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

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.

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.

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.

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.

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 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 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 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 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.

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.

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 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.

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.

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.

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.

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.