Hepatocellular CarcinomaPhase 1NCT05003895
GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Solid Tumor Malignancies
A Phase 1 study testing Cyclophosphamide, CAR-T cell and Fludarabine in people with Hepatocellular Carcinoma and Hepatocellular Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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 types of cancer. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Hepatocellular Carcinoma, Hepatocellular Cancer, Metastatic Hepatocellular Carcinoma
- What is being tested?
- Cyclophosphamide, CAR-T cell and Fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 1 siteUnited States
- Study dates
- 8 Dec 2021to 31 Dec 2027
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histopathological confirmation of HCC or other solid tumor malignancy by the NCI Laboratory of Pathology
- Participants must:
- have progressed on at least 1 prior line of treatment
- OR
- --been intolerant of at least 1 prior line of treatment.
- 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.
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- 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 OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl) (A): < 1.5x institution upper limit of normal OR >= 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.
- For participants with brain metastases: Participants with <=3 (three or fewer) brain metastases that have been treated with surgery or stereotactic radiosurgery or other form of treatment are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment.
- The study drugs are harmful to developing human fetus. For this reason, women of childbearing potential must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy. Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 4 months after the last dose of study drugs. We also recommend men with partners of childbearing potential ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Men must not freeze or donate sperm within the same period.
- HBV infected participants must be on antivirals and have HBV DNA < 100IU/mL. HCV infected participants 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
Who cannot join
- Prior systemic therapy, an investigational therapy, radiation, and/or surgery within 2 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.
- Any form of primary immunodeficiency (e.g. severe combined immunodeficiency).
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- HIV-positive participants are excluded because HIV causes complicated immune deficiency and study treatment can pose more risks for these participants.
- Participants receiving systemic steroids >= 0.5 mg prednisone equivalent/kg/day. Steroid creams, ointments, and eye drops are allowed. Dose adjustment or discontinuation of medication must occur at least 24 hours prior to conditioning chemotherapy. Use of CART cell therapy in autoimmune diseases has the potential to be associated with serious safety risk. Given that this is an evolving area of research, caution should be exercised and any decision to include participants with autoimmune diseases should be made on a case-bycase basis.
- History of severe immediate hypersensitivity reaction to cyclophosphamide or fludarabine.
- Hospitalization within 7 days prior to treatment initiation.
- 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.
- Participants who received live or attenuated vaccine or virus-based vaccine within 30 days before initiation of study therapy
- Participants with a history of seizure disorder
- Participants with an expected life expectancy of less than 3 months before initiation of study therapy.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office, 888-624-1937
About this study
Official title: Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Solid Tumor Malignancies
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 types of cancer.
Read more
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 solid tumor malignancy.
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.
Read the 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.
- GPC3 is also expressed strongly in some non-HCC solid tumor malignancies.
- We want to evaluate the role of GPC3 targeted chimeric antigen receptor (CAR)-T cells in advanced GPC3 expressing HCC as well as other advanced solid tumor malignancies with GPC3 expression.
Objective:
-To determine the safety and feasibility of T-cells, expressing a novel humanized anti-GPC3 chimeric antigen receptor, in participants with advanced solid tumor malignancy, expressing GPC3.
Eligibility:
- Histologically confirmed diagnosis of hepatocellular carcinoma or other solid tumor malignancy.
- 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 advanced hepatocellular carcinoma or other advanced solid tumor malignancy, expressing GPC3.
- 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.
- Being tested
- Cyclophosphamide, CAR-T cell, Fludarabine
- Keywords
- immuno therapy, Targeted Therapy, Leukapheresis, Gene Therapy
- Medical subject headings
- Carcinoma, Hepatocellular, Liver Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CyclophosphamideDrug
Daily x 3 doses on Day -3, -2, -1 300 mg/m2 IV infusion (200 mg/m^2 in Dose Level -1)
CAR-T cellBiological
Single infusion on Day 0
FludarabineDrug
Daily x 2 doses on Day -2 and -1 30 mg/m^2 IV infusion administered following cyclophosphamide
| Study group | Role | What they receive |
|---|---|---|
| 1/ Arm 1 | Experimental | Escalating doses of CAR-T cells Receives: Drug: Cyclophosphamide; Biological: CAR-T cell; Drug: Fludarabine |
| 2/ Arm 2 | Experimental | MTD of CAR-T cells Receives: Drug: Cyclophosphamide; Biological: CAR-T cell; Drug: Fludarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine the safety and feasibility of T-cells, expressing a novel humanized anti-GPC3 chimeric antigen receptor, in participants with advanced solid tumor malignancy, expressing GPC3.
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 participants overall and per dose level who are able to receive sufficient CAR T cells as required for the specified dose level
Measured: 15 years
Secondary outcomes (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 anti-GPC3 chimeric antigen receptor in participants with advanced solid tumor malignancy expressi...
BOR rate will be reported among the 12 participants at the final dose level, along with a 95% two-sided confidence interval
Measured: 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
To characterize overall survival (OS)
Kaplan-Meier curve and 95% confidence interval for the median OS
Measured: death
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2021
- Study start8 Dec 2021
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 38 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Tim F Greten, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05003895
- Sponsor's protocol ID
- 210030
- Other IDs
- 21-C-0030
- Status last verified
- 13 Oct 2026
- First submitted
- 12 Aug 2021
- Last updated
- 16 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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