A Phase 1, Multinational Study of MCLA-117 in Acute Myelogenous Leukemia

Acute myelogenous leukemia (AML) is the third most common leukemia worldwide
with little progress in disease outcomes for the last four decades. In the
majority of patients who have achieved remission upon induction chemotherapy,
disease relapse is observed within 3 years. Thus, improving response rate and
prolonging duration of complete response (CR), preventing relapse, improving
disease-free survival and overall survival in both younger and older AML
patient population, are unmet medical needs. Similar to AML patients, high-risk
MDS patients have very limited therapeutic options once failed standard
therapies.

MCLA-117, a human bispecific IgG antibody which targets CLEC12A and CD3, has
demonstrated preclinical proof of concept using AML patient samples. Targeting
CLEC12A-expressing cells by MCLA-117 results in eradication of malignant blasts
and their leukemic stem cells in the BM, which might be effective in
eliminating minimal residual disease (MRD) and preventing disease recurrence.
The CD3 arm of MCLA-117 recruits T-cells to the AML cells coated with the
antibody through CLEC12A binding, triggering T-cell activation, proliferation
and subsequently lysis of the antigen-positive tumor cells. Similar to AML
patients, CLEC12A is expressed in myeloblasts in the majority of patients with
high-risk MDS. The full-length IgG1 immunoglobulin format of MCLA-117 enables
administration as a conventional intravenous infusion without the necessity of
a continuous infusion. In addition, the silencing of the Fc portion of MCLA-117
might mitigate to some extent the risk of severe cytokine release symptoms in
the absence of binding to the tumor-associated antigen (CLEC12A).

MCLA-117 has the potential of being developed as an induction or consolidation
therapy for AML, or to treat Minimal Residual Disease (MRD), and as a rescue
therapy for the relapsed/refractory target patient population. Clinical
development can be explored both as single agent and in combination with
chemotherapy agents in AML. The safety profile of MCLA-117 is expected to be
acceptable with manageable neutropenia and infusion-related reactions.

Primary:
To assess the safety and tolerability of MCLA-117, in order to determine the
MTD/RP2D and frequency of administration.
Secondary:
- To assess the pharmacokinetic (PK) profile of MCLA-117 i.v. infusion
- To investigate the pharmacodynamic (PD) effects of MCLA-117 in adult AML
patients
- To determine incidence and serum titer of ADAs against MCLA-117
- To determine the cytokine profile of MCLA-117 in adult AML patients
- To evaluate the preliminary efficacy/ anti-leukemic activity of MCLA-117 in
adult AML patients

This First-in-Human, single arm, open-label, multi-national study is designed
to determine the safety, tolerability and preliminary efficacy of MCLA-117, a
full-length human IgG1 T cell redirecting bispecific antibody targeting CLEC12A
in patients with AML. The dose and frequency of the administration of MCLA-117
to be used in further clinical studies will be determined. In addition, the
preliminary PK profile, anti-drug antibodies (ADA) incidence and titer,
cytokine profile will be determined. Relevant biomarker identification will be
explored.
The study consists of two parts:
Part 1-Dose Escalation
Dose escalation cohorts with single agent MCLA-117 are planned to determine the
safety and tolerability of MCLA-117 and identify the maximum tolerated dose
(MTD) and/or recommended phase 2 dose schedule (RP2DS). Dose escalation starts
with two-patient cohorts, allowing intra-patient dose escalations until a PD
effect is observed (e.g., treatment-related adverse events, or a reduction in
BM cellularity or blast count, or reaching a dose level at which a clinically
meaningful response could be expected). From cohort 3, the design switches to a
3+3 dose escalation method with at least 33% dose increments until
dose-limiting toxicity (DLT) occurs or the RP2DS is defined. From cohort 7
onwards, patients are not preselected for CLEC12A expression level *10%.
Therefore, a modified 3+3 design is used, termed the "A+B" design (Lin and
Shih, 2001; Le Tourneau et al, 2009) with initial patient enrollment per cohort
of 3-6 patients upfront to ensure the representation of patients with CLEC12A
expression level *10%. Patients who do not complete the DLT observation period
will be replaced unless treatment discontinuation is due to DLT. DLTs will be
determined based on predefined criteria for hematologic and non-hematologic
toxicities. Adverse events (AEs) will be graded according to the National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE),
version 4.03.
A cohort review session by a Data Review Committee (DRC) with attendance of
study Investigators and relevant study team members will take place at
completion of the DLT observation period of each dose cohort. Additional
experts may be invited to attend when deemed necessary by the Sponsor or study
investigators. At this review session, a decision will be made on whether to
open the next cohort and at which dose level and dosing frequency. In addition,
the DRC will recommend measures to be taken to optimize the medical management
of possible IRRs following administration of MCLA-117.
Part 2-Expansion Cohort
Part 2 will begin once the MTD or RP2DS is determined in Part 1. This part will
consist of 2 cohorts of approximately 15 evaluable patients each (evaluable for
the first efficacy assessment), recruited in parallel. Cohort A will include
patients without prior hematopoietic stem cell transplantation, and Cohort B
will include patients with prior hematopoietic stem cell transplantation (see
exclusion criterion #3).
The following safety evaluation rules will be applied to each cohort
separately. Part 2 consists of two steps in each cohort, to further
characterize the safety, tolerability, PK, PD, cytokine profile, and
immunogenicity, and to assess preliminary efficacy of MCLA-117. The first 9
patients in each Part 2 cohort will be evaluated for safety. If in the first
cycle of treatment, * 2 out of the 9 patients experience AEs that meet the
criteria of DLT, after
discussion between Investigators and the Sponsor, the enrollment will continue
up to 15 patients in each cohort. For each Part 2 cohort, once 15 patients have
been enrolled, a new assessment of DLTs will be performed, and if * 4 out of 15
patients meet the criteria for DLT, expansion will continue in that population,
following submission and approval of a substantial protocol amendment. In this
case, it is anticipated that Part 2 of the study could be expanded up to
approximately 100 patients. If >2/9 or >4/15 patients in either of the 2
cohorts meet the criteria for DLT in either of these two DLT evaluation steps,
the Sponsor and the Investigators will discuss further exploration at the dose
level below or another intra-patient dose escalation regimen in the applicable
cohort(s).
MCLA-117 will be evaluated as a single agent in Part 2. Based on the available
data from Part 1, new preclinical data, scientific data or medical information,
the Sponsor may enroll additional patients in the expansion cohort, and/or open
additional patient cohorts either as a single agent or as a combination
treatment with standard or commonly used AML treatments or other
investigational agents (following submission of a protocol amendment).

The starting dose level was estimated based on a minimum anticipated biological
effect level (MABEL) approach. The starting dose is 25 *g flat dose (equal to
approximately 0.4 *g/kg). The MTD or the RP2DS will be established based on
incidence of DLTs in the DLT observation period only, as well as MCLA-117 PK
properties and cytokine profile, potentially supported by correlative biomarker
and ADA data.
Patients without a response may remain on treatment until disease progression,
unacceptable toxicity or discontinuation for any other reason. Patients in CR,
CRi or CRp will receive up to 6 additional cycles. MCLA-117 will be
administered intravenously over approximately 2 hours. Prolonging the duration
of infusion to up to 4 hours is permitted. The DRC may propose an increased
duration of infusion based on the data becoming available after completing each
cohort.
One treatment cycle is approximately 4 weeks and patients will be hospitalized
for the first treatment cycle. According to the investigator*s discretion,
patients may be discharged 48 hours after the C1D15 and C1D22 infusions,
provided that the patient is clinically stable and there are no signs of CRS or
other safety concerns at the time of discharge and the patient has immediate
access to medical attention. The investigator will decide if following cycles
can be completed on an outpatient basis. The study drug will be administered on
a weekly basis. However, during the first 2 weeks of administration in cycle 1
(including Day 15), a gradual intra-patient dose escalation will be applied
(ramp up).
On Day 28 of the first cycle, a BM aspiration (BMA) and BM biopsy (BMB) will be
performed. Based on BM blast count and/or based on peripheral blood cell
counts, the treating investigator will decide to continue dosing orto introduce
a pause for that patient.
Up to 13 dose levels are anticipated. A combination of an accelerated dose
escalation approach and the 3+3 dose escalation study design will be used for
the first 6 cohorts. The first two cohorts will enroll two patients per cohort
with at least one evaluable patient for the full cycle including
protocol-specified intra-patient dose escalation in consecutive doses over the
course of the first cycle. The second patient in each of these first two
cohorts will only be enrolled after the first patient in the same cohort has
completed at least 7 days of the planned treatment. Beginning at cohort 3 a
minimum of 3 evaluable patients will be required. From cohort 7 onwards with
the A+B design, a maximum of 6 patients can be enrolled at any given time
depending on the number of patients who are already considered evaluable within
that dose level.
All dose escalation decisions in Part 1 of the study and the definition of the
MTD and the RP2DS, will be made by a DRC who will convene to review all
available data. The DRC includes participation of principal investigators (or
their qualified representatives), the Sponsor*s medical director, the study
pharmacovigilance physician, the study project managers and other relevant
study team members. When required, external independent experts will be
invited. The DRC will also decide about expansion of sample size for part 2 of
the study.
The DRC could recommend alternative dose and frequency schedules before moving
to the A+B design. Starting with cohort 3, all cohorts will enroll at least 3
evaluable patients with dose increments of a minimum of 33% percent. However,
all cohorts will enroll a minimum of 3 patients with * 10% of blasts expressing
CLEC12A measured by flow cytometry at baseline (in BMA, BMB or peripheral blood
sample). The dose increments are predetermined as shown in Table 1, however,
for safety reasons, the DRC may determine a lower or intermediate dose level
not previously defined prior to opening the next cohort. The target dose per
cohort as predetermined in Table 1 cannot be exceeded. The intra-patient dose
escalation during the first 2 weeks of treatment (including the dose on Day 15)
is subject to change, based on decisions made by the DRC.
During Part 1, the starting dose (C1D1) of patients within the same cohort
(from cohort 3 and onwards) will be separated by a minimum of 24 hours between
each new patient starting treatment. Dose escalation (opening of a new cohort
of patients) will occur only after the last patient in the previous cohort has
completed at least 1 full cycle of MCLA-117 at the planned dose. During Part 2,
patients can start treatment with the RP2DS in parallel.
The decision to continue treatment for each patient depends on the results of
BMA and BMB on Day 28 of Cycle 1, according to the recommendation of the
treating investigator. From cohort 3 onwards, the protocol plans to reduce the
frequency of administration during the first cycle, given that the MCLA-117
serum half-life will increase with increasing doses.
De-escalation to an intermediate level (e.g., between the level at which DLT
occurred and the immediately lower one) will be carried out if recommended by
the DRC. Patients will be permitted to receive subsequent cycles at higher dose
levels provided such dose levels have been established as safe by the DRC. This
intra-patient dose escalation can be initiated at each next scheduled
administration upon DRC approval of that dose level.
The following dose escalation rules will apply for Cohorts 1 and 2:
1) No DLT for the first two patients and no non-disease related toxicity *
Grade 2: the dose for the next cohort will be escalated according to the
proposed scheme in Table 1.
2) No DLT but * 1 Grade 2 non-disease related toxicity for either of the first
2 patients: the dose for the next cohort will be escalated with a reduced
increment than that proposed in Table 1, which will be recommended by the DRC.
Upon switching to the 3+3 scheme, the following dose escalation rules will
apply:
1) No DLT for the first three patients: the dose for the next cohort will be
escalated according to the proposed scheme in Table 1.
2) At least 1 of the first 3 patients experiences DLT: the cohort of three
patients will be expanded to six patients at the same dose level. Subsequently,
if no other patient within the dose level experiences a DLT, dose escalation
will proceed to the next dose level according to Table 1. If two or more
patients (of the 3 to 6 patients) in the dose level experience DLT then the MTD
has been exceeded. A previous dose level will be declared the MTD.
Alternatively, an intermediate dose level could be recommended by the DRC and
tested in an additional cohort of patients.
From cohort 7 onwards the following dose escalation rules will apply:
1) no DLTs are seen in 3-6 evaluable patients or a maximum of 1 patient with
DLT is observed in 6 evaluable patients: the next dose level will be tested.
2) 1 DLT is seen in the initial cohort of 3-5 evaluable patients: additional
patients will be enrolled with up to 6 evaluable patients at that dose level.
3) 2 or more DLTs are seen at the dose level: the MTD will be declared to be
the preceding dose level. Alternatively, an intermediate dose level could be
recommended by the DRC and tested in an additional cohort of patients.
From cohort 9, the following dose escalation rules will apply:
1) no DLTs are seen in 3-6 evaluable patients: the next dose level will be
tested.
2) DLT in the ramp up period, i.e. before the highest dose in the cohort:
consider DLT information from all patients treated at this ramp up in the
current or preceding cohorts. If the posterior probability that the true DLT
rate does not exceed 33% is at least 75% then this ramp up is considered safe.
A number of DLTs and the minimum number of patients required to declare ramp up
as safe are: - 1 DLT and minimum 5 patients treated at this ramp up - 2 DLTs
and minimum 8 patients treated at this ramp up - 3 DLTs and minimum 12 patients
treated at this ramp up - 4 DLTs and minimum 15 patients treated at this ramp up
3) DLTs at the highest dose for the cohort:
3.1) 1 DLT at the highest dose for the cohort in 6 evaluable patients: proceed
to the next dose level
3.2) 2 or more DLTs are seen at the dose level: the MTD will be declared to be
the preceding dose level. Alternatively, an intermediate dose level could be
recommended by the DRC and tested in an additional cohort of patients.
3.3) 1 DLT at the highest dose for the cohort in the initial cohort of 3-5
evaluable patients: additional patients will be enrolled with up to 6 evaluable
patients at that dose level.
Patients will be permitted to receive subsequent doses beyond Cycle 1 if:
a) no significant drug-related toxicity occurs (e.g., meeting definition of
DLT),
b) in the opinion of the Investigator the patient is experiencing clinical
benefit.

Adverse events (side effects) complications and/or injury (both expected and
unexpected) are possible with any experimental medicinal products. As this is
the first time that MCLA-117 is tested in humans, there may be side effects
that cannot be predicted yet.
Based on information from laboratory tests and other anticancer drugs with some
similarity with this compound, the following adverse reactions might occur:
* Risks of administering the drug through an infusion
Symptoms like fever, chills, phlebitis, hypotension (low blood pressure),
shortness of breath, skin rash, nausea and/or vomiting can occur. These
reactions might be mild or moderate or serious. These reactions typically occur
during or after the first infusion of the drug, with incidence and severity
decreasing with subsequent infusions.
* Cytokine release syndrome and neurotoxicity
This specific reaction to the administration of the drug through an infusion is
known to occur in patients receiving treatments similar to MCLA-117. Symptoms
include: fever, fatigue, loss of appetite, muscle and joint pain, vomiting,
diarrhea, rashes, fast breathing, rapid heart rate, low blood pressure and
neurotoxicity (seizures, headache, confusion, delirium (confusion or madness),
encephalopathy (abnormal brain function), hallucinations, tremor and loss of
coordination). You will be monitored closely during and following each infusion
to observe possible signs or symptoms of this cytokine release syndrome. Due to
the possible risk of neurotoxicity (when a drug has an adverse effect on your
nervous system), it is important that you do not drive or operate heavy
machinery while on treatment with MCLA-117 and for at least 30 days after
discontinuation of treatment.
* Risk of allergic reactions
There is potential for allergic reactions with administration of MCLA-117. This
risk is considered to be low. Symptoms are similar to those described above
for infusion related reactions.
* Risk of neutropenia (reduced number of neutrophils, a subset of white blood
cells responsible to fight against infections) with an associated risk of
immune impairment and infection. Usually this is already present due to the
leukemia.
* Risk of hepatic toxicities, including liver function test abnormalities.

Pregnancy/Birth Control
The risks of taking MCLA-117 to pregnant women or an unborn baby are unknown.
Females must have a pregnancy test before the study starts and again just
before receiving the first dose of MCLA-117 (unless the previous test is done
less than 3 days ago), and again if there is an indication that you might be
pregnant. The patient will also have pregnancy test at the final study visit.
The Patient must not become pregnant during this study. If the patient is a
female of childbearing potential, the patient must use a highly effective form
of birth control during this study and until 6 months thereafter. The study
doctor will discuss with the patient which contraception methods are
acceptable.
The effects of MCLA-117 on a nursing infant are unknown; if the patient is is
breastfeeding, the patient cannot participate in the study.
If the patient is a male and can father a child, it is recommended that both
the patient and the partner use contraception until 6 months after completion
of the study.