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

Study Overview
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Brief Summary
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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
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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 starting approximately on day -5 or day -4. 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. After completion of study treatment, patients are followed up every 30 days for 30 months, every 3 months for 12 months, then periodically for at least 15 years.

Official Title
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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

Conditions
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Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Intervention / Treatment
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* Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
* Drug: Cyclophosphamide
* Biological: Durvalumab
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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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.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (JCAR014, durvalumab) Early - Dose Level 2<br>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 1 - early: start durvalumab no earlier than 7 days after JCAR014. Group 1 Dose Level 2 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group I (JCAR014, durvalumab) Late- Dose Level 1<br>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 1 - late: start durvalumab no earlier than 21 days after JCAR014 Group 1 Dose Level 1 is 225 mg Durvalumab, up to 2 x 106/kg CAR T cells . | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group I (JCAR014, durvalumab) Late - Dose Level 2<br>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 1 - late: start durvalumab no earlier than 21 days after JCAR014 Group 1 Dose Level 2 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group II (durvalumab, JCAR014) - Dose Level 1<br>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. Group 2 Dose Level 1 is 7.5 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group II (durvalumab, JCAR014) - Dose Level 2<br>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. Group 2 Dose Level 2 is 22.5 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group II (durvalumab, JCAR014) - Dose Level 3<br>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. Group 2 Dose Level 3 is 75 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group II (durvalumab, JCAR014) - Dose Level 4<br>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. Group 2 Dose Level 4 is 225 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|
| Experimental: Group II (durvalumab, JCAR014) - Dose Level 5<br>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. Group 2 Dose Level 5 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells | Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014<br>* Given IV<br>* Other names: JCAR014;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants Who Experienced Adverse Events | Toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. | 28 days post last infusion of Durvalumab, up to 1 year | 
| Dose Limiting Toxicity (DLT) Rates | Will be summarized based on the dose limiting toxicity evaluable analysis set. The target toxicity rate for the maximum tolerated dose is 30%. Outcome will be reported as a count of patients in each arm that experienced a DLT. | 28 days post first infusion of Durvalumab (for participants in Group 1) or 28 days post infusion of JCAR (for participants in Group 2) | 
| Highest Treatment Dose Administered on Study | Reporting outcome as the maximum durvalumab dose that we reached on the study. Patients were monitored for 28 days post infusion for dose limiting toxicities. The DLT rate was used to determine dose escalation. The study was terminated prior to reaching the maximum tolerated dose. | 28 days | 
| Maximum JCAR014 Cmax by Flow Cytometry | Absolute CD4+ and CD8+ CAR-T cell counts were determined by multiplying the percentages of CD3+CD4+CD8-EGFRt+ and CD3+CD4-CD8+EGFRt+ events, respectively, in a viable CD45+ lymphocyte forward/side scatter gate by an absolute lymphocyte count performed on the same day. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product. | Up to 12 months | 
| Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | Absolute CD4+ and CD8+ CAR-T cell counts were determined by multiplying the percentages of CD3+CD4+CD8-EGFRt+ and CD3+CD4-CD8+EGFRt+ events, respectively, in a viable CD45+ lymphocyte forward/side scatter gate by an absolute lymphocyte count performed on the same day. Subjects had samples analyzed at approximately days 0, 3, 7, 10, 14, 21, and 28 after CAR-T cell infusion to generate the AUC from day 0 to 28. The areas under the curve of CAR T-cell counts by flow cytometry and qPCR between time points were calculated by using a trapezoidal rule computational algorithm. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product. | Up to 28 days | 
| Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product. | Up to 12 months | 
| AUC of JCAR014 Cells by qPCR Analysis | The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Subjects had samples analyzed at approximately days 0, 3, 7, 10, 14, 21, and 28 after CAR-T cell infusion to generate the AUC from day 0 to 28.The areas under the curve of CAR T-cell counts by flow cytometry and qPCR between time points were calculated by using a trapezoidal rule computational algorithm. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product. | Up to 28 days | 
| Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product. | Up to 12 months, +/- 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | This outcome is a count of participants who experienced a best response of complete response (CR) by investigator assessment using Lugano criteria. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment. | Up to 1 year | 
| Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | This outcome is a count of participants who experienced a best response of partial response (PR) by investigator assessment using Lugano criteria. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment. | Up to 1 year | 
| Objective Response Rate by Investigator Assessment Using Lugano Criteria | ORR, defined as a count of participant with a best response of either complete response or partial response. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment. | Up to 1 year | 
| Duration of Response | Duration of response will be an average amount of days from first response assessment until progression or death for treated patients. Total number analyzed will be the patients that progressed or died, excluding those that did not progress or die. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment. | From first response to progressive disease or death, assessed up to 1 year | 
| Progression Free Survival | Outcome will be reported as a count of those who did not progress and did not die while on study. | From date of first study treatment to progressive disease or death, assessed up to 1 year | 
| Overall Survival | Outcome will be reported as a count of participants who survived while on study. Survival was assessed up to 1 year. | From date of first study treatment to death, assessed up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-L1, immunotherapy, non-Hodgkin lymphoma