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
Conditions
Keywords
PD-L1, immunotherapy, non-Hodgkin lymphoma
Brief summary
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 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.
Interventions
BIOLOGICALAutologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
DRUGCyclophosphamide
Given IV
BIOLOGICALDurvalumab
Given IV
DRUGFludarabine
Given IV
Sponsors
AstraZeneca
Juno Therapeutics, Inc., a Bristol-Myers Squibb Company
MedImmune LLC
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants Who Experienced Adverse Events | 28 days post last infusion of Durvalumab, up to 1 year | Toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. |
| Dose Limiting Toxicity (DLT) Rates | 28 days post first infusion of Durvalumab (for participants in Group 1) or 28 days post infusion of JCAR (for participants in Group 2) | 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. |
| Highest Treatment Dose Administered on Study | 28 days | 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. |
| Maximum JCAR014 Cmax by Flow Cytometry | Up to 12 months | 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. |
| Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | Up to 28 days | 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. |
| Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | Up to 12 months | 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. |
| AUC of JCAR014 Cells by qPCR Analysis | Up to 28 days | 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. |
| Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | Up to 12 months, +/- 30 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of first study treatment to death, assessed up to 1 year | Outcome will be reported as a count of participants who survived while on study. Survival was assessed up to 1 year. |
| Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | Up to 1 year | 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. |
| Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | Up to 1 year | 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. |
| Objective Response Rate by Investigator Assessment Using Lugano Criteria | Up to 1 year | 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. |
| Duration of Response | From first response to progressive disease or death, assessed up to 1 year | 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. |
| Progression Free Survival | From date of first study treatment to progressive disease or death, assessed up to 1 year | Outcome will be reported as a count of those who did not progress and did not die while on study. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Terminal Half-life of Durvalumab in Serum | Up to 12 months | — |
| Antibodies and Cellular Immune Responses to JCAR014 | 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. |
| Anti-drug Antibodies Directed Against Durvalumab | Up to 12 months | Will be assessed using a validated immunoassay in serum samples. |
| 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 | Up to 12 months | — |
| 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) | 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 CAR T Cells | Up to 12 months | Flow cytometry may be used in the blood, bone marrow, and CSF (if applicable). |
| Cmax of Durvalumab in Serum | Up to 12 months | — |
| AUC of Durvalumab in Serum | Up to 12 months | — |
| Clearance of Durvalumab in Serum | Up to 12 months | — |
Countries
United States
Participant flow
Pre-assignment details
One patient was enrolled on the trial but did not move on to treatment. They were not assigned to an arm or to a treatment dose level.
Participants by arm
| Arm | Count |
|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 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 | 5 |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 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 | 3 |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 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 | 3 |
| Group II (Durvalumab, JCAR014) - Dose Level 1 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 | 1 |
| Group II (Durvalumab, JCAR014) - Dose Level 2 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 | 1 |
| Group II (Durvalumab, JCAR014) - Dose Level 3 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 | 3 |
| Group II (Durvalumab, JCAR014) - Dose Level 4 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 | 6 |
| Group II (Durvalumab, JCAR014) - Dose Level 5 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 | 7 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 3 | 2 | 0 | 1 | 0 | 0 | 3 | 4 |
| Overall Study | Disease progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Pt moved to new therapy | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Group II (Durvalumab, JCAR014) - Dose Level 1 | Group II (Durvalumab, JCAR014) - Dose Level 2 | Group II (Durvalumab, JCAR014) - Dose Level 3 | Group II (Durvalumab, JCAR014) - Dose Level 4 | Group II (Durvalumab, JCAR014) - Dose Level 5 |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 2 Participants | 5 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Female | 10 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 19 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 2 / 3 | 0 / 3 | 1 / 1 | 0 / 1 | 0 / 3 | 3 / 6 | 4 / 7 |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 3 / 3 | 1 / 1 | 1 / 1 | 3 / 3 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 4 / 5 | 3 / 3 | 2 / 3 | 1 / 1 | 0 / 1 | 2 / 3 | 4 / 6 | 4 / 7 |
Outcome results
Primary
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.
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 844.77 Days x CD3+ CAR-T cells/μL |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 104.33 Days x CD3+ CAR-T cells/μL |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 47.96 Days x CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 32.44 Days x CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 90.78 Days x CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 160.94 Days x CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Area Under the Curve (AUC) of JCAR014 by Flow Cytometry | 71.97 Days x CD3+ CAR-T cells/μL |
Primary
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.
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | AUC of JCAR014 Cells by qPCR Analysis | 296188.95 CAR transgene copies/μg DNA x days |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | AUC of JCAR014 Cells by qPCR Analysis | 104088.38 CAR transgene copies/μg DNA x days |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | AUC of JCAR014 Cells by qPCR Analysis | 18710.77 CAR transgene copies/μg DNA x days |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | AUC of JCAR014 Cells by qPCR Analysis | 16721.68 CAR transgene copies/μg DNA x days |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | AUC of JCAR014 Cells by qPCR Analysis | 63778.63 CAR transgene copies/μg DNA x days |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | AUC of JCAR014 Cells by qPCR Analysis | 353471.10 CAR transgene copies/μg DNA x days |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | AUC of JCAR014 Cells by qPCR Analysis | 389065.24 CAR transgene copies/μg DNA x days |
Primary
Count of Participants Who Experienced Adverse Events
Toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Time frame: 28 days post last infusion of Durvalumab, up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Count of Participants Who Experienced Adverse Events | 5 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Count of Participants Who Experienced Adverse Events | 3 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Count of Participants Who Experienced Adverse Events | 3 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Count of Participants Who Experienced Adverse Events | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Count of Participants Who Experienced Adverse Events | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Count of Participants Who Experienced Adverse Events | 3 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Count of Participants Who Experienced Adverse Events | 6 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Count of Participants Who Experienced Adverse Events | 7 Participants |
Primary
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.
Time frame: 28 days post first infusion of Durvalumab (for participants in Group 1) or 28 days post infusion of JCAR (for participants in Group 2)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Dose Limiting Toxicity (DLT) Rates | 1 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Dose Limiting Toxicity (DLT) Rates | 0 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Dose Limiting Toxicity (DLT) Rates | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Dose Limiting Toxicity (DLT) Rates | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Dose Limiting Toxicity (DLT) Rates | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Dose Limiting Toxicity (DLT) Rates | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Dose Limiting Toxicity (DLT) Rates | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Dose Limiting Toxicity (DLT) Rates | 1 Participants |
Primary
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.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Highest Treatment Dose Administered on Study | 750 mg |
Primary
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.
Time frame: Up to 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Maximum JCAR014 Cmax by Flow Cytometry | 201.21 CD3+ CAR-T cells/μL |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Maximum JCAR014 Cmax by Flow Cytometry | 13.71 CD3+ CAR-T cells/μL |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Maximum JCAR014 Cmax by Flow Cytometry | 8.27 CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Maximum JCAR014 Cmax by Flow Cytometry | 3.01 CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Maximum JCAR014 Cmax by Flow Cytometry | 13.15 CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Maximum JCAR014 Cmax by Flow Cytometry | 18.13 CD3+ CAR-T cells/μL |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Maximum JCAR014 Cmax by Flow Cytometry | 7.53 CD3+ CAR-T cells/μL |
Primary
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.
Time frame: Up to 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 37647.95 CAR transgene copies/μg DNA |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 10043.68 CAR transgene copies/μg DNA |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 3690.24 CAR transgene copies/μg DNA |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 1949.22 CAR transgene copies/μg DNA |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 8295.36 CAR transgene copies/μg DNA |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 27841.31 CAR transgene copies/μg DNA |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis | 26297.43 CAR transgene copies/μg DNA |
Primary
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.
Time frame: Up to 12 months, +/- 30 days
Population: Participants analyzed are the participants with documented loss of detection of JCAR014 in blood by qPCR during follow-up.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | 113 days |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | 191 days |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | 28 days |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | 199 days |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | 183 days |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Time to Loss of JCAR014 Detection in Blood by qPCR Analysis | 64 days |
Secondary
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.
Time frame: From first response to progressive disease or death, assessed up to 1 year
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Duration of Response | 72.5 days |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Duration of Response | 47.5 days |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Duration of Response | 42 days |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Duration of Response | 35 days |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Duration of Response | 31 days |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Duration of Response | 97.75 days |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Duration of Response | 18.14 days |
Secondary
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.
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Objective Response Rate by Investigator Assessment Using Lugano Criteria | 2 Participants |
Secondary
Overall Survival
Outcome will be reported as a count of participants who survived while on study. Survival was assessed up to 1 year.
Time frame: From date of first study treatment to death, assessed up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Overall Survival | 2 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Overall Survival | 1 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Overall Survival | 3 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Overall Survival | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Overall Survival | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Overall Survival | 3 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Overall Survival | 3 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Overall Survival | 3 Participants |
Secondary
Progression Free Survival
Outcome will be reported as a count of those who did not progress and did not die while on study.
Time frame: From date of first study treatment to progressive disease or death, assessed up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Progression Free Survival | 2 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Progression Free Survival | 1 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Progression Free Survival | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Progression Free Survival | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Progression Free Survival | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Progression Free Survival | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Progression Free Survival | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Progression Free Survival | 0 Participants |
Secondary
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.
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 2 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
Secondary
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.
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (JCAR014, Durvalumab) Early - Dose Level 2 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group I (JCAR014, Durvalumab) Late- Dose Level 1 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 0 Participants |
| Group I (JCAR014, Durvalumab) Late - Dose Level 2 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 1 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 2 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 3 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 4 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 0 Participants |
| Group II (Durvalumab, JCAR014) - Dose Level 5 | Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria | 1 Participants |
Other Pre-specified
Antibodies and Cellular Immune Responses to JCAR014
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.
Time frame: Up to 12 months
Other Pre-specified
Anti-drug Antibodies Directed Against Durvalumab
Will be assessed using a validated immunoassay in serum samples.
Time frame: Up to 12 months
Other Pre-specified
AUC of Durvalumab in Serum
Time frame: Up to 12 months
Other Pre-specified
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
Other Pre-specified
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)
Flow cytometry may be used in the blood, bone marrow, and cerebrospinal fluid (CSF) (if applicable).
Time frame: Baseline up to 12 months
Other Pre-specified
Clearance of Durvalumab in Serum
Time frame: Up to 12 months
Other Pre-specified
Cmax of Durvalumab in Serum
Time frame: Up to 12 months
Other Pre-specified
Phenotype and/or Genetic Profile of Endogenous Immune Cells and CAR T Cells
Flow cytometry may be used in the blood, bone marrow, and CSF (if applicable).
Time frame: Up to 12 months
Other Pre-specified
Terminal Half-life of Durvalumab in Serum
Time frame: Up to 12 months