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

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ClinicalTrials.gov Identifier: NCT03103971
Recruitment Status : Recruiting
First Posted : April 7, 2017
Last Update Posted : July 19, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase I trial studies the side effects of autologous human anti-CD19 chimeric antigen receptor (CAR)-4-1BB-CD3zeta EGFRt-expressing CD4+/CD8+ T-lymphocytes (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.

Condition or disease Intervention/treatment Phase
Adult B Acute Lymphoblastic Leukemia BCL2 Gene Rearrangement BCL6 Gene Rearrangement CD19 Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified MYC Gene Rearrangement Recurrent Adult Acute Lymphoblastic Leukemia Recurrent B-Cell Non-Hodgkin Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Primary Mediastinal (Thymic) Large B-Cell 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 Cell Lymphoma Recurrent Transformed Non-Hodgkin Lymphoma 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 Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate preliminary safety of huJCAR014 in adult patients with CD19+ relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetic (PK) profile of huJCAR014 in CD19+ R/R aggressive B-cell NHL and ALL.

II. To assess the antitumor activity of huJCAR014 in CD19+ R/R aggressive NHL and ALL.

III. To estimate the progression free survival (PFS) and overall survival (OS) in patients with CD19+ R/R aggressive NHL and ALL treated with huJCAR014.

EXPLORATORY OBJECTIVES:

I. To assess the cellular and humoral immune responses to huJCAR014.

II. To assess the pharmacodynamic effects of huJCAR014.

III. To assess the effect of huJCAR014 product attributes on safety, PK, and antitumor activity.

IV. To assess the effect of tumor and tumor microenvironment on huJCAR014 PK and biomarkers.

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. 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 3, 2017
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : July 17, 2033


Arm Intervention/treatment
Experimental: Treatment (leukapheresis, chemotherapy, huJCAR014)
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
Given IV
Other Names:
  • Anti-CD19-CAR Genetically Engineered Autologous T Lymphocytes huJCAR014
  • Anti-CD19-CAR Genetically Engineered Autologous T-lymphocytes huJCAR014
  • Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes
  • huJCAR014

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
  • Leukocytopheresis
  • Therapeutic Leukopheresis

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Incidence of toxicity [ Time Frame: Up to 30 days after the final dose of study therapy ]
    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.

  2. Dose-limiting toxicity (DLT) rates [ Time Frame: Up to 28 days ]
    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.

  3. Maximum concentration (Cmax) of autologous human anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes (huJCAR014) cells in blood [ Time Frame: Up to 28 days ]
    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.

  4. Time to maximum concentration (Tmax), of huJCAR014 cells in blood [ Time Frame: Up to 28 days ]
    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.

  5. Area under the curve of huJCAR014 cells in blood [ Time Frame: Up to 28 days ]
    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.

  6. Presence of huJCAR014 cells in bone marrow [ Time Frame: Up to 28 days ]
    The persistence of huJCAR014 in the bone marrow at 28 days will be assessed, based on both a qPCR assay and flow cytometry.


Secondary Outcome Measures :
  1. Complete response (CR) rate [ Time Frame: Up to 15 years ]
    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

  2. Partial response (PR) rate [ Time Frame: Up to 15 years ]
    Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets.

  3. Objective response rate (ORR) [ Time Frame: Up to 15 years ]
    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.

  4. Duration of response (DOR) [ Time Frame: Up to 15 years ]
    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.

  5. Progression-free survival (PFS) [ Time Frame: From date of first huJCAR014 infusion to progressive disease or death, assessed up to 15 years ]
    KM methodology will be used to analyze PFS.

  6. Event-free survival (EFS) [ Time Frame: 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 ]
    KM methodology will be used to analyze EFS.

  7. Overall survival (OS) [ Time Frame: From date of first huJCAR014 infusion to death, assessed up to 15 years ]
    KM methodology will be used to analyze OS.


Other Outcome Measures:
  1. Cellular immune responses to huJCAR014 [ Time Frame: Up to 1 year ]
    Percentage of patients with cellular immune responses to huJCAR014.

  2. B-cell depletion in circulation [ Time Frame: Up to 1 year ]
    Percentage of patients with B cells < 0.01% in blood.

  3. Cytokine profile [ Time Frame: Up to 1 year ]
    Peak concentration of IL-6 in blood after CAR-T cell infusion.

  4. CD19 expression on tumor cells in biopsies [ Time Frame: Up to 1 year ]
    Percentage of patients with CD19-negative disease after CAR-T cell infusion.

  5. Phenotype of CAR T cells in blood [ Time Frame: Up to 1 year ]
    Percentage of patients with CAR-T cells expressing CD62L.

  6. Product attributes (e.g., cell phenotype, cytokine profiles) [ Time Frame: Up to 1 year ]
    Product attributes (e.g., cell phenotype, cytokine profiles) will be correlated with AEs, pharmacokinetic (PK), and tumor response rates.

  7. Tumor attributes (e.g., checkpoint expression) [ Time Frame: Up to 1 year ]
    Tumor attributes (e.g., checkpoint expression) on PK will be correlated with biomarkers (e.g., peripheral cytokines).



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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:

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

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

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:

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

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

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

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): NCT03103971


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Cameron J. Turtle    206-667-7073    cturtle@fredhutch.org   
Principal Investigator: Cameron J. Turtle         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Cameron Turtle Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03103971     History of Changes
Other Study ID Numbers: 9364
NCI-2017-00421 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9364 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: April 7, 2017    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites