Description:
This is a phase 1/2 trial which aims to determine the safety and feasibility of anti-CD33
chimeric antigen receptor (CAR) expressing T cells (CD33CART) in children and
adolescents/young adults (AYAs) with relapsed/refractory acute myeloid leukemia (AML). The
trial will be done in two phases: Phase 1 will determine the maximum tolerated dose of
CD33CART cells using a 3+3 trial design. Phase 2 is an expansion phase designed to evaluate
the rate of response to CD33CART.
Title
- Brief Title: Study of Anti-CD33 Chimeric Antigen Receptor-Expressing T Cells (CD33CART) in Children and Young Adults With Relapsed/Refractory Acute Myeloid Leukemia
- Official Title: Phase 1/2 Study of Anti-CD33 Chimeric Antigen Receptor-Expressing T Cells (CD33CART) in Children and Young Adults With Relapsed/Refractory Acute Myeloid Leukemia
Clinical Trial IDs
- ORG STUDY ID:
17-CD33CART
- NCT ID:
NCT03971799
Conditions
- Acute Myelogenous Leukemia
Interventions
Drug | Synonyms | Arms |
---|
CD33CART | | CD33CART |
Purpose
This is a phase 1/2 trial which aims to determine the safety and feasibility of anti-CD33
chimeric antigen receptor (CAR) expressing T cells (CD33CART) in children and
adolescents/young adults (AYAs) with relapsed/refractory acute myeloid leukemia (AML). The
trial will be done in two phases: Phase 1 will determine the maximum tolerated dose of
CD33CART cells using a 3+3 trial design. Phase 2 is an expansion phase designed to evaluate
the rate of response to CD33CART.
Detailed Description
This study consists of two phases. The objectives of Phase 1 and Phase 2 are:
Phase 1: To determine the maximum tolerated dose of lentivirally-transduced CD33-redirected
CAR-T cells (CD33CART) in children and young adults with relapsed/refractory AML
Phase 2: To determine the percentage of subjects treated with CD33CART who achieve
morphologic remission (<5% blasts in marrow) at Day 28 post-CD33CART cell infusion
Trial Arms
Name | Type | Description | Interventions |
---|
CD33CART | Experimental | All patients who receive CD33CART cell infusion | |
Eligibility Criteria
Inclusion Criteria:
1. Subjects must have CD33+ AML in second or greater relapse, post-transplant relapse, or
have demonstrated chemotherapy-refractory disease (definitions in criteria 2c) to be
eligible to participate in this trial.
2. Disease status at the time of enrollment:
1. Subjects in second or greater relapse will be eligible with relapse defined as
>5% blasts (bone marrow) after second documented complete remission
2. Any degree of detectable disease post-transplant relapse will be eligible (with
flow cytometric confirmation of CD33+ myeloid leukemia of at least 0.1%)
3. Refractory disease is defined as persistent bone marrow involvement with >5%
blasts after two courses of induction chemotherapy for patients at initial
presentation or >5% bone marrow blasts after one course of re-induction
chemotherapy for patients in relapse
3. CD33 expression must be detected on greater than 50% of the malignant cells by
immunohistochemistry or greater than 80% by flow cytometry
4. Age: Greater than or equal to 1 year of age (and at least 15 kg) and less than or
equal to 35 years of age at time of enrollment. (NOTE: The first three subjects
treated on this trial must be ≥ 16 years of age)
5. All subjects must have an allogeneic HCT donor identified with a plan to proceed to
HCT conditioning within 6 weeks of CD33CART cell infusion
6. Performance status: > 50% (for subjects > 16 years of age use Karnofsky ≥ 50%;
subjects < 16 years of age: Lansky scale ≥ 50%) Subjects who are unable to walk
because of paralysis, but who are upright in a wheelchair will be considered
ambulatory for the purpose of calculating the performance score;
7. Adequate organ function as defined by:
1. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 45% or fractional
shortening ≥28%
2. Pulmonary function: baseline oxygen saturation > 92% on room air at rest
3. Hepatic function:
- Total bilirubin < grade 2 bilirubin CTCAE version 5 (<3 x ULN) (except in
case of subjects with documented Gilbert's disease > 3 x ULN)
- AST (SGOT)/ALT (SGPT) < 5 x institutional ULN (< grade 3)
4. Renal function: Serum creatinine must be < 1.2 x institutional upper limit of
normal (ULN) according to age. If the serum creatinine is greater than 1.2 x ULN,
the patient must have a creatinine clearance (CrCl) > 70mL/min/1.73 m2 (measured
by 24 hour- urine specimen or radioisotope GFR).
8. Subjects > 18 years of age must have the ability to give informed consent according to
applicable regulatory and local institutional requirements. Legal guardian permission
must be obtained for subjects < 18 years of age. Pediatric subjects will be included
in age appropriate discussion in order to obtain assent; Adults with cognitive
impairment who are unable to consent and those with Down Syndrome are also eligible
for this protocol
9. Enrollment in the NMDP protocol: Protocol for a Research Database for Hematopoietic
Cell Transplantation, Other Cellular Therapies and Marrow Toxicity Injuries.
Exclusion Criteria:
1. Subjects with radiologically-detected CNS chloromas or CNS 3 disease (presence of ≥
5/μL white blood cells (WBCs) in cerebral spinal fluid (CSF) and cytospin positive for
blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS
leukemia such as a cranial nerve palsy from active disease). Subjects with adequately
treated CNS leukemia are eligible
2. Hyperleukocytosis (≥ 50,000 blasts/μL) or rapidly progressive disease that in the
estimation of the investigator and sponsor would compromise ability to complete study
therapy
3. Pregnancy (negative serum or urine pregnancy test must be obtained at time of
enrollment for females of childbearing potential and to be repeated 72 hours prior to
lymphodepleting chemotherapy regimen)
4. Breast feeding
5. Sexually active female subjects of childbearing potential and male subjects who are of
childbearing potential and are unwilling to practice birth control at time of
enrollment and for four months after receiving the lymphodepletion preparative regimen
6. Active or uncontrolled viral, bacterial or fungal infection. May be receiving ongoing
therapy for controlled infection
7. Treatment with any prior CAR-T therapy product
8. Recent prior therapy:
1. Systemic chemotherapy ≤ 2 weeks
2. TKI ≤ 2 weeks
- Exceptions: 6 weeks for gemtuzumab or other CD33-targeted antibody,
clofarabine or nitrosoureas;
- Exception: Subjects who are on azacytidine/decitabine may be enrolled
provided that chemotherapy is discontinued at least 1 week prior to
apheresis)
- There is no time restriction in regard to prior intrathecal chemotherapy for
initial enrollment, however, IT therapy should be performed > 72 hours prior
to apheresis:
- Steroid therapy is not allowed, unless at or below physiologic replacement
doses;
- Subjects receiving hydroxyurea may be enrolled provided there has been no
increase in dose for at least 2 weeks prior to apheresis or study enrollment
if an apheresis product was previously collected;
- Any anti-neoplastic investigational agents or monoclonal antibody therapy
should not be given within 30 days prior to apheresis (i.e. start of
protocol therapy);
3. For radiation therapy: Radiation therapy must have been completed at least 3
weeks prior to apheresis or enrollment if an apheresis product was previously
collected, with the exception that there is no time restriction if the volume of
bone marrow treated is less than 10% and also the subject has
measurable/evaluable disease outside the radiation port; Any CNS radiation will
require a 3-week washout prior to enrollment
4. For prior stem cell transplant: Subjects with a history of more than one prior
stem cell transplant will not be eligible.
9. Subjects with a history of a single allogeneic stem cell transplantation are excluded
if:
1. Subjects are less than 100 days post-transplant OR
2. Subjects have evidence of ongoing active GVHD and are taking immunosuppressive
agents (>0.5 mg/kg/methylprednisolone equivalents or other immunosuppression for
GVHD treatment) OR
3. Subjects have received DLI within 30 days prior to enrollment OR
4. Subjects are on active immunosuppression for GVHD prophylaxis (must be off for 30
days prior to enrollment)
10. HIV/HBV/HCV Infection:
1. Seropositive for HIV 1 or 2 (Subjects with HIV are at increased risk of lethal
infections when treated with marrow-suppressive therapy. Appropriate studies will
be undertaken in subjects receiving combination antiretroviral therapy in the
future should study results indicate effectiveness)
2. Seropositive for Hepatitis C or positive for Hepatitis B surface antigen (HbsAG)
11. Uncontrolled, symptomatic, intercurrent illness including but not limited to
infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia,
psychiatric illness, or social situations that would limit compliance with study
requirements or in the opinion of the site PI would pose an unacceptable risk to the
subject
12. Active second malignancy will not be eligible with the following exceptions:
1. Treatment-related or secondary CD33+ myeloid malignancy which may potentially
benefit from CD33CART (which may be considered for enrollment),
2. Carcinoma in situ of the cervix (which may be considered for enrollment),
3. Subject is in remission from a prior second malignancy (which may be considered
for enrollment).
13. History of severe, immediate hypersensitivity reaction attributed to compounds of
similar chemical or biologic composition to any agents used in study or in the
manufacturing of the cells (i.e. gentamicin).
Maximum Eligible Age: | 35 Years |
Minimum Eligible Age: | 1 Year |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum tolerated dose |
Time Frame: | Day 28 post CD33CART infusion |
Safety Issue: | |
Description: | This a dose level immediately below the level at which the enrollment is stopped due to a Dose Limiting Toxicity (DLT) |
Secondary Outcome Measures
Measure: | Feasibility of CD33CART manufacture |
Time Frame: | 2 weeks post start of CD33CART manufacture |
Safety Issue: | |
Description: | Percentage of subjects for whom the desired dose of CD33CAR-T cells can be successfully manufactured |
Measure: | Feasibility of CD33CART infusion |
Time Frame: | 6 weeks post apheresis |
Safety Issue: | |
Description: | Number of subjects able to proceed to infusion of CD33CART 6 weeks post apheresis |
Measure: | Molecular remission |
Time Frame: | Day 28 post CD33CART infusion |
Safety Issue: | |
Description: | Percentage of subjects who receive CD33CART infusion who achieve molecular remission. |
Measure: | Cytokine release syndrome (CRS), sinusoidal occlusion syndrome (SOS), or other CD33CART related toxicities |
Time Frame: | 8 weeks post CD33CART infusion |
Safety Issue: | |
Description: | CRS, or neurotoxicity, SOS, development of any toxicity that precludes proceeding to HCT |
Measure: | Allogeneic hematopoietic stem cell transplantation |
Time Frame: | 6 weeks post CD33CART infusion |
Safety Issue: | |
Description: | Percentage of subjects able to proceed to allogeneic hematopoietic stem cell transplantation following treatment with CD33CART |
Measure: | Overall survival |
Time Frame: | 1 year post HCT |
Safety Issue: | |
Description: | Overall survival will be determined as time from the start of CD33CART infusion until death |
Measure: | Progression free survival |
Time Frame: | I year post HCT |
Safety Issue: | |
Description: | Measured from infusion of CD33CART cells until the documentation of disease progression or death due to any cause, whichever occurs first. |
Measure: | Treatment related mortality |
Time Frame: | I year post HCT |
Safety Issue: | |
Description: | Treatment related mortality is defined as death occurring in a patient from causes other than disease relapse or progression. |
Measure: | Post HCT time to engraftment |
Time Frame: | Day 42 post HCT |
Safety Issue: | |
Description: | Time to engraftment is calculated from the day of HCT to the first day when the absolute neutrophil count (ANC) was > 500/mcL for three consecutive days. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Center for International Blood and Marrow Transplant Research |
Trial Keywords
- CD33CART cells
- Children/young adults
Last Updated
February 12, 2021