huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This phase I trial studies the side effects of huJCAR014 in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma or acute lymphoblastic leukemia. huJCAR014 CAR-T cells are made in the laboratory by genetically modifying a patient's T cells and may specifically kill cancer cells that have a molecule CD19 on their surfaces. In Stage 1, dose-finding studies will be conducted in 3 cohorts: Aggressive B cell NHL Low burden ALL High burden ALL In Stage 2, studies may be conducted in one or more cohorts to collect further safety, PK, and efficacy information at the huJCAR014 dose level(s) selected in Stage 1 for the applicable cohort(s). There are two separate cohorts for stage 2: Cohort 2A, CAR-naïve (n=10): patients who have never received CD19 CAR-T cell therapy. Cohort 2B, CAR-exposed (n=27): patients who have previously failed CD19 CAR-T cell therapy.

Detailed Description
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OUTLINE: This is a dose-escalation study of huJCAR014. Patients undergo leukapheresis. Beginning 1-2 weeks after leukapheresis, patients undergo lymphodepleting chemotherapy comprising either cyclophosphamide intravenously (IV) daily for 1 day and fludarabine IV daily for 3 days or cyclophosphamide and fludarabine IV daily for 3 days. Alternative lymphodepleting chemotherapy regimens maybe used if patient's clinical situation or other logistical factors dictate otherwise. Within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive huJCAR014 IV over 20-30 minutes on day 0. After completion of study treatment, patients are followed up every 30 days for the first 3 months, every 3 months for up to 12 months, and then yearly for 15 years.

Official Title
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A Two-Stage Phase 1 Open-Label Study of huJCAR014, CD19-Targeted Chimeric Antigen Receptor (CAR)-Modified T Cells Bearing a Human Binding Domain, in Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma and Acute Lymphocytic Leukemia

Conditions
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Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Adult Acute Lymphoblastic Leukemia, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Recurrent Transformed Non-Hodgkin Lymphoma, Recurrent High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Recurrent B Acute Lymphoblastic Leukemia, Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Refractory B Acute Lymphoblastic Leukemia, Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Refractory High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements

Intervention / Treatment
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* Biological: Autologous Human Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Other: Laboratory Biomarker Analysis
* Procedure: Leukapheresis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female >= 18 years of age at the time of screening consent INCLUSION CRITERIA FOR SCREENING Diagnosis of R/R B-cell NHL or ALL as defined below: Relapsed or refractory B-cell NHL meeting all of the following criteria: Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; LBCL transformed from any indolent histology; or primary mediastinal B-cell lymphoma (PMBCL) Prior treatment with an anthracycline and rituximab or another CD20-targeted agent (unless the disease is CD20-negative); transformed DLBCL (tDLBCL) must have failed treatment for DLBCL At least one of the following: Refractory disease after frontline chemo-immunotherapy Not eligible for autologous hematopoietic stem cell transplant (auto-HSCT) Relapsed or refractory disease after at least 2 lines of therapy or after auto-HSCT Relapsed or refractory disease after allogeneic hematopoietic stem cell transplant (allo-HSCT) Relapsed or refractory B-cell ALL (patients with Burkitt's lymphoma/leukemia are not eligible) All B-ALL patients must have detectable disease by morphology, flow cytometry, cytogenetic analysis (e.g. polymerase chain reaction [PCR], fluorescence in situ hybridization [FISH], karyotyping) or imaging (e.g. positron emission tomography [PET]/computed tomography [CT]) or a high likelihood of active disease Refractory: failure to achieve complete response (CR) (minimal residual disease [MRD]-negative) at the end of induction Relapsed: recurrence of disease after achieving CR Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or current tumor specimen or high likelihood of CD19 expression based on disease histology INCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION Screening evaluation appropriate for leukapheresis and T-cell collection Adequate vascular access available or planned for leukapheresis procedure (either peripheral line or surgically placed line) Documentation of CD19 expression on any prior or current tumor biopsy; patients who have received previous CD19-targeted therapy must have CD19-positive disease confirmed on a biopsy since completing the prior CD19-targeted therapy Internal review of histology Stage 2; cohort 2B (CAR-exposed) only: Relapsed disease after achieving CR at the discretion of the principal investigator (PI) or designee, after prior CD19-targeted non-huJCAR014 CAR T-cell therapy. Patients who were in CR prior to the CD19-targeted non-huJCAR014 CAR T-cell therapy may be considered eligible at the discretion of the PI or designee. OR Persistent disease after achieving PR at the discretion of the PI or designee, after prior CD19-targeted non-huJCAR014 CAR T-cell therapy. Patients who are less than 3 months from prior CD19-targeted non-huJCAR014 CAR T-cell therapy must have persistent disease on biopsy or imaging (e.g. PET-CT or CT) evidence of disease progression INCLUSION CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY AND huJCAR014 TREATMENT Successful collection of T cells for huJCAR014 manufacturing Detectable disease by imaging (for example PET +/- CT, magnetic resonance imaging [MRI]) and/or pathology evaluation Karnofsky performance status >= 60% Assessed by the investigator to have adequate bone marrow function to receive lymphodepleting conditioning chemotherapy Serum creatinine =< 1.5 x age-adjusted upper limit of normal (ULN) or calculated creatinine clearance (Cockcroft and Gault) > 30 mL/min/1.73 m^2 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x ULN and total bilirubin < 2.0 mg/dL unless due to malignancy or Gilbert's syndrome in the opinion of the PI or designee Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 dyspnea and oxygen saturation (SaO2) >= 92% on room air Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 1 month before starting lymphodepleting chemotherapy Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must agree to both of the following: Use highly effective methods of contraception for at least 6 months after the last dose of huJCAR014, and Have a negative serum pregnancy test performed within 28 days before starting lymphodepleting chemotherapy Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method for at least 6 months after the last dose of huJCAR014 Exclusion Criteria: EXCLUSION CRITERIA FOR SCREENING For patients in stage 1 only, prior treatment with any CD19 CAR T-cell therapy is excluded Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection Pregnant or breastfeeding women Any known contraindication to leukapheresis Any known and irreversible contraindication to huJCAR014 therapy Medical, psychological, familial, sociological, or geographical condition that does not permit compliance with the protocol as judged by the PI or designee, or unwillingness or inability to follow protocol procedures EXCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION History or presence of clinically relevant central nervous system (CNS) pathology that, in the opinion of the PI or designee, is a contraindication to lymphodepleting chemotherapy or huJCAR014 infusion History of another primary malignancy that has not been in remission for at least 2 years with the following exceptions: nonmelanoma skin cancer, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, or other malignancy considered by the investigator to have a low risk of relapse or progression Active autoimmune disease requiring immunosuppressive therapy, unless considered by the PI or designee to be eligible Presence of active acute or chronic graft versus host disease (GVHD) Use of any of the following: Cytotoxic or lymphotoxic agents (including prednisone > 5 mg/day or equivalent corticosteroid) within 1 week prior to leukapheresis; physiologic corticosteroid replacement, and topical or inhaled corticosteroids are not excluded GVHD therapies within 4 weeks prior to leukapheresis (e.g., calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-TNF, anti-IL-6, or anti-IL-6R) Experimental agents within 4 weeks prior to leukapheresis unless progression is documented on therapy and at least 3 half-lives have elapsed prior to leukapheresis Radiation encompassing all sites of known tumor within 6 weeks prior to leukapheresis, unless there is evidence of active disease after radiation by imaging, biopsy or clinical evaluation Allo-HSCT within 60 days prior to leukapheresis or donor lymphocyte infusion (DLI) within 6 weeks prior to leukapheresis Treatment with cladribine within 3 months prior to leukapheresis Treatment with alemtuzumab within 3 months prior to leukapheresis EXCLUSION CRITERIA FOR LYMPHODEPLETING CHEMOTHERAPY AND huJCAR014 TREATMENT Uncontrolled and serious infection Presence of active acute or chronic GVHD DLI within 6 weeks prior to lymphodepletion chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (leukapheresis, chemotherapy, huJCAR014)<br>Patients undergo leukapheresis. Beginning 14-16 days after leukapheresis, patients undergo lymphodepleting chemotherapy comprising either cyclophosphamide IV daily for 1 day and fludarabine IV daily for 3 days or cyclophosphamide and fludarabine IV daily for 3 days. Within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive huJCAR014 IV over 20-30 minutes on day 0. | Biological: Autologous Human Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes<br>* Given IV<br>* Other names: huJCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Leukapheresis<br>* Undergo leukapheresis<br>* Other names: Therapeutic Leukopheresis;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity | Will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All adverse events (AEs) will be listed and summarized. Summaries of laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities. Summaries of AEs and laboratory abnormalities will be based on the All Treated analysis set. | Up to 30 days after the final dose of study therapy | 
| Dose-limiting toxicity (DLT) rates | Observed DLT rates will be summarized based on the DLT-Evaluable analysis set. Final DLT rates at each dose level will be estimated by isotonic regression. | Up to 28 days | 
| Maximum concentration (Cmax) of autologous human anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes (huJCAR014) cells in blood | huJCAR014 will be measured in blood using quantitative polymerase chain reaction (PCR) (qPCR) and flow cytometry over 28 days after huJCAR014 infusion. Cmax is the peak concentration of huJCAR014 cells in blood in the first 28 days after infusion. | Up to 28 days | 
| Time to maximum concentration (Tmax), of huJCAR014 cells in blood | huJCAR014 will be measured in blood using quantitative PCR (qPCR) and flow cytometry over 28 days after huJCAR014 infusion. Tmax is the time to reach the maximum concentration of huJCAR014 cells in blood in the first 28 days. | Up to 28 days | 
| Area under the curve of huJCAR014 cells in blood | huJCAR014 will be measured in blood using quantitative PCR (qPCR) and flow cytometry over 28 days after huJCAR014 infusion. AUC is the calculated area under the curve of huJCAR014 concentrations in blood by time after infusion through 28 days. | Up to 28 days | 
| Presence of huJCAR014 cells in bone marrow | The persistence of huJCAR014 in the bone marrow at 28 days will be assessed, based on both a qPCR assay and flow cytometry. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate | Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the efficacy-evaluable (EE) analysis sets. In addition, CR rate will be presented based on the all-treated analysis set | Up to 15 years | 
| Partial response (PR) rate | Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets. | Up to 15 years | 
| Objective response rate (ORR) | Will be defined as the proportion of patients with a best response of either CR or PR. Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets. In addition, ORR will be presented based on the All-Treated analysis set. | Up to 15 years | 
| Duration of response (DOR) | Will be defined as the time from date of first response to relapse/progression or death. Kaplan-Meier (KM) methodology will be used to analyze DOR. | Up to 15 years | 
| Progression-free survival (PFS) | KM methodology will be used to analyze PFS. | From date of first huJCAR014 infusion to progressive disease or death, assessed up to 15 years | 
| Event-free survival (EFS) | KM methodology will be used to analyze EFS. | From the date of the first huJCAR014 infusion to death from any cause, relapse, or treatment failure, whichever occurs first, assessed up to 15 years | 
| Overall survival (OS) | KM methodology will be used to analyze OS. | From date of first huJCAR014 infusion to death, assessed up to 15 years |