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huCART19-IL18 in NHL/CLL Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04684563
Recruitment Status : Recruiting
First Posted : December 24, 2020
Last Update Posted : November 2, 2022
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Study Description
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Brief Summary:
The purpose of this study is to find the maximum dose of huCART19-IL18 cells that is safe for use in humans with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Non-hodgkin Lymphoma Biological: huCART19-IL18 Phase 1

Detailed Description:

This is a Phase I dose finding study to determine the maximum tolerated dose (MTD) and assess the safety, tolerability, manufacturing feasibility, pharmacokinetics, and preliminary efficacy of huCART19-IL18 cells in patients with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL). This trial will evaluate up to 7 dose levels using the Bayesian Optimal Interval (BOIN) design with accelerated titration to determine the maximum tolerated dose (MTD) of huCART19-IL18 cells. Subjects will be assigned to a dose level prior to study treatment based on available safety experience at the current and prior dose levels. huCART19-IL18 cells will be administered to all subjects as a single intravenous (IV) infusion or slow IV push, depending on the assigned dose level. For consistency, the huCART19-IL18 infusions will be identified as IV infusions throughout the protocol.

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This trial will evaluate up to 7 dose levels using the Bayesian Optimal Interval (BOIN) design with accelerated titration to determine the maximum tolerated dose (MTD) of huCART19-IL18 cells. Subjects will be assigned to a dose level prior to study treatment based on available safety experience at the current and prior dose levels.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of huCART19-IL18 Cells in Patients With Relapsed or Refractory CD19+ Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)
Actual Study Start Date : May 6, 2021
Estimated Primary Completion Date : May 2036
Estimated Study Completion Date : May 2036

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Dose Level 1a (DL1a)
3x10^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: Dose Level -1 (DL-1)
7x10^5 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 1a.
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: Dose Level 1b (DL1b)
3x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: Dose Level 2 (DL2)
7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: Dose Level 3 (DL3)
3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: Dose Level 4 (DL4)
7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
Experimental: Dose Level 5 (DL5)
3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
 Biological: huCART19-IL18
autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0. [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Percentage of manufacturing products that meet release criteria. [ Time Frame: 3 months ]
  2. Number of subjects who have a response [ Time Frame: 12 months ]
  3. Best Overall Response (BOR) [ Time Frame: 12 months ]
  4. Duration of Response (DOR) [ Time Frame: 12 months ]
  5. Overall Survival (OS) [ Time Frame: 12 months ]
  6. Progression free survival (PFS) [ Time Frame: 12 months ]
  7. Characterize low level disease and B cell assessment in response to huCART19-IL18 cells [ Time Frame: 12 months ]
    Polychromatic flow cytometry-based assessment of leukemia and B cells, extent and duration of leukemic response

  8. Characterize low level disease and B cell assessment in response to huCART19-IL18 cells [ Time Frame: 12 months ]
    Presence or absence of malignant B cells by Next-Generation Immunoglobulin heavy chain Sequencing (NGIS)


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent form

  2. Documentation of CD19 expression on malignant cells

    1. CLL: At time of most recent relapse
    2. NHL: Within 6 months of physician-investigator confirmation of eligibility as long as there has been no intervening CD19 directed therapy since expression confirmed. Results outside of this window may be used, if there is no accessible tumor site and the subject did not receive intervening CD19 directed therapy since CD19 expression was confirmed.

  3. Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:

    1. Have no active GVHD and require no immunosuppression
    2. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility

  4. Adequate organ function defined as:

    a. Creatinine ≤ 1.6 mg/dl b. ALT/AST ≤ 3x upper limit of normal range c. Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl) d. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air e. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA

  5. Evidence of active disease. This could include circulating disease in the blood, disease in the bone marrow by standard morphology, or in NHL patients, measurable disease per Lugano criteria.
  6. Male or female age ≥ 18 years.
  7. ECOG Performance Status that is either 0 or 1.
  8. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol

  9. Disease-specific criteria:

    a. Chronic Lymphocytic Leukemia (CLL): i. Patients with relapsed/refractory disease after at least 2 prior lines of appropriate therapy; and ii. Patients must have previously received, or be intolerant to an approved BTK inhibitor and venetoclax, unless a BTK inhibitor or venetoclax is contraindicated.

    b. Non-Hodgkin Lymphoma (NHL): i. Patients with any of the following diagnoses: Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS), germinal center or activated B-cell types; Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e. "Double or Triple Hit"); High-grade B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma.

1. Patients must have either relapsed after, or be ineligible for, prior CAR T cell therapy, and meet one of the following criteria:

  1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy and are ineligible for autologous stem cell transplant or commercial CAR T cell therapy.
  2. Relapsed/refractory disease after autologous SCT.
  3. Relapsed/refractory disease after allogeneic SCT. ii. Follicular lymphoma 1. Patients who have received at least 2 prior lines of appropriate therapy (not including single agent monoclonal antibody therapy) and progressed within 2 years after second or higher line of therapy.

iii. Mantle cell lymphoma

  1. Patients must have either failed or be ineligible for standard of care Tecartus™ (brexucabtagene autoleucel) or other investigational CAR T cell product; and

  2. Patients must also meet one of the following criteria:

    1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a BTK inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy.
    2. Relapsed/refractory disease after prior autologous SCT.
    3. Relapsed/refractory disease after prior allogeneic SCT. iv. Large cell transformation of CLL (Richter's Transformation)

1. Patients must be primary refractory or received at least 1 prior line of treatment.

Exclusion Criteria:

  1. Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
  2. Class III/IV cardiovascular disability according to the New York Heart Association Classification
  3. Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
  4. Active acute or chronic GVHD requiring systemic therapy.
  5. Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications
  6. Receipt of immune checkpoint inhibitors within 4 months prior to physician-investigator confirmation of eligibility.
  7. Receipt of prior huCART19 therapy.
  8. Active CNS disease. Note: Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
  9. Pregnant or nursing (lactating) women.
  10. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to their cancer or previous cancer treatment.
  11. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT04684563


Contacts
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Contact: Abramson Cancer Center Clinical Trials Service 855-216-0098 PennCancerTrials@emergingmed.com

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Abramson Cancer Center Clinical Trials Service    855-216-0098    PennCancerTrials@emergingmed.com   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Jakub Svoboda, MD University of Pennsylvania
More Information
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT04684563    
Other Study ID Numbers: UPCC15420
First Posted: December 24, 2020    Key Record Dates
Last Update Posted: November 2, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 University of Pennsylvania:
CLL
NHL
CAR-T cells
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
 Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell