Clinical Trials /

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

NCT03103971

Description:

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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • Mediastinal Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 9364
  • SECONDARY ID: NCI-2017-00421
  • SECONDARY ID: 9364
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT03103971

Conditions

  • 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

Interventions

DrugSynonymsArms
Autologous Human Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytesAnti-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, huJCAR014Treatment (leukapheresis, chemotherapy, huJCAR014)
Cyclophosphamide(-)-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- 138719Treatment (leukapheresis, chemotherapy, huJCAR014)
FludarabineFluradosaTreatment (leukapheresis, chemotherapy, huJCAR014)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (leukapheresis, chemotherapy, huJCAR014)ExperimentalPatients 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.
  • Autologous Human Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

        CRITERIA FOR SCREENING

          -  Ability to understand and provide informed consent

          -  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 within 6 weeks prior to leukapheresis unless there is progressive
                  disease in irradiated lesions or there are additional non-irradiated, positron
                  emission tomography (PET)-positive lesions

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity
Time Frame:Up to 30 days after the final dose of study therapy
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Complete response (CR) rate
Time Frame:Up to 15 years
Safety Issue:
Description: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
Measure:Partial response (PR) rate
Time Frame:Up to 15 years
Safety Issue:
Description:Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets.
Measure:Objective response rate (ORR)
Time Frame:Up to 15 years
Safety Issue:
Description: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.
Measure:Duration of response (DOR)
Time Frame:Up to 15 years
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:From date of first huJCAR014 infusion to progressive disease or death, assessed up to 15 years
Safety Issue:
Description:KM methodology will be used to analyze PFS.
Measure: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
Safety Issue:
Description:KM methodology will be used to analyze EFS.
Measure:Overall survival (OS)
Time Frame:From date of first huJCAR014 infusion to death, assessed up to 15 years
Safety Issue:
Description:KM methodology will be used to analyze OS.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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