Langone Medical Center | New York | New York | United States | 10016 |
| 10 | 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
Study Documents (Full-Text)
None provided.More Information
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.
- 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.
- 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.
- A2B694-101