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

• ClinicalTrials.gov Identifier: NCT03971799
• Recruitment Status: Recruiting
• First Posted: June 3, 2019
• Last Update Posted: April 5, 2023
• Sponsor: Center for International Blood and Marrow Transplant Research
• Collaborators: National Marrow Donor Program; St. Baldrick's Foundation
• Information provided by (Responsible Party): Center for International Blood and Marrow Transplant Research

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Myelogenous Leukemia	Biological: CD33CART	Phase 1; Phase 2

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: A 3+3 dose escalation design will be used to determine maximum tolerated dose in Phase 1 and Simon's two-stage design will be used to evaluate the efficacy of CD33CART in Phase 2.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 8, 2020
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2039

Arms and Interventions

Arm

Intervention/treatment

Experimental: CD33CART; All patients who receive CD33CART cell infusion

Biological: CD33CART; The treatment regimen will consist of lymphodepleting (LD) chemotherapy followed by CD33CART infusion: LD option #1 (IV fludarabine 25 mg/m2/dose administered Days -4 to -2 and IV cyclophosphamide 900 mg/m2/dose on Day -2) or LD option #2 (IV fludarabine 30 mg/m2 on days -5, -4, -3, and -2; and IV cyclophosphamide 500 mg/m2 on days -3 and -2). Subjects will then proceed to allogeneic HCT or alternative therapy as clinically applicable.

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose [ Time Frame: Day 28 post CD33CART infusion ]
   This a dose level immediately below the level at which the enrollment is stopped due to a Dose Limiting Toxicity (DLT)
2. Morphologic remission [ Time Frame: Day 28 post CD33CART infusion ]
   Percentage of subjects treated with CD33CART who achieve morphologic remission (<5% blasts in marrow)

Secondary Outcome Measures :

1. Feasibility of CD33CART manufacture [ Time Frame: 2 weeks post start of CD33CART manufacture ]
   Percentage of subjects for whom the desired dose of CD33CAR-T cells can be successfully manufactured
2. Feasibility of CD33CART infusion [ Time Frame: 6 weeks post apheresis ]
   Number of subjects able to proceed to infusion of CD33CART 6 weeks post apheresis
3. Molecular remission [ Time Frame: Day 28 post CD33CART infusion ]
   Percentage of subjects who receive CD33CART infusion who achieve molecular remission.
4. Cytokine release syndrome (CRS), sinusoidal occlusion syndrome (SOS), or other CD33CART related toxicities [ Time Frame: 8 weeks post CD33CART infusion ]
   CRS, or neurotoxicity, SOS, development of any toxicity that precludes proceeding to HCT
5. Allogeneic hematopoietic stem cell transplantation [ Time Frame: 6 weeks post CD33CART infusion ]
   Percentage of subjects able to proceed to allogeneic hematopoietic stem cell transplantation following treatment with CD33CART
6. Overall survival [ Time Frame: 1 year post HCT ]
   Overall survival will be determined as time from the start of CD33CART infusion until death
7. Progression free survival [ Time Frame: I year post HCT ]
   Measured from infusion of CD33CART cells until the documentation of disease progression or death due to any cause, whichever occurs first.
8. Treatment related mortality [ Time Frame: I year post HCT ]
   Treatment related mortality is defined as death occurring in a patient from causes other than disease relapse or progression.
9. Post HCT time to engraftment [ Time Frame: Day 42 post HCT ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 35 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 less than or equal to 35 years of age at time of enrollment.
5. All subjects must have an allogeneic HCT donor identified with a plan to proceed to HCT conditioning within 6-8 weeks of CD33CART cell infusion.
6. Patients with two prior allogenic donor stem cell transplants must be medically fit for a third allogenic donor stem cell transplant
7. 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;

8. 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).
9. 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
10. 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:

   1. At treatment enrollment:

      Patients may be on lower-intensity chemotherapy (e.g., TKIs, venetoclax, hydroxyurea, azacytidine, decitabine or similar agents) at the time of enrollment to prevent disease progression. There is no timing restriction of intrathecal chemotherapy for enrollment.

   2. Prior to apheresis: The following wash-out periods apply prior to apheresis

   i. Systemic chemotherapy ≤ 14 days with the exception of:

   • Hydroxyurea: 1 day

   • Azacytidine/decitabine and/or venetoclax: 7 days

     • Intrathecal chemotherapy ≥ 3 days
     • Tyrosine kinase inhibitors: 3 half-lives or 7 days, whichever is shorter
     • Checkpoint inhibitors or antibody-based therapies: 3 half-lives
     • Investigational anti-neoplastic agents: 28 days
     • Clofarabine or nitrosureas: 42 days
     • Steroid therapy: Not allowed unless at or below physiologic doses (eg, hydrocortisone replacement for prior adrenal insufficiency)
     • Radiation therapy: Radiation therapy (including CNS) must have been completed at least 21 days prior to apheresis with the exception of 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 field.
     • CAR T-cell therapy: Excluded unless at least 30 days from prior CAR T-cell infusion and without detectable circulating CAR T-cells

8. 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)

9. 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)
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 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).
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).

Contacts and Locations

Contacts

Contact: Hati Kobusingye; 763 406 4385; hkobusin@nmdp.org

Contact: Erin Leckrone; 763-406-5124; eleckron@nmdp.org

Locations

United States, California

Children's Hospital of Los Angeles; Recruiting

Los Angeles, California, United States, 90027

Contact: Lee Chen 323-361-8658 lchen@chla.usc.edu

Principal Investigator: Emily Hsieh, MD

United States, Colorado

Children's Hospital of Colorado; Recruiting

Aurora, Colorado, United States, 80045

Contact: Erica Deckert-Nino 720-777-6593 Erica.Deckert-Nino@childrenscolorado.org

Principal Investigator: Michael Verneris, MD

United States, Maryland

National Cancer Institute - NIH; Recruiting

Bethesda, Maryland, United States, 20892

Contact: : NCI Pediatric Leukemia Lymphoma BMT Team 240-760-6970 ncipbllbmt@mail.nih.gov

Principal Investigator: Nirali Shah, MD, MHSc

United States, Massachusetts

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Jami Brown JBROWN56@mgh.harvard.edu

Principal Investigator: Susanne Baumeister, MD

United States, Pennsylvania

The Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Pierce McGowan mcgowanp@chop.edu

Principal Investigator: Richard Aplenc, MD, PhD

Sub-Investigator: Sarah Tasian, MD

Sub-Investigator: Amanda DiNofia, MD

United States, Washington

Seattle Children's Hospital/ Fred Hutchinson Cancer Research Center; Recruiting

Seattle, Washington, United States, 98105

Contact: Subarna Bagchi subarna.bagchi@seattlechildrens.org

Principal Investigator: Katherine Tarlock, MD

Principal Investigator: Corinne Summers, MD

Sponsors and Collaborators

Center for International Blood and Marrow Transplant Research

National Marrow Donor Program

St. Baldrick's Foundation

Investigators

• Principal Investigator: Nirali Shah, MD, MHSc; National Cancer Institute (NCI)
• Principal Investigator: Richard Aplenc, MD, PhD; Children's Hospital of Philadelphia

More Information

Additional Information:

Anti-CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies 

CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Qin H, Yang L, Chukinas JA, Shah N, Tarun S, Pouzolles M, Chien CD, Niswander LM, Welch AR, Taylor N, Tasian SK, Fry TJ. Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design. J Immunother Cancer. 2021 Sep;9(9):e003149. doi: 10.1136/jitc-2021-003149. Erratum In: J Immunother Cancer. 2021 Oct;9(10):

• Responsible Party: Center for International Blood and Marrow Transplant Research
• ClinicalTrials.gov Identifier: NCT03971799
• Other Study ID Numbers: 17-CD33CART
• First Posted: June 3, 2019
• Last Update Posted: April 5, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Center for International Blood and Marrow Transplant Research:

CD33CART cells; Children/young adults

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms