A phase I/II, multicenter study evaluating the feasibility, safety, and efficacy of point-of-care manufactured 19CP02 in subjects with relapsed/refractory B-cell non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) comprises of a heterogenous group of lymphoid
malignancies, originating primarily from B lymphocytes, and to a lesser extent
from T lymphocytes and NK cells. In 2020, the reported incidence and mortality
in Europe were approximately 120.000 and 50.000 respectively. NHL are largely
comprised of mature B-cell neoplasms, which can be divided into two main
subgroups; indolent and aggressive lymphoma subtypes. Follicular lymphoma (FL)
and marginal zone lymphoma are prevalent forms of the indolent subtype, while
diffuse large B-cell lymphoma (DLBCL) and most forms of mantle cell lymphoma
(MCL) are of aggressive nature.
In recent years, several new therapies to treat NHL have been approved. These
treatments have significantly increased the overall survival rates for
patients. Despite this progress however, a large group of patients will relapse
eventually. Especially patients with primary treatment failure have a poor
prognosis.
Anti-CD19 CAR T cell therapy has proven to be a breakthrough in the treatment
of hematological malignancies with impressive response rates after a single
treatment. However, current implementation of these novel treatments in
clinical practice worldwide faces several challenges, such as the long
vein-to-vein time (from apheresis to treatment) ranged from 23 to 54 days
resulting in drop-out rates up to 33%. Also, the majority of patients requires
bridging therapy. In addition, the manufacturing comes with high costs and
logistics are very complicated.
By providing CAR T-cell manufacturing at the point-of-care, in a facility in or
in the near proximity of the clinical center, it is the aim to shorten the
vein-to-vein time to 1 week and administer a fresh product to the patient. A
fast manufacturing process is expected to improve overall clinical outcomes by
lowering drop-out rates and reducing the need for bridging therapy. If the
expected safety and efficacy can be proven, the point-of-care model has the
potential to address the current unmet medical need for r/r NHL patients.

This study has been transitioned to CTIS with ID 2022-502661-23-00 check the CTIS register for the current data.

The primary objective of the study is to evaluate the feasibility, safety, and
efficacy of point-of-care manufactured 19CP02 in subjects with
relapsed/refractory B-cell non-Hodgkin lymphoma.
In the phase I part of the study the main objective is to evaluate the safety
of 19CP02 and determine the recommended Phase 2 dose (RP2D).
In the phase II part of the study the main objective is to evaluate the
efficacy of 19CP02 in the different NHL subtypes.

Secondary objectives of the study:
# Evaluate safety of 19CP02
# Evaluate efficacy of 19CP02
# Evaluate 19CP02 pharmacokinetics and pharmacodynamics
# Evaluate feasibility of 19CP02 manufacturing

This is a phase I/II, multicenter, non-randomized, open label study.
In the phase I part of the study approximately 15 subjects with r/r NHL will be
included via a dose escalation strategy based on the Bayesian Optimal INterval
(BOIN) design. Based on the different dose levels and pre-specified
dose-limiting toxicities (DLT), the recommended phase II dose (RP2D) can be
determined.
In the phase II part of the study up to 30 additional subjects per disease
cohort (based on NHL subtype) may be enrolled. The sponsor may decide to open
one or multiple cohorts for enrollment, based on outcomes from the Phase I part
of the study.

# Leukapheresis of mononuclear cells
# Lymphodepletion chemotherapy regimen for 3 days consisting of
Cyclophosphamide IV 300 mg/m2/day and Fludarabine IV 30 mg/m2/day
# Infusion of 19CP02 consisting of a single fixed dose of autologous anti-CD19
CAR-positive T cells at the designated dose level

The study consists of a screening period, leukapheresis, 3 days of
chemotherapy, treatment at the clinic (with at least 7 days of
hospitalization), a stay in 1-hour proximity of the clinic until day 28,
intensive monitoring during the first six months, and from month 6 onwards a
3-monthly visit until month 24 or progressive disease. Long term follow-up
until a maximum of 15 years after treatment will be continued under a different
protocol. During each visit, multiple assessments will be conducted. Especially
during hospitalization, the subjects will be monitored for AEs intensively. The
subject can consider this as a burden.
Risks for subjects through study participation are mainly comprised of
(serious) adverse events as CRS, TLS, neurotoxicity, B-cell aplasia,
hypogammaglobulinemia and (serious) infections.
These potential (severe) side effects are explained in the patient information
sheet and it is of critical importance the investigator reviews these with the
potential subject prior to informed consent is given. The burden of additional
assessments and radiation exposure are approximately the same compared to when
the patient would receive different lymphoma treatment per institutional
guidelines.