Clinical Trials /

huCART19-IL18 in NHL/CLL Patients

NCT04684563

Description:

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).

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Non-Hodgkin Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: huCART19-IL18 in NHL/CLL Patients
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: UPCC15420
  • NCT ID: NCT04684563

Conditions

  • Chronic Lymphocytic Leukemia
  • Non-hodgkin Lymphoma

Interventions

DrugSynonymsArms
huCART19-IL18Dose Level -1 (DL-1)

Purpose

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).

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.

      .
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1a (DL1a)Experimental5x10^4 huCART19-IL18 cells/kg administered as a single intravenous (IV) infusion or slow IV push
  • huCART19-IL18
Dose Level -1 (DL-1)Experimental1x10^4 huCART19-IL18 cells/kg 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.
  • huCART19-IL18
Dose Level 1b (DL1b)Experimental5x10^4 huCART19-IL18 cells/kg following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
  • huCART19-IL18
Dose Level 2 (DL2)Experimental1x10^5 huCART19-IL18 cells/kg following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
  • huCART19-IL18
Dose Level 3 (DL3)Experimental5x10^5 huCART19-IL18 cells/kg following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
  • huCART19-IL18
Dose Level 4 (DL4)Experimental1x10^6 huCART19-IL18 cells/kg following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
  • huCART19-IL18
Dose Level 5 (DL5)Experimental5x10^6 huCART19-IL18 cells/kg following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push
  • huCART19-IL18

Eligibility 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:

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

          4. Adequate organ function defined as:

               1. Creatinine ≤ 1.6 mg/dl

               2. ALT/AST ≤ 3x upper limit of normal range

               3. Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0
                  mg/dl)

               4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and
                  pulse oxygen > 92% on room air

               5. 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.

             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 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.

          4. Relapse/refractory disease after CAR T cell therapy. 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 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.

          4. Relapsed/refractory disease after prior CAR T cell therapy. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0.
Time Frame:12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of manufacturing products that meet release criteria.
Time Frame:3 months
Safety Issue:
Description:
Measure:Number of subjects who have a response
Time Frame:12 months
Safety Issue:
Description:
Measure:Best Overall Response (BOR)
Time Frame:12 months
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:12 months
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:12 months
Safety Issue:
Description:
Measure:Progression free survival (PFS)
Time Frame:12 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Pennsylvania

Trial Keywords

  • CLL
  • NHL
  • CAR-T cells

Last Updated

December 24, 2020