Trial to Determine the Efficacy and Safety of JCAR017 in Adult Participants With Aggressive B-Cell Non-Hodgkin Lymphoma

Phase 2

Completed

Conditions: Lymphoma, Non-Hodgkin

Interventions: Drug: JCAR017

Registration Number: NCT03484702

Lead Sponsor: Celgene

Brief Summary: The purpose of this study is to evaluate the efficacy and safety of JCAR017 in participants with aggressive B-cell non-Hodgkin lymphoma (B-NHL)

Detailed Description: This is a study to determine the efficacy and safety of JCAR017 in adult participants with aggressive B-cell NHL. The study will enroll participants in Europe and Japan with diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS; de novo or transformed follicular lymphoma \[tFL\]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (HGBL), follicular lymphoma Grade 3B (FL3B), and primary central nervous system lymphoma (PCNSL). Participants with secondary central nervous system (CNS) involvement are allowed.

Once enrolled, participants will undergo leukapheresis to enable JCAR017 cell product generation. Upon successful JCAR017 cell product generation, participants will receive lymphodepleting chemotherapy followed by infusion of JCAR017. JCAR017 will be administered by intravenous infusion. Participants will be followed for approximately 2 years after their JCAR017 infusion for safety, disease status, survival and health-related quality of life.

Delayed adverse events following exposure to gene modified T cells will be assessed and long-term persistence of these modified T cells will continue to be monitored under a separate long-term follow-up protocol for up to 15 years after JCAR017 infusion as per competent authority guidelines.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 113

Inclusion Criteria

Histological confirmation of diagnosis at last relapse
Adequate organ function
Adequate vascular access for leukapheresis procedure

Exclusion Criteria

Prior history of malignancies, other than aggressive relapsed/refractory Non-Hodgkin Lymphoma, unless the participant has been in remission for ≥ 2 years with the exception of non-invasive malignancies
Received previous CD19-targeted therapy
Progressive vascular tumor invasion, thrombosis, or embolism

Other protocol-defined inclusion/exclusion criteria apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Administration of JCAR017	JCAR017	-

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) Per Independent Review Committee in Cohorts 1, 2 and 3	From JCAR017 infusion until disease progression, end of study, the start of another anticancer therapy, or hemopoietic stem cell transplant (HSCT) (up to approximately 63 months)	Overall response rate (ORR) by Independent Review Committee (Cohorts 1, 2, 3). ORR is the percent of participants with best overall response of complete response (CR) or partial response (PR). Complete response via PET-CT: * Lymph nodes/extralymphatic: Score 1, 2, 3a with/without residual mass on 5-point scale * New lesions: No * Bone marrow: No FDG-avid disease Complete response via CT scan: * Lymph nodes/extralymphatic: Target nodes/nodal masses ≤ 1.5 cm longest transverse diameter. * Nonmeasured lesion: No * New lesions: No * Bone marrow: Normal Partial response via PET-CT: * Lymph nodes/extralymphatic: Score 4, 5b, reduced uptake from baseline * New lesions: No * Bone marrow: Residual uptake higher than normal, reduced from baseline Partial response via CT scan: * Lymph nodes/extralymphatic: 50% decrease in sum of diameters of \<= 6 target measurable nodes/extranodal sites * Nonmeasured lesion: No * Organ enlargement: Spleen length decreased \> 50% * New lesions: No
Overall Response Rate (ORR) Per Investigator in Cohort 4	From JCAR017 infusion until disease progression, end of study, the start of another anticancer therapy, or hemopoietic stem cell transplant (HSCT) (up to approximately 63 months)	Overall response rate (ORR) is the percent of participants with best overall response of complete response (CR) or partial response (PR). Complete response via PET-CT: * Lymph nodes/extralymphatic: Score 1, 2, 3a with/without residual mass on 5-point scale * New lesions: No * Bone marrow: No FDG-avid disease Complete response via CT scan: * Lymph nodes/extralymphatic: Target nodes/nodal masses ≤ 1.5 cm longest transverse diameter. * Nonmeasured lesion: None * New lesions: No * Bone marrow: Normal Partial response via PET-CT: * Lymph nodes/extralymphatic: Score 4, 5b, reduced uptake from baseline * New lesions: None * Bone marrow: Residual uptake higher than normal, reduced from baseline Partial response via CT scan: * Lymph nodes/extralymphatic: 50% decrease in sum of diameters of \<= 6 target measurable nodes/extranodal sites * Nonmeasured lesion: None/normal * Organ enlargement: Spleen length decreased \> 50% * New lesions: No
Overall Response Rate (ORR) Per Investigator in Cohort 5	From JCAR017 infusion until disease progression, end of study, the start of another anticancer therapy, or hemopoietic stem cell transplant (HSCT) (up to approximately 63 months)	Overall response rate (ORR) determined by Investigator assessment after JCAR017 infusion. The ORR is the percent of participants with best overall response (BOR) of either complete response (CR), complete response unconfirmed (Cru) or partial response (PR). Complete response (CR): * Brain imaging: No contrast enhancement * Corticosteroid dose: None * Eye examination: Normal * Cerebrospinal fluid cytology: Negative Complete response unconfirmed (CRu): * Brain imaging: No contrast enhancement, Minimal abnormality * Corticosteroid dose: Any * Eye examination: Normal, minor RPE abnormality * Cerebrospinal fluid cytology: Negative Partial response (PR): * Brain imaging: 50% decrease in enhancing tumor, no contrast enhancement. * Corticosteroid dose: Irrelevant * Eye examination: Minor RPE abnormality, decrease in vitreous cells or retinal infiltrate. * Cerebrospinal fluid cytology: Negative, persistent or suspicious
Number of Participants With Adverse Events in Cohort 7	From leukapheresis to end of study (up to approximately 63 months)	An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Serious Adverse Events (SAEs) in Cohort 7	From leukapheresis to end of study (up to approximately 63 months)	A serious adverse event (SAE) is defined as any adverse event (AE) occurring at any dose that: * Results in death; * Is life-threatening (ie, in the opinion of the Investigator, the participant is at immediate risk of death from the AE); * Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay). * Results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions); * Is a congenital anomaly/birth defect; * Constitutes an important medical event. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Increase From Baseline in Select Hematology Parameters - Cohort 7	At Baseline and Day 29 after JCAR017 infusion	JCAR017 treatment-emergent laboratory abnormalities are defined as an abnormality that, compared to baseline, worsens by at least one grade after JCAR017 infusion. The baseline value is defined as the last available recorded value on or prior to the date of JCAR017 infusion. Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening), Grade 5 (Death).
Number of Participants With Increase From Baseline in Select Serum Chemistry Parameters - Cohort 7	At Baseline and Day 29 after JCAR017 infusion	JCAR017 treatment-emergent laboratory abnormalities are defined as an abnormality that, compared to baseline, worsens by at least one grade after JCAR017 infusion. The baseline value is defined as the last available recorded value on or prior to the date of JCAR017 infusion. Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening), Grade 5 (Death).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events in Cohorts 1, 2, 3, 4, and 5	From leukapheresis to end of study (up to approximately 63 months)	An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Serious Adverse Events (SAEs) in Cohorts 1, 2, 3, 4, and 5	From leukapheresis to end of study (up to approximately 63 months)	A serious adverse event (SAE) is defined as any adverse event (AE) occurring at any dose that: * Results in death; * Is life-threatening (ie, in the opinion of the Investigator, the participant is at immediate risk of death from the AE); * Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay). * Results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions); * Is a congenital anomaly/birth defect; * Constitutes an important medical event. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Increase From Baseline in Select Hematology Parameters - Cohorts 1, 2, 3, 4, and 5	At Baseline and Day 29 after JCAR017 infusion	JCAR017 treatment-emergent laboratory abnormalities are defined as an abnormality that, compared to baseline, worsens by at least one grade after JCAR017 infusion. The baseline value is defined as the last available recorded value on or prior to the date of JCAR017 infusion. Grade 1 = Mild, Grade 2 =Moderate, Grade 3 =Severe, Grade 4 =Life-threatening, Grade 5 =Death.
Number of Participants With Increase From Baseline in Select Serum Chemistry Parameters - Cohorts 1, 2, 3, 4, and 5	At Baseline and Day 29 after JCAR017 infusion	JCAR017 treatment-emergent laboratory abnormalities are defined as an abnormality that, compared to baseline, worsens by at least one grade after JCAR017 infusion. The baseline value is defined as the last available recorded value on or prior to the date of JCAR017 infusion. Grade 1 = Mild, Grade 2 =Moderate, Grade 3 =Severe, Grade 4 =Life-threatening, Grade 5 =Death.
Overall Response Rate (ORR) in Cohort 7	From JCAR017 infusion until disease progression, end of study, the start of another anticancer therapy, or hemopoietic stem cell transplant (HSCT) (up to approximately 63 months)	ORR by Independent Review Committee. ORR is the percent of participants with best overall response of complete response (CR) or partial response (PR). Complete response via PET-CT: * Lymph nodes/extralymphatic: Score 1, 2, 3a with/without residual mass on 5-point scale * New lesions: No * Bone marrow: No FDG-avid disease Complete response via CT scan: * Lymph nodes/extralymphatic: Target nodes/nodal masses ≤ 1.5 cm longest transverse diameter. * Nonmeasured lesion: None * New lesions: No * Bone marrow: Normal Partial response via PET-CT: * Lymph nodes/extralymphatic: Score 4, 5b, reduced uptake from baseline * New lesions: None * Bone marrow: Residual uptake higher than normal, reduced from baseline Partial response via CT scan: * Lymph nodes/extralymphatic: 50% decrease in sum of diameters of \<= 6 target measurable nodes/extranodal sites * Nonmeasured lesion: None/normal * Organ enlargement: Spleen length decreased \> 50% * New lesions: No
Complete Response Rate (CRR)	From JCAR017 infusion until disease progression, end of study, the start of another anticancer therapy, or hemopoietic stem cell transplant (HSCT) (up to approximately 63 months)	Complete response rate is defined as percentage of participants achieving a best overall response of complete response. Complete response via PET-CT: * Lymph nodes/extralymphatic: Score 1, 2, 3a with/without residual mass on 5-point scale * New lesions: No * Bone marrow: No FDG-avid disease Complete response via CT scan: * Lymph nodes/extralymphatic: Target nodes/nodal masses ≤ 1.5 cm longest transverse diameter. * Nonmeasured lesion: None * New lesions: No * Bone marrow: Normal Complete response (CR) (Cohort 5): * Brain imaging: No contrast enhancement * Corticosteroid dose: None * Eye examination: Normal * Cerebrospinal fluid cytology: Negative Complete response unconfirmed (CRu) (Cohort 5): * Brain imaging: No contrast enhancement, Minimal abnormality * Corticosteroid dose: Any * Eye examination: Normal, minor RPE abnormality * Cerebrospinal fluid cytology: Negative
Event Free Survival (EFS)	From JCAR017 infusion to death due to any reason, progressive disease, or starting a new anticancer therapy (up to approximately 63 months).	Event-free survival is from JCAR017 infusion to death from any cause, progressive disease, or starting a new anticancer therapy. If a participant did not have an EFS event prior to data cutoff, EFS was censored at last disease assessment. Progressive disease (PD): * Target nodes/nodal masses: PPD progression. * Extranodal lesion: LDi \> 1.5 cm and increase by ≥ 50% from PPD nadir. * Splenomegaly: \> 50% of prior increase from baseline or by at least 2 cm from baseline. * Nonmeasured lesions: New or clear progression. * New lesions: Regrowth of previously resolved lesions. * Bone marrow: New or recurrent Progressive Disease (Cohort 5): * Brain imaging: \> 25% increase in enhancing lesion from baseline or best response. * Eye Exam: Increased vitreous cell counts or progressive retinal or optic nerve infiltration. * New lesion or site of disease
Progression Free Survival (PFS) Using European Medicines Agency (EMA) Criteria	From JCAR017 infusion to progressive disease or death due to any reason, whichever occurred first (up to approximately 63 months)	Progression-free survival is defined as the interval from the date of JCAR017 infusion to progressive disease or death due to any cause, whichever occurred first. Per European Medicines Agency (EMA) criteria, participants who did not experience progressive disease and who did not die before the data cutoff date were censored at the time of the last visit with adequate response assessment when the participants were known not to have progressed. Estimated using Kaplan-Meier product-limit estimates.
Overall Survival (OS)	From the date of JCAR017 infusion to the date of death due to any reason (up to approximately 63 months).	Overall survival is defined as the interval from the date of JCAR017 infusion to the date of death due to any reason. Data from surviving participants was censored at the last time that the participant was known to be alive. Estimated using Kaplan-Meier product-limit estimates.
Duration of Response (DOR)	From JCAR017 infusion until disease progression, death due to any reason, end of study, the start of another anticancer therapy, or hemopoietic stem cell transplant (HSCT) (up to approximately 63 months)	DOR is from first response (complete response (CR), CR unconfirmed (CRu) or partial response (PR)) to progression (PD) or death. Those without PD or death were censored at the last assessment. CR via PET-CT: Lymph/extralymph: Score 1/2/3a w/w-out resid mass, no new lesions, No FDG-avid disease in bone marrow (BM) CR via CT scan: Lymph/extralymph: Target/nodal ≤ 1.5 cm, no new lesions, normal BM CR Cohort 5: No contrast enhance, no corticosteroid, normal eye exam, neg CSF cytology CRu Cohort 5: No contrast enhance, min abnorm, normal eye exam, neg CSF cytology PR via PET-CT: Lymph/extralymph: Score 4/5b, red uptake, no new lesions, resid uptake incr, reduced in BM PR via CT scan: Lymph/extralymph: 50% decr in sum of diam ≤ 6 target/extranodal, no new/nonmeasured lesions, Organ enlarge: Spleen decr \> 50% PR Cohort 5: 50% decr in enhancing tumor, no contrast enhance, Eye exam: Minor abnorm, decr in vitreous cells/retinal infiltrate, negative, persist or suspic CSF cytology.
Maximum Concentration (Cmax) of JCAR017 by qPCR	At baseline and up until 24 months post JCAR017 infusion	Cmax is the maximum or peak concentration of drug reached in the plasma following a dose of the drug. Quantitative polymerase chain reaction (qPCR) was used to determine Cmax by detecting the JCAR017 transgene. Baseline is defined as the last available recorded value on or prior to the date of JCAR017 infusion.
Time to Peak Concentration (Tmax) of JCAR017 by qPCR	At baseline and up until 24 months post JCAR017 infusion	Time to maximum concentration (Tmax) is the time it takes for a drug to reach the maximum concentration (Cmax) after administration. Quantitative polymerase chain reaction (qPCR) was used to determine Tmax by detecting the JCAR017 transgene. Baseline is defined as the last available recorded value on or prior to the date of JCAR017 infusion.
Total Exposure to JCAR017 as Measured by Area Under the Curve (AUC) of JCAR017 by qPCR	At baseline and up until 24 months post JCAR017 infusion	Area Under the Curve (AUC) represents the total exposure of participants to study drug. Quantitative polymerase chain reaction (qPCR) was used to determine AUC by detecting the JCAR017 transgene. Baseline is defined as the last available recorded value on or prior to the date of JCAR017 infusion.
Percent of Participants With Presence of JCAR017 Transgene in Peripheral Blood by qPCR	At Day 29 and Months 2, 3, 6, 9, 12, 18, and 24 post JCAR017 infusion.	Persistence is defined as a transgene count greater than or equal to the lower limit of detection (LLOD) of 5 copies per reaction. Data obtained after the start of a new anti-cancer therapy were excluded. qPCR = Quantitative polymerase chain reaction.
Change From Baseline in European Organisation for Research and Treatment of Cancer - Quality of Life C30 Questionnaire (EORTC QLQ-C30) Scores	At baseline and Day 1, 29, 60, 90, 180, 270, 365, 545, and 730 post JCAR017 infusion.	The EORTC QLQ-C30 consists of five functional scales (physical, role, emotional, cognitive, social), three symptom scales (fatigue, nausea/vomiting, pain), a global health status/health-related quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties). The questionnaire is scored on a 4-point Likert scale: 1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much. The raw score is the average of the items contributing to the scale. The final scores are calculated via linear transformation of raw scores and range from 0 to 100. For functional scales higher scores indicate better QoL. For symptom scales and single items lower scores indicate fewer symptoms, i.e. better QoL. Baseline the last available recorded scores on or prior to the date of JCAR017 infusion. Only global health, fatigue, physical and cognitive functioning subscales were assessed.
Change From Baseline in Functional Assessment of Cancer Treatment-Lymphoma "Additional Concerns" Subscale (FACT-LymS) Scores	At baseline and Day 1, 29, 60, 90, 180, 270, 365, 545, and 730 post JCAR017 infusion.	The Functional Assessment of Cancer Treatment-Lymphoma "Additional concerns" subscale (FACT-LymS) consists of the FACT-General scale and a 15-item lymphoma-specific additional concerns subscale (LYM). This scale addresses symptoms and functional limitations that are important to lymphoma patients. Only the LYM subscale was administered in this study. The LYM items are scored on a 0 ("Not at all") to 4 ("Very much") response scale. Items are aggregated to a single score on a 0-60 scale. Lower scores indicate better health outcomes. Baseline the last available recorded scores on or prior to the date of JCAR017 infusion.

Trial Locations

Locations (20): Local Institution - 402
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Milan, Italy
Local Institution - 501
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London, United Kingdom
Local Institution - 502
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Manchester, Lancashire, United Kingdom
Local Institution - 602
🇯🇵
Minato-ku, Tokyo, Japan
Local Institution - 601
🇯🇵
Chuo-ku, Tokyo, Japan
Local Institution - 451
🇪🇸
Barcelona, Spain
Local Institution - 153
🇩🇪
Ulm, Germany
Local Institution - 301
🇳🇱
Rotterdam, Netherlands
Local Institution - 101
🇦🇹
Wien, Austria
Local Institution - 351
🇧🇪
Gent, Belgium
Local Institution - 551
🇫🇮
Helsinki, Finland
Local Institution - 202
🇫🇷
Lille, France
Local Institution - 152
🇩🇪
Dresden, Germany
Local Institution - 203
🇫🇷
Paris Cedex 10, France
Local Institution - 201
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Pierre Benite cedex, France
Local Institution - 155
🇩🇪
Heidelberg, Germany
Local Institution - 151
🇩🇪
Köln, Germany
Local Institution - 154
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München, Germany
Local Institution - 401
🇮🇹
Torino, Italy
Local Institution - 251
🇨🇭
Bern, Switzerland