A dose-escalation, open label phase I study to assess the safety, feasibility and preliminary efficacy of HA-1H TCR modified T cells, MDG1021, in patients with relapsed or persistent hematologic malignancies after allogeneic hematological stem cell transplantation with or without unmanipulated donor lymphocyte infusion.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment
of choice for a number of otherwise incurable hematologic malignancies. The
elimination of malignant cells after allo-HSCT or donor lymphocyte infusion
(DLI) results in part from a *graft versus leukemia or graft versus
lymphoma* (GVL) effect that is mediated by donor T cells recognizing
polymorphic minor histocompatibility antigens (MiHAs) on recipient cells. MiHAs
are encoded by polymorphic genes, presented as peptides bound to MHC molecules
on recipient cells, i.e. malignant cells, that may elicit immune responses when
they are recognized by effector T cells. The MiHA HA-1H that is highly
expressed in leukemia and normal hematopoietic cells, but not on cells outside
of the hematopoietic system, is a compelling target for immunotherapy after
allo-HSCT with or without DLI in a constellation of a donor not carrying the
immunogenic HA-1H variant and the recipient having the immunogenic HA-1H
variant. The MiHA HA-1H is presented on HLA-A*02:01
Hence, an adoptive immunotherapy using HLA-A*02:01 restricted HA-1H TCR T cells
targeting the immunogenic form of HA-1H harbors the potential to cause a the
therapeutic antileukemic effect and minimize other toxicities, while
potentially ensuring durable remission.
In the general population, approximately 25% of people present both HA-1 and
the HLA-A*02:01-restricting allele. About 15% to 20% of patients who undergo
allo-HSCT or DLI for their hematological malignancy would be suitable for HA-1H
TCR T cell immunotherapy when the donor has an HA-1H or HLA-A02 mismatch.
This constitutes the rationale to conduct a phase I study to assess the safety,
feasibility as well as to evaluate preliminary efficacy of the administration
of HA-1H TCR transduced patients own T cells (MDG1021) and establish its
maximum tolerated dose (MTD) or recommended dose for development (RP2D).

Primary objectives for the dose-escalation part of the study:
• To assess the safety and tolerability of HA-1H TCR transduced T cells
(MDG1021) in patients with relapsed or persistent hematologic malignancies
after allo-HSCT with or without unmanipulated DLI.
• To establish the MTD and/or RP2D of MDG1021.
Primary objective for the expansion part of the study:
To assess the safety and tolerability, as assessed by NCI CTCAE v5.0, of HA-1H
TCR transduced T cells (MDG1021) at the selected RP2D in relapsed or persistent
hematologic malignancies after allo-HSCT with or without unmanipulated DLI.

Secondary objective for both parts of the study:
• To evaluate clinical response to MDG1021, including overall response (ORR),
overall survival (OS), progression free survival (PFS) and duration of response
(DoR)
To assess the quality of life

Feasibility objective for both parts of the study:
To assess the feasibility of manufacturing and administering of MDG1021

Exploratory objectives for both parts of the study:
• To evaluate HA-1H TCR transduced T cells with respect to in vivo
expansion and persistence.
• To evaluate HA-1H TCR transduced T cells function and phenotype in vivo and
in vitro
• To investigate biomarkers and molecular signatures, potentially related to
safety, anti-tumor activity, the mode-of-action of MDG1021 and / or the
pathophysiology of the disease
• To evaluate disappearance of recipient hematopoiesis (chimerism analysis)

A dose-escalation, open label phase I study to assess the safety, feasibility
and preliminary efficacy of HA-1H TCR modified T cells, MDG1021, in patients
with relapsed or persistent hematologic malignancies following allogenic
hematological stem cell transplantation (allo-HSCT) with or without
unmanipulated DLI.
After having provided signed informed consent, subjects will undergo testing
for eligibility to participate in the phase I study. Eligible subjects must
have a positive genotype for HLA-A*02:01 and HA-1H (i.e. the immunogenic form
of HA-1), while the donor must either be HLA-A*02:01 positive but negative for
HA-1H or have a single HLA mismatch being HLA-A*02:01 negative. Furthermore, at
least 10x10^6 donor CD8+ T cells should be harvested by leukapheresis from the
patient to initiate MDG1021 production.
The aim of the study is to determine the RP2D of MDG1021 that will be
determined on the basis of safety and ability to manufacture a cohort specific
MDG1021 dose. The dose-escalation part of the study is designed to assess the
safety and the MTD of MDG1021, using a standard 3+3 cohort design, with up to 3
additional subjects to be enrolled in case of dose limiting toxicity (DLT).
Subjects will receive the investigational medical product (IMP) on study day 1
by a single IV transfusion and will remain in the study for 1 year. Thereafter,
the patient will be offered to participate in a long-term follow-up study as
mandated by the regulatory requirements for gene modified advanced therapy
medicinal products (ATMP).
The MTD is defined as the highest dose level of MDG1021 at which not more than
1 patient experiences a DLT in a specific dose cohort, assessed by National
Cancer Institute common terminology criteria for adverse events (NCI CTCAE
v5.0) and further defined below.
The data monitoring safety board (DSMB) will be involved in the decision to
escalate to the next dose level of MDG1021.
The first MDG1021 cohort will include 3 eligible subjects to receive Dose 1
(D1). If no DLT occurs the D2 dose cohort of MDG1021 will be initiated. If for
1 out of 3 subjects DLT occurs, up to 3 additional subjects will receive D1. If
1 out of 6 subjects have a DLT, the RP2D for MDG1021 is defined to be D1,
unless the DSMB recommends to escalate to D2. If > 1 subject have a DLT, the
study may be discontinued, pending recommendation of the DSMB.
The second MDG1021 cohort will include 3 eligible subjects to receive Dose 2
(D2). If no DLT occurs the D3 dose cohort of MDG1021 will be initiated. If 1
out of 3 subjects DLT occurs, of up to 3 additional subjects will receive D2.
If 1 out of 6 subjects have a DLT, the RP2D for MDG1021 is defined to be D2,
unless the DSMB recommends to escalate to D3. If > 1 subjects have a DLT, the
RP2D for MDG1021 is defined to be D1.
The third MDG1021 cohort will include 3 eligible subjects to receive Dose 3
(D3). If for 1 out of 3 subjects DLT occurs, up to 3 additional subjects will
receive D3. If 1 out of 6 subjects have a DLT, the RP2D for MDG1021 is defined
to be D3. If > 1 subject have a DLT, the RP2D for MDG1021 is defined to be D2.
Manufacturing could potentially result in an out of specification (OOS) IMP,
however, since this is a patient derived, patient specific, last treatment
option material, every effort will be made to make it available for treatment
due to ethical reasons. Patients, who are treated with OOS IMP, will be
analyzed in the full analysis data set (FAS), but not in the per protocol data
set (PP).
A DLT event is defined as any of the following events occurring at any dose
level of the dose escalation part of the study, excluding toxicity that is
clearly and directly related to disease progression or intercurrent illness:
• Graft versus host disease (GVHD): Onset of acute GVHD overall grade >= III
within 4 weeks after IMP administration
• Hematological DLT: Prolonged cytopenia CTCAE grade >= 4 not resolved at day
28, newly developed and not attributable to underlying disease, bridging or
lymphodepleting regimen
• Non-hematological DLT: Any CTCAE Grade >= 3 toxicity will be considered as DLT
except from:
• Cytokine release syndrome (CRS; CRS graded according Lee et al. 2018) CTCAE
grade 3
• CRS CTCAE grade 4 responding to treatment within 48 h (Lee et al., 2018)
• aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
increase CTCAE grade 3 that does resolve to <= Grade 1 within 14 days
• Nervous system disorders CTCAE grade 3 in the absence of CRS
• Nervous system disorders CTCAE grade 4 in the absence of CRS that do respond
to treatment within 48 hours
• Transfusion-related toxicities that can be treated or controlled to grade <= 2
by medical management
• Tumor lysis syndrome (TLS) CTCAE grade 3
• TLS CTCAE grade 4 that does resolve within 7 days
• Electrolyte abnormalities CTCAE grade 3
• Electrolyte abnormalities of CTCAE grade 4 that do resolve to <= grade 2
within 72 hours with or without treatment
• Isolated asymptomatic elevations of biochemical laboratory values
which respond to medical intervention
• Fatigue
Any other unacceptable toxicity at least possibly related to the transfusion of
MDG1021 in the view of the investigator and the DSMB.
Upon completion of the dose-escalation part of the study, 20 eligible patients
will be treated in the expansion part of the study with MDG1021 at the RP2D to
further evaluate safety, feasibility and preliminary efficacy.

MDG1021, the IMP, is a gene modified ATMP which contains autologous T cells,
expressing the HLA-A*02:01 restricted TCR targeting HA-1H, in a 0.9% saline
solution with human serum albumin in a total volume of 100 mL in a standard
infusion bag.
Three dose levels of MDG1021 will be investigated to determine the RP2D. The
following dose levels will be administered by a single intravenous (IV)
transfusion up to 30 minutes:
• D1: target dose of 0.3x10^6 HA-1H transduced T cells/kg BW ±20% in 100 mL
• D2: target dose of 1x10^6 HA-1H transduced T cells/kg BW ±20% in 100 mL
• D3: target dose of up to 3x10^6 HA-1H transduced T cells/kg BW ±20% in 100
mL, whereas the lower range for D3 is >D2 (i.e. >1.2x10^6)
The following rules apply to IMP administration:
• Dose calculation will not be increased above 120 kg body weight.
• In case of BW decrease of >20% between screening and IMP administration the
dose will be adjusted by limiting the infused volume of the IMP accordingly to
the maximum dose allowed
• In case of a serious intolerability event it should be evaluated, according
to the patient situation and the administered dose, whether the IMP
administration should continue, interrupted or discontinued. A rescue therapy
correlating to the seriousness of symptoms should be initiated when appropriate.
• Manufacturing could potentially result in an out of specification (OOS)
product, however, since this is a patient derived, patient specific, last
treatment option material, every effort will be made to make it available for
treatment due to ethical reasons:
o If all safety release criteria are met (free of microbial contamination
etc.), but not all parameters regarding identity, potency or purity (i.e.
transduction rate), then the IMP can be administered after a decision by the
investigator that is supported by the sponsor, although a certification by the
qualified person (QP) might be missing.
o If the dose of the IMP per kg body weight could not be reached during
manufacturing, the IMP can be administered, after a decision of the
investigator that is supported by the sponsor, even without certification by
the QP, if a minimal dose of at least 0.3x10^6 ±20% cells/kg BW can be
achieved.

The infusion of HA-1H TCR transduced T cells can suppress and cure blood or
bone marrow disease, but there is no certainty. Disadvantages of taking part in
the study can include the possible side effects and detrimental effects.