awaiting agreement with Sponsor

This phase I trial studies the side effects and best dose of RPCAR01 chimeric antigen receptor (CAR) T cells and to see how well it works in treating patients with GPC3 expressing hepatocellular carcinoma (HCC) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). In GPC3 expressing HCC cancerous cell tissue overexpresses, or makes too much of, a protein called "GPC3" on the surface of those cells (while only rarely expressed in healthy tissue). RPCAR01 is a genetically modified T cell (a part of the immune system) product that targets GPC3 and decreases the inhibition of T cells by a protein called transforming growth factor beta (TGFB). The drug is prepared by taking T cells from the blood by a procedure called "leukapheresis." The T cells are then modified to make them target GPC3 and disrupt TGFB which may help the body's immune system identify and kill GPC3 tumor cells. Lymphodepletion chemotherapy with cyclophosphamide and fludarabine involves receiving a short course of chemotherapy to kill T cells before receiving the RPCAR01 CAR T cell infusion. Giving RCAR01 CAR T cells may be safe, tolerable, and/or effective in treating patients with advanced or metastatic GPC3 expressing HCC.

PRIMARY OBJECTIVE:

I. To assess the safety, toxicity, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of autologous genetically modified CAR T cells administered as a single infusion targeting GPC3 in adult patients with advanced or metastatic GPC3 expressing hepatocellular carcinoma.

SECONDARY OBJECTIVE:

• To assess anti-tumor activity and in vivo persistence of adoptively transferred CAR T cells.
• Safety and treatment tolerability

EXPLORATORY OBJECTIVES:

I. To assess serial serum cytokine levels and C-reactive protein (CRP) levels following CAR T cell infusions.

II. To identify biomarkers associated with treatment response. III. To investigate the milieu of the tumor microenvironment pre and post exposure to CAR T cell therapy.

IV. To assess circulating tumor-derived deoxyribonucleic acid (Ct DNA) levels pre and post CAR T cell therapy.

V. To assess circulating CAR T cell expansion and persistence.

OUTLINE: This is a dose escalation study of anti-GPC3-CAR autologous T lymphocytes (RPCAR01) CAR T cell.

Patients undergo leukapheresis within 28 days prior to RPCAR01 CAR T cell infusion. Patients then receive cyclophosphamide intravenously (IV) over 2 hours and fludarabine IV over 30 minutes on days -5, -4, and -3 and RPCAR01 CAR T cells IV over 15 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition (MUGA) during screening and blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Patients may also optionally undergo tissue sample collection throughout the trial.

After completion of study treatment, patients are followed up at days 2, 3, 4, 5, 6, 7, 14, and 28, months 2, 4, 6, 8, 10, and 12, and then as per separate long term follow up study for up to 15 years.

Inclusion Criteria:

• ≥ 18 years of age
• Pathologically confirmed diagnosis of hepatocellular carcinoma. Mixed hepatocellular cholangiocarcinoma histology will be excluded in this trial
• Must have received at least 2 recommended standard of care lines of therapy for HCC which include checkpoint inhibition and a tyrosine kinase inhibitor such as lenvatinib
• Tissue confirmation of expression of GPC3 with immunohistochemistry (IHC) on archival tissue. ≥ 50% of tumor cells should be IHC 1+ or greater GPC3 intensity
• Presence of measurable disease, with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at the time of intervention consent. Previously treated lesions are acceptable as long as there is a new confirmed measurable component
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1
• Life expectancy of at least 3 months
• Patients with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti HBV therapy should be on a suppressive antiviral therapy prior to initiation of therapy
• Patients with a history of hepatitis C virus (HCV) infection should have completed curative antiviral treatment and have a HCV viral load below the limit of quantification
• Patients with HIV should have CD4+ T-cell (CD4+) counts ≥ 350 cells/µL within 3 months of study enrollment
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 65,000/mcL
• Total bilirubin ≤ 1.5 x 1.3 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional upper limit of normal (ULN)
• Creatinine clearance ≥ 50 mL/min (Cockroft-Gault)
• Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• Patients eligible for curative surgical or locoregional treatment options at the time of screening will not be included in the clinical trial.
• Patients with underlying Child-Pugh B or C liver cirrhosis (score of 7 or over)
• Patient does not have archival tumor tissue available for GPC3 testing
• Patients with a recent history of ongoing active bleeding
• Patients who have a current medical history of alcohol abuse
• Patient with a history of grade 2 or greater immune mediated toxicities of a major organ or a history of autoimmune hepatitis, pneumonitis or myocarditis
• Participants who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. A washout period of 2 weeks is required prior to leukapheresis
• Participants with known leptomeningeal disease or brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Concomitant systemic glucocorticoid use at a dose equivalent to > 10 mg daily prednisone at the time of leukapheresis and/or within 4 weeks of CAR T infusion
• Clinical or radiographic evidence of bowel obstruction or need for parenteral hydration and/or nutrition
• Active autoimmune disease
• Prior history of seizure disorder
• Pregnancy or breast-feeding female participants
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Unwilling or unable to follow protocol requirements
• Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug