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

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ClinicalTrials.gov Identifier: NCT05442515
Recruitment Status : Not yet recruiting
First Posted : July 5, 2022
Last Update Posted : August 12, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses.

Objective:

To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL.

Eligibility:

People aged 3 to 35 with ALL or related B-cell lymphoma that has not been cured by standard therapy.

Design:

Participants will be screened. This will include:

Physical exam

Blood and urine tests

Tests of their lung and heart function

Imaging scans

Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone.

Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord.

Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells.

Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment.

Participants will be admitted to the hospital. Their own modified T cells will be returned to their body.

Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....


Condition or disease Intervention/treatment Phase
Acute Lymphoid Leukemia B-Cell Leukemia Leukemia, Lymphocytic, B Cell B-Cell Lymphoma Lymphoma, Non-Hodgkin Drug: fludarabine Drug: cyclophosphamide Biological: CD19/CD22-CAR-transduced T cells Phase 1 Phase 2

Detailed Description:

Background:

  • Despite improvements in therapy, acute lymphoblastic leukemia (ALL) contributes to significant morbidity and mortality for children and young adults with cancer. CD19-CAR and CD22-CAR therapy have proven highly effective in inducing remission in patients with relapsed/refractory disease.
  • Immune escape has been observed by several groups following CD19-CAR and CD22- CAR therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 and/or CD22 expression observed in these cases.
  • The challenges encountered with currently available CD19- and CD22-directed CAR T cells in B-ALL demonstrates the need for combinatorial treatment strategies simultaneously targeting two antigens, such as CD19 and CD22, to enhance the long-term effectiveness of CARs.
  • We have previously treated patients with B-ALL on a phase 1/2 clinical trial using a bivalent CD19/22 CAR T-cell as a first combinatorial treatment strategy. This CAR T-cell construct is well-tolerated and has yielded responses however there has been limited CAR T cell expansion and persistence. Additionally, the previously tested CD19/CD22 bivalent CAR T-cell construct is limited in its ability to target CD22.
  • This new CD19/22 targeted construct being tested in this clinical trial has improved dual targeting capability based on preclinical data/evaluation.

Objectives:

  • Phase I: Assess the safety of administering escalating doses of autologous CD19/CD22- CAR engineered T cells in children and young adults who are CAR-naive/have received interim hematopoietic stem-cell transplantation (HSCT) or who are CAR-pre-treated with CD19+CD22+ B cell ALL or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.
  • Phase II: Determine the efficacy of CD19/CD22 therapy in participants who are CAR- naive/interim HSCT or who are CAR pre-treated.

Eligibility:

-Participants between >= 3 years and <= 35 years of age, with CD19+/CD22+ B cell ALL or lymphoma who have relapsed or have refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options.

Design:

  • Phase I, 3 + 3 dose escalation design across 4 cohorts (B-ALL: A: CAR-naive/interim HSCT vs. B: CAR-pre-treated and B-lymphoma: C: CAR-naive/interim HSCT vs. D: CAR-pre-treated) using the following dose levels: -1: 3 x 10^5 transduced T cells/kg (+/- 20%); 1: 1 x 10^6 transduced T cells/kg (+/- 20%); 2: 3 x 10^6 transduced T cells/kg (+/- 20%); and 3: 1 x 10^7 transduced T cells/kg (+/- 20%). Cohorts will enroll concurrently.
  • Participants will be treated based on prior therapy:

    • CAR naive participants (including those who have received an interval HSCT after a prior CAR T-cells): Will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m^2/d x 3 on Days -4, -3, -2) and cyclophosphamide (900 mg/m^2/d x 1 on Day -2) followed by infusion of CD19/CD22-CAR T-cells on D0.
    • CAR pre-treated participants: Will receive increased lymphodepleting preparative regimen of fludarabine (30 mg/m2/d x 4 on Days -5, -4, -3, -2) and cyclophosphamide (600 mg/m2/d x 2 on Days -3, -2) followed by infusion of CD19/CD22-CAR T-cells on D0.
  • Participants will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, and other biologic correlatives.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 146 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Dose Escalation Study of CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies
Estimated Study Start Date : August 17, 2022
Estimated Primary Completion Date : July 1, 2027
Estimated Study Completion Date : July 1, 2029


Arm Intervention/treatment
Experimental: 1/Phase I Dose Escalation-with standard LD
CD19/CD22-CAR-transduced T cells at escalating dose + standard LD
Drug: fludarabine
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)

Drug: cyclophosphamide
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion.

Biological: CD19/CD22-CAR-transduced T cells
CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen

Experimental: 2/Phase I Dose Escalation- with intensified LD
CD19/CD22-CAR-transduced T cells + standard LD
Drug: fludarabine
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)

Drug: cyclophosphamide
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion.

Biological: CD19/CD22-CAR-transduced T cells
CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen

Experimental: 3/Phase II Dose Expansion- with standard LD
CD19/CD22-CAR-transduced T cells + standard LD
Drug: fludarabine
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)

Drug: cyclophosphamide
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion.

Biological: CD19/CD22-CAR-transduced T cells
CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen

Experimental: 4/Phase II Dose Expansion- with intensified LD
CD19/CD22-CAR-transduced T cells + intensified LD
Drug: fludarabine
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)

Drug: cyclophosphamide
Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion.

Biological: CD19/CD22-CAR-transduced T cells
CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen




Primary Outcome Measures :
  1. Safety [ Time Frame: 30 days post CAR T infusion ]
    Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells in children and young adults who are CAR-naive/have received interim HSCT or who are CAR-pre-treated with CD19+CD22+ B cell ALL or lymphoma following a cyclophosphamide/fludarabine LD.

  2. Efficacy [ Time Frame: Monthly until 3 months post CAR T infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, up to 2 years after the entry date of the last participant. ]
    Determine the efficacy of CD19/CD22 therapy in participants who are CAR-naive/interim HSCT or who are CAR pre-treated.


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: Monthly until 3 months post infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, for up to two years from the entry date of the last participant ]
    Phase I: Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with CD19+CD22+ B cell ALL or lymphoma.

  2. Progression free survival (PFS) and Overall survival (OS) [ Time Frame: Up to two years after the last participant has entered. ]
    Evaluate PFS and OS in participants, separately by phase II cohort

  3. Persistence and expansion [ Time Frame: Up to two years after the last participant has entered. ]
    Evaluate persistence and expansion of C19/CD22-CAR T cells in children and young adults with CD19+CD22+ B-ALL or lymphoma

  4. Adverse Events [ Time Frame: 30 days post CAR T infusion ]
    Phase II: Assess the safety of CD19/CD22 therapy in participants who are CAR-naive/interim HSCT or who are CAR pre-treated.

  5. Feasibility [ Time Frame: Up to two years after the last participant has entered. ]
    Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established release criteria.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Diagnosis

  • Participant must have:

    • Pathology confirmed B cell ALL (inclusive of CML with ALL transformation) or high- grade lymphoma (e.g., Burkitt s lymphoma, B-lymphoblastic lymphoma, diffuse large B- cell lymphoma)

      ---Patients with low-grade lymphoma (e.g., follicular lymphoma or mantle cell lymphoma) will be excluded unless there is transformation to high-grade disease

    • Participants must have a disease that is relapsed or refractory after at least one standard chemotherapy regimen and at least one salvage treatment and must either be ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have recurred after SCT.
    • Participants who have undergone autologous SCT will be eligible, and participants that have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they have no evidence of graft-versus- host disease (GVHD) and have been without immunosuppressive agents for at least 30 days.
    • Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor.
    • Participants must have measurable or evaluable disease at the time of enrollment, defined by any evidence of minimal residual disease or PET-avid disease (lymphoma).
  • CD22/CD19 expression

    • CD9 must be detected on >15% of the malignant cells by immunohistochemistry or > 80% by flow cytometry. In general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples, and the most easily available tissue sample in each participant will be used.
    • CD22 must be detected and expression levels will be documented when available, but a specific level of expression is not an eligibility requirement; it may be documented as positive.
  • Age >= 3 years of age and <= 35 years of age at time of enrollment.
  • Clinical Performance status: Participants >=16 years of age: Karnofsky >= 50%; Participants < 16 years of age: Lansky scale >= 50%. Participants 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.
  • Participants must have adequate organ and marrow function as defined below:

    • leukocytes >= 750/mcL*
    • platelets >= 50,000/mcL*
    • total bilirubin <= 2 X ULN (except in the case of participants with documented Gilbert s disease > 3x ULN)
    • AST(SGOT)/ALT(SGPT) <= 10 X institutional upper limit of normal
    • creatinine <= the maximum for age listed in the table below

OR

  • measured creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above the max listed below per age.

    • Age (Years) <= 5 Maximum Serum Creatinine (mg/dL) <= 0.8
    • Age (Years) 6 to <= 10 Maximum Serum Creatinine (mg/dL) <= 1.0
    • Age (Years) >10 Maximum Serum Creatinine (mg/dL) <=1.2

      • a participant will not be excluded because of pancytopenia >= Grade 3 if it is due to underlying bone marrow involvement by leukemia

        • Central nervous system (CNS) Status

          1. Participants with leukemia with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:
  • CNS 1, defined as absence of blasts in CSF on cytospin preparation, regardless of the number of WBCs;
  • CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

    • CNS 2a: < 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts;
    • CNS 2b: >=10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts;
    • CNS 2c: >=10/uL RBCs; >=5/uL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.

      • Participants of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving lymphodepletion (LD)
      • Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and until 1 month after the administration of CAR.
      • Cardiac function: Left ventricular ejection fraction >= 45% or fractional shortening >=28%
      • Pulmonary Function
  • Baseline oxygen saturation >92% on room air at rest
  • Participants with respiratory symptoms must have a DLCO/adjusted > 45%. For children who are unable to cooperate for PFTs they must not have dyspnea at rest or known requirement for supplemental oxygen.

    • Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
    • Ability and willingness of participant or Legally Authorized Representative (LAR) to co-enroll on 15-C-0028: Follow-up Evaluation for Gene-Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials.

EXCLUSION CRITERIA:

Participants meeting any of the following criteria are not eligible for participation in the study:

  • Recurrent or refractory ALL limited to isolated testicular or isolated CNS disease.
  • Participants with radiologically detected active CNS lymphoma or isolated CNS disease
  • Hyperleukocytosis (>= 50,000 blasts/microliter)
  • Participant pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed at screening).
  • Participants will be excluded related to the following prior therapy criteria:

Systemic chemotherapy, anti-neoplastic investigational agents, or antibody based therapies <= 2 weeks (6 weeks for clofarabine or nitrosoureas) prior to apheresis with the following exception:

-No time restriction with prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) or ALL maintenance-type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor for participants with Ph+ ALL) provided there is recovery from any acute toxic effects.

Radiation therapy <= 3 weeks prior to apheresis with the following exception:

-No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window.

History of allogeneic stem cell transplantation prior to apheresis that meet the any of the following criteria:

  • Less than 100 days post-transplant
  • Evidence of active graft-versus-host disease (GVHD)
  • Taking immunosuppressive agents within 30 days prior to apheresis.

Less than 6 weeks post donor lymphocyte infusion (DLI)

History of prior CAR therapy or other adoptive cell therapies prior to apheresis that meet either of the two the following criteria:

  • Less than 30 days post-infusion
  • Circulating CAR T cells (or genetically modified cells) >5% by flow cytometry in peripheral blood
  • Current/active HIV infection, as measured by seropositivity for HIV antibody.
  • Current/active HBV/HCV Infection as measured by seropositivity for hepatitis C or positive for Hepatitis B surface antigen (HbsAG).
  • Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and participant is in remission;
  • 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.
  • Uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the participant;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05442515


Contacts
Layout table for location contacts
Contact: NCI Pediatric Leukemia, Lymphoma Transpl (240) 760-6970 ncilltct@mail.nih.gov
Contact: Nirali N Shah, M.D. (240) 760-6970 shahnn@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nirali N Shah, M.D. National Cancer Institute (NCI)
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05442515    
Other Study ID Numbers: 10000324
000324-C
First Posted: July 5, 2022    Key Record Dates
Last Update Posted: August 12, 2022
Last Verified: July 21, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
CD-19 expressing tumor
CD-22 Expressing Tumor
Adoptive Immunotherapy
Philadelphia chromosome + ALL
Lymphoma
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists