A global randomized multicenter Phase 3 trial to compare the efficacy and safety of JCAR017 to standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (TRANSFORM)

Disease Background
Non-Hodgkin lymphomas (NHLs) comprise a heterogeneous group of malignancies.
Within Europe, the incidence of NHL is approximately 49,533 new cases annually
with 20,347 deaths per year.

In the United States (US), it is estimated that approximately 72,580 new cases
of NHL will be diagnosed and approximately 20,150 subjects will die of their
disease per year.

Diffuse large B-cell lymphoma is the most frequent lymphoma subtype,
representing approximately 30% of all NHL.
Diffuse large B-cell lymphoma is a heterogeneous disease with several
histological and molecular subtypes. The largest subgroup is DLBCL.
Despite follicular lymphoma being an indolent lymphoma type, follicular
lymphoma Grade 3B is regarded as an aggressive lymphoma. Clinical behavior is
very similar to DLBCL, and follicular lymphoma frequently undergoes
histological transformation into DLBCL.
Despite overall improvement in outcomes of DLBCL, approximately one-third of
subjects do not respond to initial therapy or will relapse (relapsed/refractory
[R/R] disease) that remains a major cause of mortality.

Compound Background: CD19 as a Therapeutic Target
CD19 is a 95-kDa glycoprotein present on B-cells from early development until
differentiation into plasma cells. It is a member of the immunoglobulin
superfamily and a component of a B-cell surface signal transduction complex
that positively regulates signal transduction through the B-cell receptor.

CD19 is an attractive therapeutic target because it is expressed by most B-cell
malignancies, including B-cell NHL. Importantly, the CD19 antigen is not
expressed on hematopoietic stem cells or on any normal tissue apart from those
of the B-cell lineage.

JCAR017 Investigational Drug Product
The final JCAR017 investigational drug product (also known as lisocabtagene
maraleucel or liso-cel) includes two individually formulated CD4+CAR+ and CD8+
CAR+ frozen T cell suspensions in media containing dimethyl sulfoxide (DMSO)
that are thawed and infused separately. JCAR017 is administered by intravenous
(IV) infusion.

The CD19-specific CAR and truncated human epidermal growth factor receptor
(EGFRt) are introduced into autologous CD8+ and CD4+ T cells ex vivo using a
replication-incompetent, self inactivating lentiviral vector. The
CD19-specific CAR includes an scFv binding domain derived from a murine
CD19-specific monoclonal antibody (mAb; FMC63) and 4-1BB and CD3* chain
signaling domains. The EGFRt protein is expressed as a separate cell surface
protein for purposes of cell tracking.

Please refer to the Investigator*s Brochure for detailed information concerning
the available pharmacology, toxicology, clinical studies, and adverse event
profile of the investigational product (IP).

Primary Objective:
To compare the efficacy in subjects treated with JCAR017 versus subjects
treated according to standard of care (SOC) defined as event-free survival
(EFS)

Key Secondary Objectives:
To compare additional parameters of efficacy in subjects treated with JCAR017
versus subjects treated according to SOC defined as complete response rate
(CRR), progression-free survival (PFS), and overall survival (OS)

Secondary Objectives:
• To compare other parameters of efficacy, defined as duration of response
(DoR), overall response rate (ORR), and PFS on next line of treatment (PFS-2)
• To compare efficacy rates (EFS, PFS, OS) at 6, 12, 24 and 36 months after
randomization
• To compare safety defined as type and frequency of adverse events (AEs),
serious adverse events (SAEs), and laboratory abnormalities
• To compare the safety and efficacy in clinical, histological and molecular
subgroups
•


For other secondary objectives please refer to the protocol.

This is a randomized, open-label, parallel-group, multi-center, Phase 3 study
to demonstrate the efficacy and safety of JCAR017 (also known as lisocabtagene
maraleucel or liso-cel) versus SOC salvage therapies in subjects with
aggressive B-cell NHL (defined as diffuse large B-cell lymphoma [DLBCL] not
otherwise specified [NOS], de novo or transformed indolent NHL), high grade
B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL
histology (double-hit lymphoma/ triple-hit lymphoma [DHL/THL]), primary
mediastinal (thymic) large B-cell lymphoma [PMBCL], T cell/histiocyte-rich
large B-cell lymphoma [THRBCL] or follicular lymphoma Grade 3B [FL3B]) who are
refractory to front-line immunochemotherapy or have relapsed within 12 months
and are eligible for HDCT and HSCT. The time of relapse is calculated from the
date of the first disease assessment confirming a complete response (CR)
obtained with first-line treatment for disease under study, to the date of
first assessment demonstrating a relapse.

During screening, a tumor biopsy will be collected for central confirmation of
diagnosis.

During screening, all subjects will undergo an unstimulated leukapheresis to
enable JCAR017 product generation.

Subjects will be randomized to receive either:
• Arm A (SOC): three cycles of SOC salvage therapy. Responding subjects are
expected to proceed to HDCT and HSCT
• Arm B (JCAR017): lymphodepleting (LD) chemotherapy followed by JCAR017
infusion

Subjects in Arm B may receive bridging therapy with a protocol-defined SOC
regimen to stabilize their disease during JCAR017 manufacturing.
Investigational therapies are not allowed.

Subjects will be followed for safety and efficacy for up to 3 years under this
protocol.

If requested by the investigator, subjects in Arm A may be allowed to receive
JCAR017 upon central confirmation of one of the following criteria:
• Failure to achieve CR or PR by 9 weeks post-randomization (after 3 cycles of
SOC)
• Progression at any time
• Need to start a new antineoplastic therapy due to efficacy concerns after 18
weeks post-randomization

Subjects who cross over to JCAR017 will be followed in the study for up to 1
year after the JCAR017 infusion. All subjects who received JCAR017 will
continue to be monitored for long-term safety and efficacy after exposure to
gene-modified T cells under a separate long-term follow-up (LTFU) protocol for
up to 15 years after JCAR017 infusion, as per competent authority guidelines.

The conduct of the study will be overseen by a scientific steering committee
(SSC).

The study will be conducted in compliance with International Council for
Harmonisation (ICH) Good Clinical Practices (GCPs).

Standard of care chemotherapy (Arm A) or experimental therapy (Arm B)

Arm B:

LD chemotherapy with intravenous (IV) fludarabine (30 mg/m2/day for 3 days)
plus cyclophosphamide IV (300 mg/m2/day for 3 days) (flu/cy) concurrently
followed at least 2 days later by JCAR017 infusion (100 x 10(to 6) chimeric
antigen receptor [CAR]+ T cells)

Participation in the study will involve risks from the study procedures, from
treatment with lymphodepleting chemotherapy and from treatment with JCAR017.
The two most significant side effects that have been observed to occur with
genetically modified T cells in previous studies are cytokine release syndrome
(CRS) and neurologic toxicity.
Participation in the study also means additional time from participants (up to
24 hospital visits), additional or longer hospital stays up to 14 days,
additional tests and instructions to be followed.

Although, the risks are significant for the participating subjects, they are
acceptable when balanced against the anticipated efficacy of JCAR017 in this
disease population provided that there is meticulous clinical management.

JCAR017 offers substantial potential clinical activity to patients with
relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL). Current
clinical data demonstrated that the remission rate for relapsed DLBCL subjects
treated with JCAR017 is significantly improved compared to historical data.
Therefore, JCAR017 may provide an opportunity to increase the rates and
duration of remissions thereby potentially extending survival for a population
with historically dismal clinical outcomes. Currently available treatments for
relapsed or refractory DLBCL have limited activity. The prognosis is poor,
especially for subjects having relapsed after multi-agent salvage chemotherapy
and ASCT, or are ineligible to transplant.

Despite recent advances in the treatment of B-cell malignancies, many patients
relapse or have refractory disease and remain incurable with current treatment
options. Novel therapies are therefore urgently needed.

In conclusion, the current benefit-risk profile for JCAR017 after
administration of the lymphodepleting chemotherapy is considered acceptable in
the proposed clinical study given the potential for a durable remission, the
overall manageable safety profile, and the plan for risk mitigation of
potential safety concerns associated with JCAR017 administration, including
routine trial safety surveillance practices.