Clinical Trials /

Study of Anti-CD33 Chimeric Antigen Receptor-Expressing T Cells (CD33CART) in Children and Young Adults With Relapsed/Refractory Acute Myeloid Leukemia

NCT03971799

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

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

DrugSynonymsArms
CD33CARTCD33CART

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

NameTypeDescriptionInterventions
CD33CARTExperimentalAll patients who receive CD33CART cell infusion
  • CD33CART

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 30 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:

             i. Total bilirubin < grade 2 bilirubin CTCAE version 5 (<3 x ULN) (except in case of
             subjects with documented Gilbert's disease > 3 x ULN)

             ii. AST (SGOT)/ALT (SGPT) < 5 x institutional ULN (< grade 3) d.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. Recent prior therapy:

               -  Systemic chemotherapy ≤ 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) or 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);

               -  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

          8. Subjects with a history of a single allogeneic stem cell transplantation are excluded
             if:

               -  Subjects are less than 100 days post-transplant OR

               -  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

               -  Subjects have received DLI within 30 days prior to enrollment OR

               -  Subjects are on active immunosuppression for GVHD prophylaxis (must be off for 30
                  days prior to enrollment)

          9. HIV/HBV/HCV Infection:

             i. 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)

             ii. Seropositive for Hepatitis C or positive for Hepatitis B surface antigen (HbsAG)

         10. 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

         11. Active second malignancy with exception for in situ carcinoma of the cervix or
             treatment-related or secondary CD33+ myeloid malignancy (which may be eligible),
             unless the tumor was treated with curative intent at least two years previously and
             subject is in remission

         12. 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:30 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

January 8, 2020