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.
- 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.
