Description:
This is a gene transfer study for patients with a type of blood cancer called Acute
Lymphoblastic Leukemia (ALL) that has come back or has not gone away after 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. For
example, T lymphocytes can kill cancer cells but there normally are not enough of them to
kill all the cancer cells. Some researchers have taken T cells from a person's blood, grown
more of them in the laboratory and then given them back to the person.
The antibody used in this study targets CD19, CD20 and CD22. This antibody sticks to ALL
cells because of a substance on the outside of these cells called CD19, CD20 and/or CD22. For
this study, the antibody to CD19, CD20 and CD22 has been changed so that instead of floating
free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is
joined to them, they are called chimeric antigen receptor- T cells or CAR-T cells.
In the laboratory, we have also found that T cells work better if we also add proteins that
stimulate them. One such protein is called 4-1BB. Adding the 4-1BB molecule makes the cells
grow better and last longer in the body, giving them a better chance of killing the leukemia
cells. In this study we are going to attach the CD19/CD20/CD22 chimeric receptor that has
4-1BB added to the patient's T cells. We will then test how long the cells last.
These T cells, called "TriCAR" T cells are investigational products not approved by the Food
and Drug Administration (FDA).
Title
- Brief Title: CAR-T Cell, B-cell Acute Lymphoblastic Leukemia (TriCAR)
- Official Title: Trivalent Autologous T-Lymphocytes Co-Expressing Three Chimeric Antigen Receptors Targeting CD19, CD20 and CD22 in Acute B-Lineage Leukemia (TriCAR)
Clinical Trial IDs
- ORG STUDY ID:
H-49235 TriCAR
- NCT ID:
NCT05010564
Conditions
Purpose
This is a gene transfer study for patients with a type of blood cancer called Acute
Lymphoblastic Leukemia (ALL) that has come back or has not gone away after 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. For
example, T lymphocytes can kill cancer cells but there normally are not enough of them to
kill all the cancer cells. Some researchers have taken T cells from a person's blood, grown
more of them in the laboratory and then given them back to the person.
The antibody used in this study targets CD19, CD20 and CD22. This antibody sticks to ALL
cells because of a substance on the outside of these cells called CD19, CD20 and/or CD22. For
this study, the antibody to CD19, CD20 and CD22 has been changed so that instead of floating
free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is
joined to them, they are called chimeric antigen receptor- T cells or CAR-T cells.
In the laboratory, we have also found that T cells work better if we also add proteins that
stimulate them. One such protein is called 4-1BB. Adding the 4-1BB molecule makes the cells
grow better and last longer in the body, giving them a better chance of killing the leukemia
cells. In this study we are going to attach the CD19/CD20/CD22 chimeric receptor that has
4-1BB added to the patient's T cells. We will then test how long the cells last.
These T cells, called "TriCAR" T cells are investigational products not approved by the Food
and Drug Administration (FDA).
Detailed Description
The TriCAR T-cells were made in the laboratory by stimulating the patient's blood with growth
factors to make the T cells grow. To get the CD19/CD20/CD22 antibody and 4-1BB to attach to
the surface of the T cell, we inserted the antibody gene into the T cell. This is done using
a virus called a retrovirus that has been made for this study and will carry the antibody
gene into the T cell.
Enrolled patients will be assigned a dose of TriCAR T-cells. Prior to receiving the TriCAR
T-cells patients will receive two chemotherapy medications, cyclophosphamide (for 2 days) and
fludarabine (4 days).
An injection of TriCAR T-cells will be given into a vein through an IV at the assigned dose.
The injection will take from 1 to 20 minutes. Before receiving the infusion of TriCAR T-cells
patients may be pre-medicated with Benadryl and Tylenol. Patients will be monitored for up to
3 hours after the injection, and will have to remain locally for at least 3 weeks.
If after a 4-week evaluation period, the patient has a complete response, they may proceed to
bone marrow transplant, and will be removed from the treatment portion of the study.
Before treatment, patients will undergo a series of tests:
- Physical exam and History
- Blood tests to measure blood cells, kidney and liver function
- Pregnancy test for female patients who are of childbearing potential
- Measurements of your leukemia tumor cells by bone marrow studies
- Echocardiogram
- Imaging such as PET scans, CT scans or MRIs will be obtained if needed
During and after treatment, patients will receive these standard medical tests:
- History and physical examination: pre-infusion of T cells (pre-day 0, day 0) and at day
1, 4, 7, 10, 14, 28 and 63 post infusion of T- cells. Subsequently, history will be
taken at 3-, 6-, and 12-months post infusion of T-cells, and then yearly for a total of
15 years.
- Blood tests to measure blood cells, kidney and liver function (On Days 4, 7, 10, 14, 28
and 63; then at month 3, 6, and 12; then yearly to year 15)
- Measurements of your leukemia tumor cells by bone marrow studies 3-6 weeks after the
infusion, possibly 9-12 weeks after the infusion and then per standard of care.
- Imaging such as PET scans, CT scans or MRIs will be obtained, if needed, 4-6 weeks
following the infusion
Blood Draws:
Blood will be taken before the chemotherapy drugs, 2-4 hours after the T cell infusion, at
around day 7, day 10, day 14, day 28 and day 63 after the infusion, at 3 months, 6 months, 9
months, at 1 year, every 6 months for 4 years, then yearly for a total of 15 years.
Additional doses of TriCAR T-cells (re-treatment): Up to three additional infusions of
TriCAR-T cells may be given if eligible.
In the event of your death, we will request permission from your next of kin to perform an
autopsy to learn more about the effect of this experimental treatment on your cancer.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Autologous TriCAR T-Cells and lymphodepletion chemotherapy | Experimental | Three dose levels will be evaluated. The TriCAR T-cells will be administered after lymphodepletion chemotherapy with Cyclophosphamide and fludarabine. | |
Eligibility Criteria
Inclusion Criteria for Procurement:
1. Diagnosis of refractory or recurrent B cell Acute Lymphoblastic Leukemia (B-ALL) with
expression of CD19, CD20 and/or CD22
2. Projected age greater than or equal to 12 months at the time of TriCAR T cell infusion
3. Life expectancy of greater than or equal to 8 weeks
4. Weight greater than or equal to 10 kg
5. Subjects greater than or equal to 18 years of age must have the ability to give
informed consent according to applicable regulatory and local institutional
requirements. Legal guardian's consent must be obtained for subjects < 18 years of
age. Assent will be obtained from pediatric subjects and according to applicable
regulatory and local institutional requirements. Adults with cognitive impairment who
are unable to consent and those with Down's syndrome are also eligible for this
protocol with consent/assent according to applicable regulatory and local
institutional requirements.
6. Unless a subject has a previously obtained apheresis/phlebotomy product that is
acceptable and available for manufacturing of CAR-T cells, the subject must
discontinue all anti-cancer agents and, in the opinion of the investigator, have
recovered from significant acute toxic effects of:
1. Chemotherapy and biologic agents: All chemotherapy and biologic therapy not
specifically mentioned below must be discontinued greater than or equal to 7 days
prior to collection, with the exception of intrathecal chemotherapy and
maintenance chemotherapy but greater than or equal to 72 hours prior to
collection (for the subset of subjects who relapse during maintenance); both of
which may be administered at any point pre-study or upon enrollment
2. Steroid use: All systemic corticosteroid therapy (unless physiologic replacement
dosing of less than or equal to 12mg/m2/day hydrocortisone or equivalent) must be
discontinued greater than or equal to 7 days prior to collection
3. Tyrosine Kinase Inhibitor (TKI) use: All TKIs must be discontinued greater than
or equal to 3 days prior to collection
4. Hydroxyurea: must be discontinued greater than or equal to 1 day prior to
collection
5. Prior CAR-T cell therapy: must be at least 30 days from most recent CAR-T cell
infusion prior to collection
6. Immunotherapy directed at leukemia: No antibodies within three (3) half-lives
prior to collection (or within 4 weeks) whichever is shorter. This includes
Antithymocyte globulin (ATG) formulations.
7. Anti T-cell Antibodies, Alemtuzumab: must be discontinued greater than or equal
to 8 weeks prior to collection
7. Absolute Lymphocyte count (ALC) greater than or equal to 100 cells/μL
8. Subject willing to participate in long-term follow-up for up to 15 years if enrolled
in the study
Inclusion Criteria for T-cell Therapy
1. Age greater than or equal to 12 months
2. Weight greater than or equal 10.0 Kg
3. Life expectancy of greater than or equal 6 weeks
4. B-ALL with no prior history of allo-HCT with one of the following:
1. Second or subsequent marrow relapse with or without extramedullary disease
2. First marrow relapse at the end of re-induction with marrow having greater than
or equal 0.01% blasts by morphology &/or flow cytometry with or without
extramedullary disease
3. Primary refractory disease defined by having greater than or equal 5% blasts in
the marrow by morphology and/or minimal residual (MRD) testing after 2 or more
separate induction regimens
4. Subject has an indication for allo-HCT but deemed ineligible (including subjects
who have persistent MRD prior to allo-HCT)
5. CD19(+) or CD19(-) relapse or refractory ALL after infusion of CD19-targeted
immunotherapy including CAR-T cells or blinatumomab (CD20 or CD22 expression is
required for CD19- B-ALL).
Or B-ALL recurrent after allo-HCT defined as having greater than or equal 0.01% marrow
disease
5. Available transduced T-cells with greater than or equal 15% expression of CD19, CD20
or CD22 CAR by flow cytometry.
6. Prohibited medications:
1. Cranial radiation therapy (inclusive of TBI) greater than or equal to 4 weeks
2. Cytotoxic chemotherapy greater than or equal to 2 days
3. Tyrosine Kinase Inhibitors greater than or equal to 7 days
7. Total Bilirubin: less than or equal to 3X upper limit of normal (ULN) for age OR
conjugated bilirubin less than or equal to 2mg/dl, except in subjects with Gilbert's
syndrome where a total bilirubin level of up to 5.3 mg/dL will be acceptable
8. ALT less than or equal to 5 times upper limit of normal
9. Adequate renal function defined as serum creatinine that is less than or equal to
maximum based on age/gender (as per table below) or Creatinine clearance or GFR (as
measured or estimated by Cockcroft Gaultor Schwartz) greater than or equal 50
mL/min/1.73m2
10. Pulse oximetry of greater than or equal 90% on room air
11. Left ventricular fractional shortening (LVFS) greater than or equal 28% confirmed by
echocardiogram or left ventricular ejection fraction (LVEF) greater than or equal 45%
confirmed by echocardiogram (MUGA or MRI heart may replace echocardiogram).
12. Lansky score of greater than or equal 50% (age greater than or equal 1 and < 16 years)
or Karnofsky score of greater than or equal 50% (age greater than or equal 16 years)
13. Donor lymphocyte infusions (DLI) completed > 6 weeks prior to CAR-T cell infusion
14. Subjects of childbearing/fathering potential must agree to use highly effective
contraception from the time of initial T cell infusion through 12 months following the
last T cell infusion
15. Subjects > 18 years of age must have the ability to give informed consent according to
applicable regulatory and local institutional requirements. Legal guardian's consent
must be obtained for subjects < 18 years of age. Assent will be obtained from
pediatric subjects and according to applicable regulatory and local institutional
requirements. Adults with cognitive impairment who are unable to consent and those
with Down's Syndrome are also eligible for this protocol with consent/assent according
to applicable regulatory and local institutional requirements.
Exclusion Criteria for Procurement:
1. Active malignancy other than disease under study
2. CNS 3 involvement with leukemia that, in the opinion of the investigator, cannot be
controlled (to CNS 2 or 1) during the interval between enrollment and CAR-T cell
infusion
3. If history of allogeneic hematopoietic cell transplant (allo-HCT): active GVHD, or
receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks
prior to enrollment
4. Presence of active severe infection, defined as:
1. positive blood culture within 48 hours of collection, OR
2. fever above 38.2° C, AND clinical signs of infection within 48 hours of
collection (unless fever is attributed to leukemia)
3. active viral infections including infection with HIV, hepatitis B, hepatitis C or
HTLV
5. Primary immunodeficiency syndrome
6. Pregnant or breastfeeding
7. Presence of any condition that, in the opinion of the investigator, would prohibit the
subject from undergoing treatment under this protocol
8. History of symptomatic CNS pathology or ongoing symptomatic CNS pathology requiring
medical intervention, including paresis, aphasia, cerebrovascular ischemia/hemorrhage,
severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis,
coordination or movement disorder (subjects with non-febrile seizure disorder
controlled on anti-epileptic medication and without seizure activity within 3 months
are eligible)
Exclusion Criteria for T-cell Therapy
1. Pregnant or lactating
2. Presence of any condition that, in the opinion of the PI or designee, would prevent
the patient from undergoing protocol-based therapy.
3. Active CNS involvement by ALL, defined as CNS-3 or symptomatic CNS 2 (Refer to
appendix III for definitions of CNS status). Note: Asymptomatic CNS2 or patients with
history of CNS disease that has been effectively treated will be eligible. Patients
that have a significant neurologic deterioration will be not be eligible for T cell
infusion until alternate therapies result in neurological stabilization.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 12 Months |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Dose-limiting toxicity (DLT) rate by CTCAE v5.0 |
| Time Frame: | within 28 days of the TriCAR T cell infusion. |
| Safety Issue: | |
| Description: | Defined as the proportion of patients, within the assigned dose level, with DLT evaluated as any grade 3 or 4 toxicity as determined by CTCAE (v5.0) which is unmanageable, unexpected and unrelated to lymphodepletion, and that is probably or definitely attributable to the study protocol occurring within 28 days of the TriCAR T cell infusion |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Not yet recruiting |
| Lead Sponsor: | Baylor College of Medicine |
Trial Keywords
- Relapsed or refractory B-Cell Leukemia
- TriCAR T-Cells
- Cyclophosphamide
- Fludarabine
Last Updated
August 25, 2021
