A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies

Participants enrolled in Phase 1 are considered evaluable for DLTs if they received an infusion of conforming JCAR017 cell product and at least one dose of the combination agent and completed the specified DLT evaluation period or if they have received an infusion of conforming JCAR017 cell product and at least one dose of the combination agent and experience a DLT during the DLT evaluation period.

Percentage of participants achieving a complete response (CR). CR is complete radiologic response (CRR) and complete metabolic response (CMR). CR was measured using CT and PET and assessed for the presence of index and non-index lesions, spleen size, and the absence of new lesions or diseased bone marrow.

To be considered as having CRR participants had to have all of the following:

• Index lesions - longest transverse diameter of nodal lesions ≤ 1.5 cm and the absence of extranodal disease.
• Non-index lesions - the absence of non-index lesions.
• Spleen size <13 cm
• The absence of new lesions
• Normal bone marrow assessment

To be considered as having CMR participants had to have all of the following:

• A score of 1, 2, or 3 with or without residual mass on 5-PS for index and non-index lesions.
• The absence of new lesions
• No evidence of FDG-avid disease in marrow and a normal bone marrow assessment

The EORTC QLQ-C30 is composed of five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/health-related quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire is scored on a 4-point Likert response scale: 1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much.

The raw score is calculated as the average of the items that contribute to the scale. The final scores are calculated via linear transformation of raw scores and range from 0 to 100.

For functional scales (physical, role, emotional, social, cognitive and global health) higher scores indicate better QoL.

For symptom scales (fatigue, nausea and vomiting and pain) and single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) lower scores indicate fewer symptoms, i.e. better QoL.

The EuroQol- 5 Dimensions of Health Visual Analogue Scale (EQ-5D VAS) records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are scored from 0 to 100 i.e., 'The worst health you can imagine' (score of 0) to 'The best health you can imagine' (score of 100). Higher scores indicate better health outcomes.

An 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) is also considered an AE. All participants were monitored for AEs during the study. Assessments included monitoring of any or all of the following parameters: the participant's clinical symptoms, laboratory, pathological, radiological or surgical findings, physical examination findings, or findings from other tests and/or procedures.

An SAE is any AE occurring at any dose that:

• Results in death;
• Is life-threatening (i.e., 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.

White blood cell, and platelet counts. Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in percent of white blood cells was measured using differential blood tests. A differential blood test is a blood test that measures the percentage and number of each type of white blood cell (WBC) - neutrophils, lymphocytes, monocytes, eosinophils and basophils - as well as abnormal cell types if they are present. These results are reported as percentages and absolute values, and compared against reference ranges to determine whether the values are normal, low, or high. Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in erythrocyte (also known as red blood cell) numbers was measured using a test called a red blood cell count. Baseline is defined as the last measurement on or prior to any study treatment.

The change in the proportion of red blood cells in the blood was measured using a hematocrit test. A hematocrit test measures the volume of packed red blood cells relative to whole blood. This is represented as a ratio. Baseline is defined as the last measurement on or prior to any study treatment.

The change from baseline in hemoglobin levels was measured using a hemoglobin test. A hemoglobin test measures the levels of hemoglobin in the blood. Hemoglobin is a protein in red blood cells that carries oxygen from the lungs to the rest of the body. Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in alanine aminotransferase (ALT) alkaline phosphatase (ALP), and aspartate aminotransferase (AST). Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in serum albumin and protein levels. Serum protein level tests are blood tests that measure the number of proteins in the blood. Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in serum Beta-2-Microglobulin levels was measured using a beta-2 microglobulin (B2M) tumor marker test. Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in serum bicarbonate levels was measured using a serum bicarbonate test. Baseline is defined as the last measurement on or prior to any study treatment.

Change from baseline in activated partial thromboplastin and prothrombin times. Activated partial thromboplastin time and prothrombin time are blood tests that measure how long it takes for blood to form a clot. Baseline is defined as the last measurement on or prior to any study treatment.

D-dimer is a substance that is produced in the body when blood clots are broken down. The D-dimer laboratory test measures the level of D-dimer in the blood and is often used to help diagnose or rule out conditions related to blood clotting, such as deep vein thrombosis (DVT) or pulmonary embolism (PE). Elevated levels of D-dimer may indicate the presence of a blood clot, but other factors can also cause an increase in D-dimer levels. Therefore, the D-dimer test is typically used in combination with other diagnostic tests to help make an accurate diagnosis. Baseline is defined as the last measurement on or prior to any study treatment.

Fibrinogen is a protein that plays a role in a number of processes in the body, including blood clot formation, wound healing, inflammation, and blood vessel growth. Baseline is defined as the last measurement on or prior to any study treatment.

The Prothrombin International Normalized Ratio (INR) is used to determine the clotting tendency of blood. The INR is derived from prothrombin time (PT) which is calculated as a ratio of the patient's PT to a control PT. Baseline is defined as the last measurement on or prior to any study treatment.

PFS is defined as time from JCAR017 infusion to disease progression or death from any cause.

Progressive disease (PD) was measured using CT and PET as an increase in size index and non-index lesions, spleen size, and the presence of new lesions or diseased bone marrow.

Summarized using Kaplan-Meier estimates.

Time from JCAR017 infusion to death. Data from surviving participants was censored at the last time that the participant was known to be alive.

Summarized using Kaplan-Meier estimates.

The ORR is the percent of participants achieving an objective response of partial response (PR) or better according to the Lugano Criteria for Response Assessment (Cheson, 2014), prior to start of another non-study anticancer therapy.

Complete response (CR) assessed by CT-scan:

• Index lesions: Nodal Disease: ≤ 1.5 cm in largest transverse diameter, Extranodal Disease: Absent
• Non-index lesions: Absent,
• Spleen: <13 cm
• New lesions: None
• Bone marrow: Normal

Partial response (PR) assessed by CT-scan:

• Index lesions: >=50% decrease from baseline in shortest diameter
• Non-index lesions: No increase,
• Spleen: >50% decrease from baseline in enlarged portion
• New lesions: None
• Bone marrow: N/A Overall Response (OR) = CR + PR

DOR is defined as the time from first response to disease progression or death from any cause.

Summarized using Kaplan-Meier estimates.

EFS is defined as time from JCAR017 infusion to disease progression, starting a new antilymphoma therapy, or death from any cause, whichever occurred first.

Cmax is the maximum or peak concentration of drug reached in the plasma following a dose of the drug.

qPCR was used to determine Cmax by detecting the JCAR017 transgene.

Time to maximum concentration (Tmax) is the time it takes for a drug to reach the maximum concentration (Cmax) after administration.

qPCR was used to determine Tmax by detecting the JCAR017 transgene.

Area Under the Curve" (AUC) represents the total exposure of participants to study drug. qPCR was used to determine AUC by detecting the JCAR017 transgene.