huCART19-IL18 in NHL/CLL Patients

Sponsor

University of Pennsylvania (Other)

Overall Status

Recruiting

CT.gov ID

NCT04684563

Collaborator

(none)

Enrollment

Location

Arms

179.8

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Anticipated 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.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

Anticipated Primary Completion Date :

May 1, 2036

Anticipated Study Completion Date :

May 1, 2036

Arms and Interventions

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

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0. [12 months]

Secondary Outcome Measures

Percentage of manufacturing products that meet release criteria. [3 months]
Number of subjects who have a response [12 months]
Best Overall Response (BOR) [12 months]
Duration of Response (DOR) [12 months]
Overall Survival (OS) [12 months]
Progression free survival (PFS) [12 months]
Characterize low level disease and B cell assessment in response to huCART19-IL18 cells [12 months]
Polychromatic flow cytometry-based assessment of leukemia and B cells, extent and duration of leukemic response
Characterize low level disease and B cell assessment in response to huCART19-IL18 cells [12 months]
Presence or absence of malignant B cells by Next-Generation Immunoglobulin heavy chain Sequencing (NGIS)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent form
Documentation of CD19 expression on malignant cells
CLL: At time of most recent relapse
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.
Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:
Have no active GVHD and require no immunosuppression
Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility
Adequate organ function defined as:

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

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.
Male or female age ≥ 18 years.
ECOG Performance Status that is either 0 or 1.
Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol
Disease-specific criteria:

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.
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.

Patients must have either relapsed after, or be ineligible for, prior CAR T cell therapy, and meet one of the following criteria:
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.
Relapsed/refractory disease after autologous SCT.
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.

Mantle cell lymphoma

Patients must have either failed or be ineligible for standard of care Tecartus™ (brexucabtagene autoleucel) or other investigational CAR T cell product; and
Patients must also meet one of the following criteria:
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.
Relapsed/refractory disease after prior autologous SCT.
Relapsed/refractory disease after prior allogeneic SCT. iv. Large cell transformation of CLL (Richter's Transformation)
Patients must be primary refractory or received at least 1 prior line of treatment.

Exclusion Criteria:

Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.
Class III/IV cardiovascular disability according to the New York Heart Association Classification
Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
Active acute or chronic GVHD requiring systemic therapy.
Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications
Receipt of immune checkpoint inhibitors within 4 months prior to physician-investigator confirmation of eligibility.
Receipt of prior huCART19 therapy.
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.
Pregnant or nursing (lactating) women.
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.
Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.