Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    38
  • sponsor
    National Cancer Institute (NCI)
Updated on 28 October 2022
cancer
measurable disease
immunohistochemistry
EGFR

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.

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.

Details
Condition Hepatocellular Carcinoma, Hepatocellular Cancer, Metastatic Hepatocellular Carcinoma
Treatment cyclophosphamide, Fludarabine, CAR-T cell
Clinical Study IdentifierNCT05003895
SponsorNational Cancer Institute (NCI)
Last Modified on28 October 2022

Eligibility

Yes No Not Sure

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

Child-Pugh class B or C liver function
> 325 mg/day or clopidogrel)
Prior systemic therapy, an investigational therapy, radiation, and/or surgery within 4
Any form of primary immunodeficiency (e.g. severe combined immunodeficiency)
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
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
Hospitalization within 7 days prior to treatment initiation
aspirin
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
Subjects with a history of seizure disorder
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
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 an expected life expectancy of less than 3 months before initiation of
study therapy
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