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

This study is currently recruiting participants.
Verified December 2017 by Fred Hutchinson Cancer Research Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT02706405
First Posted: March 11, 2016
Last Update Posted: December 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
AstraZeneca
Juno Therapeutics, Inc.
MedImmune LLC
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
  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 or has not responded to previous treatment. JCAR014 is made of patients' 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.

Condition Intervention Phase
BCL2 Gene Rearrangement BCL6 Gene Rearrangement Diffuse Large B-Cell Lymphoma, Not Otherwise Specified High-Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements MYC Gene Rearrangement Recurrent Diffuse Large B-Cell Lymphoma Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014 Drug: Cyclophosphamide Biological: Durvalumab Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Area under the curve (AUC) of JCAR014 by flow cytometry [ Time Frame: Up to 28 days ]
  • Area under the curve (AUC) of JCAR014 cells by quantitative polymerase chain reaction (qPCR) analysis [ Time Frame: Up to 28 days ]
  • Dose limiting toxicity rates [ Time Frame: 28 days ]
    Will be summarized based on the dose limiting toxicity evaluable analysis set. Final dose limiting toxicity rates at each dose level will be estimated by isotonic regression. The target toxicity rate for the maximum tolerated dose is 30%.

  • Incidence of toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: 30 days ]
    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.

  • Maximum JCAR014 concentration (Cmax) by flow cytometry [ Time Frame: Up to 12 months ]
  • Maximum JCAR014 concentration (Cmax) in blood by quantitative polymerase chain reaction (qPCR) analysis [ Time Frame: Up to 12 months ]
  • Maximum tolerated dose (MTD) of durvalumab in combination with JCAR014 determined as the dose level with the DLT estimate closest to the target toxicity level of 30% [ Time Frame: 28 days ]
    Will be estimated per isotonic regression.

  • Time to loss of JCAR014 detection in blood by quantitative polymerase chain reaction (qPCR) analysis [ Time Frame: Up to 12 months ]

Secondary Outcome Measures:
  • Anti-drug antibodies (ADAs) directed against durvalumab [ Time Frame: Up to 12 months ]
    Will be assessed using a validated immunoassay in serum samples.

  • Antibodies and cellular immune responses to JCAR014 [ Time Frame: Up to 12 months ]
    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.

  • Area under the concentration-time curve (AUC) of durvalumab in serum [ Time Frame: Up to 12 months ]
  • Clearance of durvalumab in serum [ Time Frame: Up to 12 months ]
  • Duration of response [ Time Frame: From first response to progressive disease or death, assessed up to 15 years ]
    Kaplan-Meier methodology will be used.

  • Maximum durvalumab concentration (Cmax) in serum [ Time Frame: Up to 12 months ]
  • 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 ]
    Objective response rate 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.

  • Overall survival [ Time Frame: From date of first study treatment to death, assessed up to 15 years ]
    Kaplan-Meier methodology will be used.

  • Progression free survival [ Time Frame: From date of first study treatment to progressive disease or death, assessed up to 15 years ]
    Kaplan-Meier methodology will be used.

  • Rate of complete response (CR) by investigator assessment using Lugano criteria [ Time Frame: Up to 15 years ]
    The rates of complete response will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets.

  • Rate of partial response (PR) by investigator assessment using Lugano criteria [ Time Frame: Up to 15 years ]
    PR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets.

  • Terminal half-life of durvalumab in serum [ Time Frame: Up to 12 months ]

Other Outcome Measures:
  • B-cell depletion in circulation, profile of soluble circulating proteins such as cytokines and chemokines, and changes in the level of detectable soluble PD-L1 [ Time Frame: Up to 12 months ]
    Will be assessed.

  • Change in the phenotype of tumor cells (e.g., expression of PD-L1) and of the tumor microenvironment (e.g., infiltration by chimeric antigen receptor [CAR] T cells) [ Time Frame: Baseline up to 12 months ]
    Flow cytometry may be used in the blood, bone marrow, and cerebrospinal fluid (CSF) (if applicable).

  • Phenotype and/or genetic profile of endogenous immune cells and chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 12 months ]
    Flow cytometry may be used in the blood, bone marrow, and CSF (if applicable).


Estimated Enrollment: 42
Actual Study Start Date: November 15, 2016
Estimated Study Completion Date: December 1, 2033
Estimated Primary Completion Date: December 1, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group I (JCAR014, durvalumab)
Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 28 (may occur as early as day 21) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity.
Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Other Names:
  • Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ CM T-lymphocytes JCAR014
  • JCAR014
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
Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Experimental: Group II (durvalumab, JCAR014)
Patients receive durvalumab IV over 60 minutes on days -1 and -28 (may occur as early as day 21), and JCAR014 IV over 20-30 minutes on day 0. Patients may receive durvalumab IV over 60 minutes every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity.
Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Other Names:
  • Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ CM T-lymphocytes JCAR014
  • JCAR014
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
Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies

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.

TERTIARY OBJECTIVES:

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 intravenously (IV) on day -5 or -4 to -2 and fludarabine phosphate IV on days -4 to -2.

GROUP I: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 28 (may occur as early as day 21) 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 days -1 and 28, (may occur as early as day 21), and JCAR014 IV over 20-30 minutes on day 0. Patients may receive durvalumab IV over 60 minutes every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1, 2, and 3 months, every 3 months for 1 year, and then periodically for at least 15 years.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • 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
  • 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:

  • 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
  • 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
  • CRITERIA 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
  • CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB: Uncontrolled infection
  • CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB: 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)
  • CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND 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.
  Contacts and Locations
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): NCT02706405


Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Immunotherapy Trials Intake, SCCA    206-606-4668    immunotherapy@seattlecca.org   
Principal Investigator: Cameron J. Turtle         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
AstraZeneca
Juno Therapeutics, Inc.
MedImmune LLC
National Cancer Institute (NCI)
Investigators
Principal Investigator: Cameron Turtle Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT02706405     History of Changes
Other Study ID Numbers: 9457
NCI-2015-02286 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9457 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
R01CA136551 ( U.S. NIH Grant/Contract )
First Submitted: February 24, 2016
First Posted: March 11, 2016
Last Update Posted: December 11, 2017
Last Verified: December 2017

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

Keywords provided by Fred Hutchinson Cancer Research Center:
PD-L1
immunotherapy
non-Hodgkin lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
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
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
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