Description:
This study enrolls patients who have GPC3-positive solid tumors currently. Patients may be
considered if the cancer has come back, has not gone away after standard treatment or the
patient cannot receive standard treatment. This research study uses special immune system
cells called GAP T cells, a new experimental treatment.
The body has different ways of fighting infection and disease. No single way seems perfect
for fighting cancers. This research study combines two different ways of fighting cancer:
antibodies and T cells. Antibodies are types of proteins that protect the body from
infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special
infection-fighting blood cells that can kill other cells, including cells infected with
viruses and tumor cells. Both antibodies and T cells have been used to treat patients with
cancers. They have shown promise, but have not been strong enough to cure most patients.
Investigators have found from previous research that they can put a new gene into T cells
that will make them recognize cancer cells and kill them. In preclinical studies, the
investigators made several genes called a chimeric antigen receptor (CAR), from an antibody
called GC33 that recognizes glypican-3, a proteoglycan found on solid tumors including
pediatric liver cancers (GPC3-CAR). This study will test T cells genetically engineered with
a GPC3-CAR (GAP T cells) in patients with GPC3-positive solid tumors (currently only
enrolling liver tumors).
The GAP T cells are an investigational product not approved by the Food and Drug
Administration.
The purpose of this study is to find the biggest dose of GAP T cells that is safe, to see how
long they last in the body, to learn what the side effects are and to see if the GAP T cells
will help people with GPC3-positive solid tumors. This study enrolls patients who have
GPC3-positive solid tumors (currently only enrolling liver tumors).
Title
- Brief Title: Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Patients With Pediatric Solid Tumors (GAP)
- Official Title: Glypican 3-specific Chimeric Antigen Receptor Expressed in Autologous T Cells as Immunotherapy for Patients With Pediatric Solid Tumors
Clinical Trial IDs
- ORG STUDY ID:
H-39410- GAP
- SECONDARY ID:
GAP
- NCT ID:
NCT02932956
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Cytoxan | Cyclophosphamide | GAP T cells + Fludarabine and Cytoxan |
| Fludara | Fludarabine | GAP T cells + Fludarabine and Cytoxan |
Purpose
This study enrolls patients who have GPC3-positive solid tumors currently. Patients may be
considered if the cancer has come back, has not gone away after standard treatment or the
patient cannot receive standard treatment. This research study uses special immune system
cells called GAP T cells, a new experimental treatment.
The body has different ways of fighting infection and disease. No single way seems perfect
for fighting cancers. This research study combines two different ways of fighting cancer:
antibodies and T cells. Antibodies are types of proteins that protect the body from
infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special
infection-fighting blood cells that can kill other cells, including cells infected with
viruses and tumor cells. Both antibodies and T cells have been used to treat patients with
cancers. They have shown promise, but have not been strong enough to cure most patients.
Investigators have found from previous research that they can put a new gene into T cells
that will make them recognize cancer cells and kill them. In preclinical studies, the
investigators made several genes called a chimeric antigen receptor (CAR), from an antibody
called GC33 that recognizes glypican-3, a proteoglycan found on solid tumors including
pediatric liver cancers (GPC3-CAR). This study will test T cells genetically engineered with
a GPC3-CAR (GAP T cells) in patients with GPC3-positive solid tumors (currently only
enrolling liver tumors).
The GAP T cells are an investigational product not approved by the Food and Drug
Administration.
The purpose of this study is to find the biggest dose of GAP T cells that is safe, to see how
long they last in the body, to learn what the side effects are and to see if the GAP T cells
will help people with GPC3-positive solid tumors. This study enrolls patients who have
GPC3-positive solid tumors (currently only enrolling liver tumors).
Detailed Description
Approximately 24-30 subjects will participate in the treatment part of this study.
Maximum of 180 mL of blood (not exceeding 3ml/kg/day) is collected from patients to grow the
T cells and a retrovirus (a special virus that can insert the GPC3 CAR gene into the T cells)
is used to genetically engineer them. After the CAR gene was put into the T cells, the
investigators make sure that they are able to kill GPC3 positive solid tumor cells in the
laboratory.
LYMPHODEPLETION CHEMOTHERAPY:
Several studies suggest that the infused T cells need room to be able to proliferate and
accomplish their functions and that this may not happen if there are too many other T cells
in circulation. Because of that, participants will receive treatment with cyclophosphamide
(Cytoxan) and fludarabine for 3 days before receiving the T-cell infusion. These drugs will
decrease the numbers of the participants' own T cells before the investigators infuse the GAP
T CELLS.
WHAT THE INFUSION WILL BE LIKE:
After making these cells, they will be frozen. If the patient agrees to participate in this
study, at the time the patient is scheduled to be treated, the cells will be thawed and
injected into the patient over 5 to 10 minutes. The participant will receive the GAP T CELLS
48 to 72 hours after completing the chemotherapy.
This is a dose escalation study, which means that the investigators do not know the highest
dose of GAP T cells that is safe. To find out, the investigators will give the cells to at
least 3 participants at one dose level. If that is safe, the investigators will raise the
dose given to the next group of participants. The dose each patient gets depends on how many
participants get the agent before that patient and how they react. The investigator will tell
each patient this information. This will help the participant think about possible harms and
benefits. Since the treatment is experimental, what is likely to happen at any dose is not
known.
All of the treatments will be given by the Center for Cell and Gene Therapy at Texas
Children's Hospital.
Medical tests before treatment:
- Physical exam and History
- Blood tests to measure blood cells, kidney and liver function.
- Pregnancy test (if the participant is a female who can get pregnant)
- If the participant is infected with the hepatitis B virus (HBV) the investigators will
do a test to measure the levels of the virus
- Measurements of the participant's tumor by scans and the tumor marker alfa-fetoprotein
(AFP), if the participant's tumor produces this protein.
Medical tests during and after treatment:
- Physical exams and History
- Blood tests to measure blood cells, kidney and liver function
- If the participant is infected with the hepatitis B virus (HBV) the investigators will
repeat the test and monitor the levels of the virus
- Measurements of the participant's tumor by scans (4-6 weeks after the infusion) and AFP
(if applicable at 1, 2, and 4 weeks after the infusion).
- Tumor biopsy between 2-4 weeks after the infusion and as clinically indicated
thereafter. For additional clinically indicated tumor biopsies, investigators will ask
for a portion of the sample for research.
FOLLOW-UP STUDIES
The investigators will follow the participant during and after the injections. To learn more
about the way the T cells are working in the participant's body, up to 60 mL (upto 12
teaspoons, no more than 3ml/kg/day) of blood will be taken from the participant before the
chemotherapy, before the T-cell infusion, 1 to 4 hours after the infusion, 3 to 4 days after
the infusion (this time point is optional ) at 1 week, 2 weeks, 4 weeks and 8 weeks after the
injection, every 3 months for 1 year, every 6 months for 4 years and then every year for the
next 10 years. Total participation time for this study will be 15 years.
During the time points listed above, if the T cells are found in the participant's blood at a
certain amount an extra 5 mL of blood may need to be collected for additional testing.
The investigators will use this blood to look for the frequency and activity of the cells
that the investigators have given; that is, to learn more about the way the T cells are
working and how long they last in the body. The investigators will also use this blood to see
if there are any long-term side effects of putting the new gene (chimeric antigen receptor,
CAR) into the cells. In addition to the blood draws, because the participants have received
cells that have had a new gene put in them, the participants will need to have long term
follow up for 15 years so the investigators can see if there are any long-term side effects
of the gene transfer.
Once a year, the participants will be asked to have their blood drawn and answer questions
about their general health and medical condition. The investigators may ask the participants
to report any recent hospitalizations, new medications, or the development of conditions or
illness that were not present when the participants enrolled in the study and may request
that physical exams and/or laboratory tests be performed if necessary.
When tumor biopsy is performed for clinical reasons the investigators will request permission
to obtain excess sample to learn more about the effects of the treatment on the participant's
disease.
In the event of death, the investigators will request permission to perform an autopsy to
learn more about the effects of the treatment on the participant's disease and if there were
any side effects from the cells with the new gene.
In addition, the investigators would like to ask for participant permission to use tumor
biopsy for research purposes only. Associated risk with the biopsy will be discussed with
each participant in detail in a procedure specific consent form. The investigators will test
the sample to see if the GAP T cells can be found in the tumor and what effect they had on
the tumor cells.
If participants develop a second abnormal cancer growth, significant blood or nervous system
disorder during the trial, a biopsy sample of the tissue will be tested.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| GAP T cells + Fludarabine and Cytoxan | Experimental | GPC3-Car (GAP T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors. | |
Eligibility Criteria
Procurement Eligibility
Inclusion Criteria:
- Relapsed or refractory GPC3-positive* solid tumors (currently only enrolling liver
tumors)
- Age ≥ 1 year and ≤ 21 years
- Lansky or Karnofsky score ≥60%
- Life expectancy ≥16 weeks
- Child-Pugh-Turcotte score <7 (for patients with hepatocellular carcinoma only)
- Informed consent explained to, understood by and signed by patient/guardian.
Patient/guardian given copy of informed consent
Exclusion Criteria:
- History of hypersensitivity reactions to murine protein-containing products OR
presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who
have received prior therapy with murine antibodies)
- History of organ transplantation
- Known HIV positivity
- Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus
infections)
- Severe previous toxicity from cyclophosphamide or fludarabine
Treatment Eligibility
Inclusion Criteria:
- Age ≥ 1 year and ≤ 21 years
- Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular
carcinoma only)
- Life expectancy of ≥ 12 weeks
- Lansky or Karnofsky score ≥ 60%
- Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only)
- Adequate organ function:
- Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min
- serum AST< 5 times ULN
- total bilirubin < 3 times ULN for age
- INR ≤1.7 (for patients with hepatocellular carcinoma only)
- absolute neutrophil count > 500/microliter
- platelet count > 25,000/microliter (can be transfused)
- Hgb ≥7.0 g/dl (can be transfused)
- pulse oximetry >90% on room air
- Recovered from acute toxic effects of all prior chemotherapy and investigational
agents before entering this study
- Sexually active patients must be willing to utilize one of the more effective birth
control methods for 3 months after the T-cell infusion.
- Informed consent explained to, understood by and signed by patient/guardian.
Patient/guardian given copy of informed consent
Exclusion Criteria
- Pregnancy or lactation
- Uncontrolled infection
- Systemic steroid treatment (greater than or equal to 0.5 mg prednisone
equivalent/kg/day, dose adjustment or discontinuation of medication must occur at
least 24 hours prior to CAR T cell infusion)
- Known HIV positivity
- Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus
infections)
- History of organ transplantation
- History of hypersensitivity reactions to murine protein-containing products OR
presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who
have received prior therapy with murine antibodies)
- Severe previous toxicity from cyclophosphamide or fludarabine
GPC3 expression will be evaluated by standard immunohistochemistry (IHC). A tumor is
considered GPC3 positive, when the staining is Grade 2 (>25% positive tumor cells) or above
with an intensity score of 2 or above on a scale of 0 to 4.
| Maximum Eligible Age: | 21 Years |
| Minimum Eligible Age: | 1 Year |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Number of Patients with Dose Limiting Toxicity |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the GPC3-CAR T cells. Specifically those which are Grade 5; non-hematologic Grade 3-4 not returning to Grade 2 within 72 hours; Grade 2-4 allergic reaction; Hematologic Grade 4 that fails to return to Grade 2 or baseline (whichever is more severe) within 14 days; all grade 4 CRS and neurologic toxicities and grade 3 CRS and neurologic toxicities that fail to return to Grade 1 within 7 days. |
Secondary Outcome Measures
| Measure: | Percent of Patients with best response as either complete remission or partial remission |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | Response rates will be estimated as the percent of patients whose best response is either complete remission or partial remission by combining the data from the two patients. To compare with historical data, a 95% confidence interval will be calculated for the response rate. |
| Measure: | Median T cell persistence |
| Time Frame: | 15 years |
| Safety Issue: | |
| Description: | as measured by PCR |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Baylor College of Medicine |
Trial Keywords
- GPC3-CAR T cells
- GPC3
- Glypican
- Liver cancer
Last Updated
January 8, 2021
