Multicenter, open-label, adaptive design phase I trial with genetically modified T-cells carrying Universal Chimeric Antigen Receptors (UniCAR02-T) in combination with CD123 target module (TM123) for the treatment of patients with hematologic and lymphatic malignancies positive for CD123

The UniCAR platform is a next-generation modular CAR technology with *switch
on/switch off* mechanism allowing a repeated stop-go CAR T therapy to increase
patient safety. UniCAR02-T is a T-cell which harbors a chimeric antigen
receptor consisting of an extracellular antibody-derived binding moiety against
a peptide tag fused to combined intracellular signaling chains of human CD28
and CD3 zeta. Autologous human T-cells are genetically modified to UniCAR02-T
and re-infused into patients. A recombinant protein adaptor termed TM123 is
co-administered to patients. UniCAR02-T cells are cross-linked to
CD123-expressing leukemic cells by TM123 and eliminate targeted cells.
In this ongoing phase I trial, UniCAR02-T-CD123 leukemic blast reduction was
seen in the treatment of CD123 positive AML with relapsed or refractory disease
in Phase I. Blast reduction was observed in 8 out of 16 patients. Toxicities
were well tolerated or could be mitigated by pausing the Target Module (TM)
administration.
Protocol V10-0:
Based on the favorable safety and durable responses observed in patients
treated with 4 cycles of TM, in this amendment study patients will now be
offered further consolidation cycles to maximize treatment benefit. Treatment
can be continued until relapse, unacceptable toxicity, or potentially curative
treatment option (e.g. alloHSCT), for maximum treatment duration of 1 year
(starting in protocol Version 10).
Additionally, a phase 1b expansion of up to 20 patients will be initiated to
further characterize safety, inform optimal dose selection for phase 2 (RP2D)
and confirm the preliminary evidence of clinical activity in a broader
population. The 20 patients will be randomized into 2 arms and treated with two
selected tolerated doses from the escalation phase. The patient population in
dose escalation has been focused on heavily pre-treated relapsed and/or
refractory AML patients (including patients in morphological remission who have
converted from MRD negative to MRD positive). The sponsor may also, based on
emerging study data, pause enrollment of any of the eligible populations (i.e.
R/R AML, MRD+ AML, BPDCN) if unacceptable toxicity within that population or
inadequate clinical activity is observed to warrant continued enrollment

Protocol V11-0:
The estimated DLT probability for the highest of 16 initially defined dose
levels after isotonic regression is 0.13, which is below the lower escalation
boundary of 0.157 indicating further escalation is reasonable. Also, duration
of response was limited thus far and more and deeper responses are deemed
necessary for successful treatment, which has led to amending the protocol to
re-initiate further TM123 dose escalation with up to two more dose levels.
Assessment of safety, PK-, engraftment- and response data will determine
whether escalation up until the highest TM dose level of 12 mg will be
performed. The decision on further escalation will be taken based on DSMB
recommendation and an assessment of the benefit/risk ratio for the patients in
order to avoid unnecessary high doses if no benefit is to be expected.
During a scientific advisory board held in December 2023, AML experts indicated
that the Lymphodepletion regimen used, existing of 30mg/m2 Fludarabine and
300mg/m2 Cyclophosphamide was relatively mild and conservative and might not
create the optimal conditions for optimal engraftment and expansion of the
CAR-T cells. Published literature on other CAR-T cells indicates usage of
higher doses of Cyclophosphamide and hence the dose of Cyclophosphamide will
now be increased to 600mg/m2 (Ramos et al. 2020; Sallman et al. 2022; Hirayama
et al. 2019; Saberian et al. 2021).
Relapsed and/or refractory AML patients often experience rapid progression and
are often not stable without treatment. This can provide challenges as
apheresis and manufacturing of CAR-T can take a considerable amount of time,
increasing the risk of progression and death prior to CAR-T treatment being
available or prior to CAR-T cells being able to expand in the patient and
actively eradicate leukemic blasts. Therefore, during the aforementioned
advisory board meeting it was recommended to reduce the maximum blast count at
entry of the study to 30% at screening (or below 40% in 2 consecutive
measurements at least 1 month and no more than 2 months apart). This is
implemented in V11 of the protocol along with exclusion of hyperproliferative
AML requiring cytoreductive treatment to decrease the number of pre-treatment
complications caused by rapidly progressing disease and thus provide a
realistic chance for patients to actually be treated with UniCAR02-T-CD123.

This study has been transitioned to CTIS with ID 2024-515827-12-00 check the CTIS register for the current data.

The primary objective of the phase 1a dose escalation was to assess the safety
and to determine the maximum tolerated dose and the incidence of dose limiting
toxicities (DLT) during the DLT period (infusion period of UniCAR02-T in
combination with TM123).

The primary objectives of the phase 1b expansion will be continued
characterization of the safety profile of the product, to establish the RP2D
and to further investigate the efficacy of UniCAR02-T in combination with TM123.

Key secondary objectives of both phases include additional evidence of
biological and clinical activity including best response rate, PFS and OS, as
well as response to consolidation cycles.

Open-label, adaptive design, multicenter, phase 1a dose escalation followed by
phase 1b dose expansion.

Initiation cycle (IC):
Following a preconditioning (lymphodepletion, LD) with 600 mg/m2
cyclophosphamide and 30 mg/m2 fludarabine for 3 days, intravenous (IV) infusion
of a single dose of UniCAR02-T is scheduled for day 1.
TM123 per dose level (maximum 12 mg/d) will be administered as continuous
infusion from day 1 four hours before UnCAR02-T onwards for 20 days. Infusion
of 500 million UniCAR02-T cell dose is administered on day 1. DLT evaluation
period will start on day 1 and lasts for additional 7 days after end of
infusion of TM123 (in total 28 days).
During UniCAR02-T production period, disease control with standard treatments
for refractory or relapsed leukemia is allowed until 7 days before start of LD.

Consolidation cycles (CC):
Each of the CCs will consist of 12 days of continuous TM123 administration (12
days x 24 hours of application), followed by a rest period of 7 - 14 days.
Patients who tolerate TM123 and UniCAR02 T and show no disease progression are
candidates for consolidation cycles(CCs). CC treatment will continue with the
same TM123 dose level assigned for the IC until relapse, unacceptable toxicity,
or potentially curative treatment option (e.g. alloHSCT), for maximum 1 year
since the start of the study treatment. Patients who do not qualify for a CC
will be followed up by continuing with EOT visits.

Safety follow-up will be after 3 and 6 months (12 and 24weeks) after start of
last TM123 application. For patients in continuing morphological CR (CR, CRh,
CRi) all additional disease status assessments and investigations will be
performed as per institutional standard of care, and will be recorded until
morphological relapse or the completion of the study.

Long-term follow-up will be performed annually and lasts in total 15 years from
date of last UniCAR02-T administration.

The study intervention per patient will last 20 days of TM123 infusion whereas
20 days count as active drug treatment period and is followed by a DLT
observation period of 7 days after the end of the TM123 infusion. For patients
benefitting from the treatment and receiving consolidation cycles, the
intervention will last until end of the last cycle.

The total study duration per patient lasts until last Safety FU after start of
last TM123 administration.
End of study is defined by the last safety follow up visit of the last treated
patient.

After end of study long-term FU will be performed annually for a period of 15
years from date of last UniCAR02-T administration. However, an initial clinical
study report will be generated after the last enrolled patient reaches the
6-month safety follow-up visit.

The studied investigational medicinal product is administered to humans for the
first time, therefore only very few data regarding possible side effects are
available so far. However, drugs similar in design and structure for the
treatment of leukemias or lymphomas have already been tested worldwide and have
also been approved by the authorities.
During study participation, side effects may occur due to the investigational
drug or as a result of study procedures. Some side effects will decrease in the
short term, and some side effects may persist for a longer period of time. It
must be considered that administration of UniCAR02-T-CD123 may cause serious
physical or organic damage or even death. However, unlike other CAR-T cell
therapies that have already been clinically tested, the studied investigational
compound UniCAR02-T-CD123 has a cut-off mechanism by stopping the infusion of
the target TM123 that can prevent the occurrence of severe side effects.