Clinical Trials /

JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

NCT02706405

Description:

This phase Ib trial studies whether anti-CD19-chimeric antigen receptor (CAR) lentiviral vector-transduced autologous T cells (JCAR014) and durvalumab are safe in combination and can work together in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). JCAR014 is made of each patient's immune cells (T cells) that have a new gene added to them in a laboratory, which programs them to kill lymphoma cells. Durvalumab is a type of drug called a monoclonal antibody, targeted to PD-L1 that may help immune cells attack cancer cells more effectively and thus help JCAR014 work better.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Double-Hit Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Transformed Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
  • Official Title: A Phase 1b Study of JCAR014, Autologous T Cells Engineered to Express a CD19-Specific Chimeric Antigen Receptor, in Combination With Durvalumab (MEDI4736) for Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 9457
  • SECONDARY ID: NCI-2015-02286
  • SECONDARY ID: 9457
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: R01CA136551
  • SECONDARY ID: RG6616001
  • NCT ID: NCT02706405

Conditions

  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ CM T-lymphocytes JCAR014, JCAR014Group I (JCAR014, durvalumab)
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- 138719Group I (JCAR014, durvalumab)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Group I (JCAR014, durvalumab)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Group I (JCAR014, durvalumab)

Purpose

This phase Ib trial studies whether anti-CD19-chimeric antigen receptor (CAR) lentiviral vector-transduced autologous T cells (JCAR014) and durvalumab are safe in combination and can work together in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). JCAR014 is made of each patient's immune cells (T cells) that have a new gene added to them in a laboratory, which programs them to kill lymphoma cells. Durvalumab is a type of drug called a monoclonal antibody, targeted to PD-L1 that may help immune cells attack cancer cells more effectively and thus help JCAR014 work better.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety of JCAR014 in combination with durvalumab in adult patients with
      relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).

      II. To determine the maximum tolerated dose (MTD) of durvalumab in combination with JCAR014.

      III. To characterize the pharmacokinetic (PK) profile of JCAR014.

      SECONDARY OBJECTIVES:

      I. To assess the antitumor activity of JCAR014 in combination with durvalumab in R/R B-cell
      NHL.

      II. To estimate the duration of response (DOR), progression-free survival (PFS), and overall
      survival (OS) in patients treated with JCAR014 in combination with durvalumab.

      III. To characterize the PK profile of durvalumab.

      IV. To assess the immunogenicity of JCAR014 and durvalumab.

      EXPLORATORY OBJECTIVE:

      I. To assess the pharmacodynamic effects of JCAR014 and durvalumab in blood and within the
      tumor.

      OUTLINE: This is a dose-escalation study of durvalumab administered with a single fixed dose
      of JCAR014. Patients are assigned to 1 of 2 treatment arms, listed as Groups 1 and 2 below.

      LYMPHODEPLETING CHEMOTHERAPY: All patients receive cyclophosphamide and fludarabine
      intravenously (IV) for 3 days from day -4 to -2.

      GROUP I: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60
      minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in
      the absence of disease progression or unacceptable toxicity.

      GROUP II: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30
      minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence
      of disease progression or unacceptable toxicity.

      Patients are followed during treatment then periodically for at least 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (JCAR014, durvalumab)ExperimentalPatients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity.
  • Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
  • Cyclophosphamide
  • Durvalumab
  • Fludarabine Phosphate
Group II (durvalumab, JCAR014)ExperimentalPatients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
  • Cyclophosphamide
  • Durvalumab
  • Fludarabine Phosphate

Eligibility Criteria

        Inclusion Criteria:

        INCLUSION CRITERIA FOR SCREENING:

          -  Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified
             (NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements;
             primary mediastinal B-cell lymphoma (PMBCL); or DLBCL transformed from indolent
             histology with one of the following:

               -  Persistent disease after first-line chemo-immunotherapy

               -  Relapse after first-line chemo-immunotherapy and not eligible for autologous
                  hematopoietic stem cell transplant (HCT)

               -  Relapse or persistent disease after at least two lines of therapy or after
                  autologous HCT

          -  Ability to understand and provide informed consent

        INCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION:

          -  Screening evaluation appropriate for leukapheresis and T-cell collection

          -  Evidence of CD19 expression on any prior or current tumor specimen or a high
             likelihood of CD19 expression based on disease histology

        INCLUSION CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB:

          -  Successful collection of T cells for JCAR014 manufacturing

          -  Documentation of CD19 expression on any prior or current tumor biopsy

          -  Internal review of histology

          -  Detectable positron emission tomography (PET)-positive disease

          -  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)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN and
             total bilirubin =< 2 x ULN

          -  Adequate pulmonary function, defined as Common Terminology Criteria for Adverse Events
             (CTCAE) grade =< 1 dyspnea and oxygen saturation (SaO2) >= 92% on room air; patients
             with clinically significant pulmonary dysfunction, as determined by medical history
             and physical exam should undergo pulmonary function testing and must have a forced
             expiratory volume in 1 second (FEV1) >= 50% of predicted value or diffusing capacity
             of the lung for carbon monoxide (DLCO; corrected) >= 40% of predicted value

          -  Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >= 35%
             as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA)

          -  Women of reproductive potential (defined as all women physiologically capable of
             becoming pregnant) must agree to use suitable methods of contraception for 90 days
             after the last dose of study therapy (durvalumab or JCAR014)

          -  Males who have partners of reproductive potential must agree to use an effective
             barrier contraceptive method for 90 days after the last dose of study therapy
             (durvalumab or JCAR014)

        Exclusion Criteria:

        EXCLUSION CRITERIA FOR SCREENING:

          -  Subjects with known active central nervous system (CNS) involvement by malignancy;
             subjects with prior CNS disease that has been effectively treated will be eligible if
             treatment was completed at least 3 months prior to enrollment and there is no evidence
             of disease or stable abnormalities on repeat imaging

          -  Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other
             systemic immunosuppression within 4 days prior to leukapheresis; topical and/or
             inhaled steroids are permitted

          -  Prior treatment with any CD19 CAR T-cell therapy

          -  Prior allogeneic HCT

          -  Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection

          -  Pregnant or breastfeeding women

          -  Known exclusion criteria for leukapheresis, JCAR014, or durvalumab therapy

        EXCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION:

          -  Subjects with known active central nervous system (CNS) involvement by malignancy;
             subjects with prior CNS disease that has been effectively treated will be eligible if
             treatment was completed at least 3 months prior to enrollment and there is no evidence
             of disease or stable abnormalities on repeat imaging

          -  Prior treatment with programmed cell death (PD)-1, PD-ligand (L)1, cytotoxic T
             lymphocyte-associated protein 4 (CTLA 4) targeted therapy, or tumor necrosis factor
             receptor superfamily (TNFRSF) agonists including CD134 (OX40), CD27, CD137 (4-1BB),
             and CD357 (glucocorticoid-induced tumor necrosis factor receptor family-related
             protein [GITR])

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., ulcerative colitis, Crohn's disease], celiac
             disease, or other serious chronic gastrointestinal conditions associated with
             diarrhea; autoimmune vasculitis; systemic lupus erythematosus; Wegener syndrome
             [granulomatosis with polyangiitis]; myasthenia gravis; Graves' disease; rheumatoid
             arthritis, hypophysitis, uveitis, etc.) within 3 years prior to the planned start of
             treatment; the following are exceptions to this criterion:

               -  Vitiligo

               -  Alopecia

               -  Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement

               -  Psoriasis not requiring systemic treatment

               -  Other conditions considered to be low risk of serious deterioration by the
                  principal investigator (PI)

          -  History of any one of the following cardiovascular conditions within the past 6
             months: class III or IV heart failure as defined by the New York Heart Association
             (NYHA), cardiac angioplasty or stenting, myocardial infarction, or unstable angina;
             history of other clinically significant cardiac disease that, in the opinion of the PI
             or designee, is a contraindication to lymphodepleting chemotherapy, JCAR014 infusion,
             or durvalumab infusion is also excluded

          -  History or presence of clinically relevant CNS pathology such as epilepsy, seizure,
             paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease,
             cerebellar disease, or psychosis; history of other organic brain syndrome that in the
             opinion of the PI or designee is a contraindication to lymphodepleting chemotherapy,
             JCAR014 infusion or durvalumab infusion

          -  History of solid organ transplantation

        EXCLUSION CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB:

          -  For lymphodepletion chemotherapy, JCAR014 and durvalumab: Subjects with known active
             CNS involvement by malignancy; subjects with prior CNS disease that has been
             effectively treated will be eligible if treatment was completed at least 3 months
             prior to enrollment and there is no evidence of disease or stable abnormalities on
             repeat imaging

          -  Uncontrolled infection

          -  Receipt of live, attenuated vaccine within 28 days prior to the first dose of
             durvalumab (Note: enrolled patients should not receive live vaccine during the study
             and for 180 days after the last dose of durvalumab)

          -  Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other
             systemic immunosuppression is not permitted within 72 hours prior to JCAR014 infusion;
             topical and/or inhaled steroids are permitted.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame:30 days
Safety Issue:
Description:All adverse events will be listed and summarized. Summaries of laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities. Summaries of adverse events and laboratory abnormalities will be based on the All Treated analysis set.

Secondary Outcome Measures

Measure:Rate of complete response (CR) by investigator assessment using Lugano criteria
Time Frame:Up to 15 years
Safety Issue:
Description:The rates of CR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the efficacy evaluable (EE) analysis sets.
Measure:Rate of partial response (PR) by investigator assessment using Lugano criteria
Time Frame:Up to 15 years
Safety Issue:
Description:PR 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, defined as the proportion of patients with a best response of either complete response or partial response) by investigator assessment using Lugano criteria
Time Frame:Up to 15 years
Safety Issue:
Description:ORR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets. In addition, objective response rate will be presented based on the All Treated analysis set, where patients with non-evaluable response will be treated as non-responders.
Measure:Duration of response
Time Frame:From first response to progressive disease or death, assessed up to 15 years
Safety Issue:
Description:Kaplan-Meier methodology will be used.
Measure:Progression free survival
Time Frame:From date of first study treatment to progressive disease or death, assessed up to 15 years
Safety Issue:
Description:Kaplan-Meier methodology will be used.
Measure:Overall survival
Time Frame:From date of first study treatment to death, assessed up to 15 years
Safety Issue:
Description:Kaplan-Meier methodology will be used.
Measure:Cmax of durvalumab in serum
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:AUC of durvalumab in serum
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:Clearance of durvalumab in serum
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:Terminal half-life of durvalumab in serum
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:Antibodies and cellular immune responses to JCAR014
Time Frame:Up to 12 months
Safety Issue:
Description:Cellular immune responses to JCAR014 will be considered in patients who have two consecutive negative assays for JCAR014 or who have recovered endogenous B cells. Cellular responses to JCAR014 will be evaluated by assessing reactivity of patient peripheral T cells to JCAR014. Peripheral blood will be collected for these studies.
Measure:Anti-drug antibodies directed against durvalumab
Time Frame:Up to 12 months
Safety Issue:
Description:Will be assessed using a validated immunoassay in serum samples.

Details

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

Trial Keywords

  • PD-L1
  • immunotherapy
  • non-Hodgkin lymphoma

Last Updated

January 3, 2020