GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)

• ClinicalTrials.gov Identifier: NCT05003895
• Recruitment Status: Recruiting
• First Posted: August 13, 2021
• Last Update Posted: January 23, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

A new cancer treatment takes a person s own T cells, modifies them in a laboratory so they can better fight cancer cells, and then gives them back to the person. Researchers want to see if this treatment can help people with a certain type of liver cancer.

Objective:

To see if a personalized immune treatment, anti-GPC3 CAR-T cells, is safe.

Eligibility:

Adults aged 18 years and older who have Glypican-3 (GPC3) positive HCC, a type of liver cancer.

Design:

Participants will be screened with the following:

Blood and urine tests

Medical history

Physical exam

Heart function tests

Review of their symptoms and their ability to perform their normal activities

Tumor biopsy

Imaging scan of the chest, abdomen, and pelvis

Participants will have leukapheresis. They may have an IV (intravenous catheter, a small tube put into an arm vein) inserted into each arm or get a central line. Blood will be removed. A machine will separate the white blood cells from their blood. The rest of their blood will be returned to them.

Participants will be admitted to the hospital for about 2 weeks. They will get the chemotherapy drugs fludarabine and cyclophosphamide by IV for 3 days. Then they will receive the modified white blood cells by IV.

Participants will have frequent blood draws. They will give blood and tumor samples for research.

Participants will have follow-up visits for the next 15 years. Then they will be contacted by email or phone for the rest of their life. If their disease does not get worse after 5 years, they will continue to be invited to do imaging studies every 6 months.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma; Hepatocellular Cancer; Metastatic Hepatocellular Carcinoma	Drug: Cyclophosphamide; Biological: CAR-T cell; Drug: Fludarabine	Phase 1

Detailed Description:

Background:

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-associated mortality with an average life expectancy of 6-9 months

Despite the success of several studies showing efficacy in treating HCC, most clinical trials have failed to prove a survival advantage.

Adoptive T-cell therapy exploits the natural ability of T-cells to recognize and eliminate their target.

GPC3 is a cell surface protein that is expressed in nearly all HCC yet is undetectable in normal adult hepatic tissues.

We want to evaluate the role of GPC3 targeted chimeric antigen receptor (CAR)-T cells in advanced GPC3 expressing HCC.

Objective:

To determine the safety and feasibility of T-cells, expressing a novel humanized anti-GPC3 chimeric antigen receptor, in participants with advanced HCC, expressing GPC3.

Eligibility:

Histologically confirmed diagnosis of hepatocellular carcinoma

GPC3 positivity of >= 25% by immunohistochemistry

At least 1 measurable lesion by RECIST v 1.1 criteria

Age >= 18 years

Design:

We plan to conduct a phase I dose escalation designed clinical trial using CAR (hYP7)-T cells in participants with GPC3 expressing advanced hepatocellular carcinoma.

Participants will undergo leukapheresis

Participants will receive a lymphocyte depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused CAR-expressing T cells

Following the T cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.

The participants will be closely monitored during the first year after cell infusion and followed for life.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)
• Actual Study Start Date: December 8, 2021
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1/ Arm 1; Escalating doses of CAR-T cells	Drug: Cyclophosphamide; Daily x 3 doses on Day -3, -2, -1 300 mg/m2 IV infusion (200 mg/m2 in Dose Level -1); Biological: CAR-T cell; Single infusion on Day 0; Drug: Fludarabine; Daily x 2 doses on Day -2 and -1 30 mg/m2 IV infusion administered following cyclophosphamide
Experimental: 2/ Arm 2; MTD of CAR-T cells	Drug: Cyclophosphamide; Daily x 3 doses on Day -3, -2, -1 300 mg/m2 IV infusion (200 mg/m2 in Dose Level -1); Biological: CAR-T cell; Single infusion on Day 0; Drug: Fludarabine; Daily x 2 doses on Day -2 and -1 30 mg/m2 IV infusion administered following cyclophosphamide

Outcome Measures

Primary Outcome Measures :

1. To determine the safety and feasibility of T-cells, expressing a novel humanized anti-GPC3 chimeric antigen receptor, in patients with advanced HCC, expressing GPC3 [ Time Frame: 15 years ]
   Safety will be reported based on DLTs per dose level as well as reporting specific grades and types of toxicity encountered. Feasibility will be reported descriptively as the fraction of patients overall and per dose level who are able to receive sufficient CAR T cells as required for the specified dose level

Secondary Outcome Measures :

1. To characterize overall survival (OS) [ Time Frame: death ]
   Kaplan-Meier curve and 95% confidence interval for the median OS
2. To determine the best overall response (BOR) rate according to Response Evaluation Criteria (by RECIST v 1.1) of treatment with T-cells, expressing a novel humanized anti-GPC3 chimeric antigen receptor in participants with advanced HCC, expressi... [ Time Frame: every 2-month for the first year, every 3 month for the second year, every 4 month for the third year, and every 6 month afterward until disease progression ]
   BOR rate will be reported among the 12 participants at the final dose level, along with a 95% two-sided confidence interval

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:
• Histopathological confirmation of HCC by the NCI Laboratory of Pathology

• Subjects must:

  • have progressed on the prior first line of standard therapy

OR

--been intolerant of the standard of care chemotherapy for HCC.

• Participants must have at least 1 focus of disease that is amenable to mandatory tumor biopsy prior to study treatment initiation to determine tumor GPC3 expression and be willing to undergo this. Ideally, the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigators.
• Tumor must have GPC3 positivity of >= 25% by immunohistochemistry on freshly collected biopsy
• Participants must have at least 1 measurable lesion by RECIST version 1.1
• Participants must have a disease that is not amenable to potentially curative resection, ablation, or transplantation.
• Age >= 18 years.
• Performance status (ECOG) 0-1
• Participants must have adequate organ and marrow function as defined below:

ANC: >= 1,000/mcL

Platelets: >= 75,000/mcL

Hemoglobin: >= 8 g/dL

total bilirubin: If cirrhosis present: Part of Child Pugh requirement

If no cirrhosis: bilirubin should be <= 1.5 x ULN

ALT or AST: <= 5 x ULN.

Creatinine: < 1.5x institution upper limit of normal

OR

Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl) (A):

>= 50 mL/min/1.73 m(2) for participant with creatinine levels >= 1.5 X institutional ULN

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);

AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

(A)Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.

• Normal cardiac ejection fraction (>= 50% by echocardiogram) and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 4 weeks before treatment initiation.
• Room air oxygen saturation of 92% or greater.
• Treatment-related toxicities must be resolved to <= grade 1.
• The study drugs are harmful to developing human fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at the study entry, for the duration of study therapy, and up to 180 days after the last dose of the study drug(s). 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.
• HBV infected subjects must be on antivirals and have HBV DNA < 100IU/mL. HCV infected subjects can be enrolled with close HCV RNA level monitoring.
• Participants must be able to understand and be willing to sign a written informed consent.
• For participants that do not have a legally authorized representative in place, one must be identified before study treatment starts

EXCLUSION CRITERIA:

• Prior systemic therapy, an investigational therapy, radiation, and/or surgery within 4 weeks prior to treatment initiation.
• Prior administration of anti-PD-1 or anti-PD-L1 antibodies or other agents that in the opinion of the PI can stimulate immune activity and interfere with an infusion of CAR-T cells within 8 weeks prior to treatment initiation.
• Child-Pugh class B or C liver function
• 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.

Note: Participants with a history of abnormal pulmonary function tests but stable obstructive or restrictive pulmonary disease may be eligible per PI discretion.

-Participants who require anticoagulation (e.g. warfarin) or anti-platelet therapy (e.g. aspirin

> 325 mg/day or clopidogrel).

• Any form of primary immunodeficiency (e.g. severe combined immunodeficiency).
• HIV-positive participants are excluded because HIV causes complicated immune deficiency and study treatment can pose more risks for these participants.

• Participants with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to participants with a history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or CIDP, myasthenia gravis; systemic autoimmune diseases such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn s, ulcerative colitis, hepatitis; and participants with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome.

  --NOTE: participants with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Participants with rheumatoid arthritis and other arthropathies, Sjogren s syndrome, and psoriasis controlled with topical medication and participants with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and the potential need for systemic treatment but should otherwise be eligible.

• History of severe immediate hypersensitivity reaction to cyclophosphamide or fludarabine.
• Hospitalization within 7 days prior to treatment initiation.
• Systemic corticosteroid therapy of any dose within 14 days prior to the treatment initiation. Corticosteroid creams, ointments, and eye drops are allowed.
• Participants with known central nervous system metastases are excluded because of their poor prognosis and progressive neurologic dysfunction, secondary to metastases, that would confound the evaluation of adverse events, especially neurologic toxicity, which is common with CAR-T cells, used in this study.
• Pregnant women are excluded from this study because study therapy can cause fetal harm.

Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with study therapy, breastfeeding should be discontinued if the mother is treated with study drugs.

• Subjects who received live or attenuated vaccine or virus-based vaccine within 30 days before initiation of study therapy
• Subjects with a history of seizure disorder
• Subjects with an expected life expectancy of less than 3 months before initiation of study therapy.

Contacts and Locations

Contacts

Contact: Donna M Hrones, C.R.N.P.; (240) 858-3155; donna.mabry@nih.gov

Contact: Tim F Greten, M.D.; (240) 760-6114; gretentf@mail.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tim F Greten, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT05003895
• Other Study ID Numbers: 210030; 21-C-0030
• First Posted: August 13, 2021
• Last Update Posted: January 23, 2023
• Last Verified: January 19, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

immuno therapy; Targeted Therapy; Leukapheresis; Gene Therapy

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Cyclophosphamide; Fludarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists