huCART19-IL18 in CD19+ Cancers

Study Overview
=================
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 CD19+ cancers.

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 CD19+ cancers. Up to 7 total dose levels will be evaluated using the Bayesian Optimal Interval (BOIN) design with accelerated titration in order to determine the maximum tolerated dose (MTD) of huCART19-IL18 cells within each of the following disease-specific cohorts: Cohort A: Non-Hodgkin Lymphoma (NHL) Cohort B: Chronic Lymphocytic Leukemia (CLL) Cohort C: Acute Lymphoblastic Leukemia (ALL)

Official Title
-----------------
Phase I Trial of huCART19-IL18 Cells in Patients With Relapsed or Refractory CD19+ Cancers

Conditions
-----------------
Chronic Lymphocytic Leukemia, Non-hodgkin Lymphoma, Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Biological: huCART19-IL18


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Signed informed consent form Documentation of CD19 expression on malignant cells a. Cohort A (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. b. Cohorts B (CLL) and C (ALL): At time of most recent relapse 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 ALT/AST ≤ 3x upper limit of normal range Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl) Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA Evidence of active disease within 12 weeks of physician-investigator confirmation of eligibility. . 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. Disease-specific criteria: a. Cohort A (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: Relapsed/refractory disease after at least 2 prior lines of appropriate therapy and are ineligible for autologous stem cell transplant; OR Relapsed/refractory disease after autologous SCT; OR Relapsed/refractory disease after allogeneic SCT. ii. Follicular lymphoma Patients must have either relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND 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 Patients must have either failed standard of care CAR T cell therapy (e.g. Tecartus™, etc) or other investigational CAR T cell product, OR be ineligible for standard of care Tecartus™; 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; OR Relapsed/refractory disease after prior autologous SCT; OR 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. b. Cohort B (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. c. Cohort C (ALL): i. Patients with b-cell acute lymphoblastic leukemia. Note: Chronic myeloid leukemia (CML) lymphoid blast crisis is considered a sub-type of relapsed B-ALL, thus will be encompassed in our definition of B-ALL throughout; AND ii. Patients with 2nd or greater relapse or refractory disease as defined by one of the following criteria: Recurrent disease in the blood or bone marrow identified morphologically, by IHC or flow; OR Isolated CNS disease. Note: Patients with prior/current history of CNS3 disease will only be eligible for treatment if the CNS disease is responsive to therapy; OR Recurrent extramedullary disease at other (non-CNS) sites if disease response can be assessed radiographically. Note: Patients with recurrent extramedullary disease do not need to have detectable blood or bone marrow involvement; OR Any relapse after allogeneic SCT; OR Patients with refractory disease as defined by one of the following: Failure to achieve remission (<5% bone marrow blasts or ongoing extramedullary or CNS disease) after 2 cycles of induction chemotherapy; OR Patients that achieve remission but remain MRD+ after ≥2 cycles of induction chemotherapy. 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. RETIRED WITH PROTOCOL AMENDMENT V7 Receipt of prior huCART19 therapy. CNS disease as defined by disease-cohort as follows: Cohorts A + B: 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. Cohort C: CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NHL Dose Level 1a (DL1a)<br>3x10^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: NHL Dose Level -1 (DL-1)<br>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<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: NHL Dose Level 1b (DL1b)<br>3x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: NHL Dose Level 2 (DL2)<br>7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: NHL Dose Level 3 (DL3)<br>3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: NHL Dose Level 4 (DL4)<br>7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: NHL Dose Level 5 (DL5)<br>3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: CLL Dose Level 1b (DL1b)<br>3x10^6 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 2. | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: CLL Dose Level 2 (DL2)<br>7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: CLL Dose Level 3 (DL3)<br>3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: CLL Dose Level 4 (DL4)<br>7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: CLL Dose Level 5 (DL5)<br>3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: ALL Dose Level 1b (DL1b)<br>3x10^6 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 2. | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: ALL Dose Level 2 (DL2)<br>7x10^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: ALL Dose Level 3 (DL3)<br>3x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: ALL Dose Level 4 (DL4)<br>7x10^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|
| Experimental: ALL Dose Level 5 (DL5)<br>3x10^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push | Biological: huCART19-IL18<br>* autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of dose-limiting toxicities (DLTs). |  | 3 months | 
| Determination of Maximum Tolerated Dose (MTD) |  | 3 months | 
| Percentage of manufacturing products that meet release criteria. |  | 3 months | 
| Overall Response Rate (ORR). | Cohort A (NHL) and Cohort B (CLL) | 3 months | 
| Overall Remission Rate (ORR). | Cohort C (ALL) | 1 months | 
| Best Overall Response (BOR) | Cohort A (NHL) and Cohort B (CLL) | 3 months | 
| Best Overall Response (BOR) |  | 6 months | 
| Duration of Response (DOR) |  | 12 months | 
| Overall Survival (OS) |  | 12 months | 
| Progression free survival (PFS) |  | 12 months | 
| Event Free Survival (EFS) | Cohort C (ALL) | 12 months | 
| Characterize low level disease and B cell assessment in response to huCART19-IL18 cells | Polychromatic flow cytometry-based assessment of leukemia and B cells, extent and duration of leukemic response | 12 months | 
| Characterize low level disease and B cell assessment in response to huCART19-IL18 cells | Presence or absence of malignant B cells by Next-Generation Immunoglobulin heavy chain Sequencing (NGIS) | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CLL, NHL, CAR-T cells