Phase 1/2 dose escalation and cohort expansion study evaluating MCLA-158 (Petosemtamab) as single agent or in combination in advanced solid tumors

Colorectal cancer (CRC) is the third most-diagnosed cancer in Europe and the
United States, and 30% of patients with CRC present with metastatic disease
(Schmoll et al, 2012; Torre et al, 2015). Epidermal growth factor receptor
(EGFR) is frequently mutated or overexpressed in CRC and many other cancers
including the lung, colon, head and neck, and pancreas among others. Antibodies
targeting the extracellular domain of EGFR and small molecule inhibitors
targeting the intracellular kinase domain of EGFR are used extensively in the
standard of care management of these cancers.
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a
G-protein-coupled, seven-transmembrane-domain receptor for R-spondins which are
potent WNT signal enhancers and stem cell growth factors (de Lau et al, 2011).
It is present in intestinal stem cells found in the base of intestinal crypts,
and other normal differentiated cell types including brain, endometrium,
muscle, ovary and pancreas. LGR5 is highly regulated and maintains a small
number of native stem cells in their undifferentiated state in the base of the
colonic crypt. It is also expressed in primary and metastatic colon cancer in
animal models (de Sousa e Melo et al, 2017; Shimokawa et al, 2017) and
LGR5-positive cells have been shown to play a role of in establishing and
maintaining liver metastasis. Cancer stem cells (CSCs) of various origins
including colorectal cancer (CRC) stem cells are LGR5-positive. WNT has also
been shown to be an oncogenic driver in many cancers, and is the most commonly
altered pathway in CRC. Dysregulation of the WNT/β-catenin axis results in
uncontrolled proliferation and dissemination of CSCs that form the primary
tumor and ultimately metastatic lesions. LGR5 signal enhancement is proposed to
be important in stem cell renewal, maintaining cells in the stem cell program,
and the upregulation of LGR5 expression observed in adenocarcinomas (Martin et
al, 2017) is consistent with the link between WNT signal strength, stem cell
signature, and colon CSC behavior.
Rationale for developing MCLA-158 in EGFR-driven tumors
MCLA-158 is a common light chain human full-length IgG1 bispecific antibody
with enhanced ADCC activity, targeting the EGFR and the LGR5, two receptors
which are critical for the growth and survival of CSCs. The convergence of the
WNT and EGFR signaling pathways provides both oncogenic and mitogenic drivers
in CRC stem cells. CRC stem cells play a central role not only in tumor
initiation and growth, but also in tumor relapse and resistance to anticancer
therapies.
Via its bispecific mode of action, it is hypothesized that MCLA-158 induces
antitumor activity by simultaneously binding and blocking oncogenic drivers and
proliferative signaling in CRC stem cells. MCLA-158*s enhanced
antibody-dependent cell-mediated cytotoxicity (ADCC) properties are expected to
augment these antitumor effects via the recruitment of immune effector cells
that directly kill tumors. MCLA-158 has demonstrated strong inhibitory growth
activity in patient-derived tumor organoids and was significantly more active
in organoids derived from CRC tumors than from normal tissue. Importantly
normal tissue organoids are dependent on R-spondin for growth but the activity
of MCLA-158 in normal organoids was no different to that of the EGFR-targeting
antibody cetuximab. The bispecific format of MCLA-158 confers greater potency
than combining each targeting arm against LGR5 and EGFR as separate monoclonal
antibodies. In vivo experiments with patient-derived and organoid-derived
xenografts have demonstrated activity in RAS wildtype (RASwt) and RAS mutant
(RASmut) CRC models. Beyond CRC, activity has been observed in patient-derived
xenograft (PDX) models that co-express elevated LGR5 and EGFR mRNA levels
according to RNA sequencing data. MCLA-158 demonstrated significant antitumor
activity in the majority of PDX models of head and neck squamous cancer,
gastric adenocarcinoma, and esophageal squamous cell carcinoma, in both the
KRASwt and KRASmut settings. While MCLA-158 inhibits EGFR signaling, the LGR5
arm acts as a simple docker of the antibody targeting it to CRC cells, and does
not appear to block R-spondin binding to LGR5 or modulate the WNT signaling
pathway, consistent with its lack of activity in normal tissue organoids.


Planned early MCLA-158 development
The clinical strategy for the development of MCLA-158 involves a phase 1/2
study with an initial dose-finding part for single-agent MCLA-158 in mCRC
patients progressing on oxaliplatin- and irinotecan-based chemotherapies ±
antiangiogenic therapy to determine the recommended phase 2 dose (RP2D). In an
expansion part, activity, safety, and tolerability of MCLA-158 at the
single-agent R2PD will be evaluated in cohorts of selected solid tumor
indications with dependency on EGFR signaling. Eligible indications may include
locally advanced unresectable or metastatic head and neck squamous cell
carcinoma (HNSCC), anogenital squamous cell carcinoma (SCC), non-small cell
lung cancer (NSCLC; SCC and non-SCC), gastric/gastroesophageal junction
adenocarcinoma with EGFR amplification or high EGFR expression, endometrial
adenocarcinoma, pancreatic adenocarcinoma, and CRC KRASwt.

This study has been transitioned to CTIS with ID 2024-513627-16-01 check the CTIS register for the current data.

Dose escalation
Primary
• To determine the RP2D of single-agent petosemtamab in mCRC patients who have
progressed on chemotherapy, with or without an anti-VEGF therapy, and with an
anti-EGFR therapy (if RASwt)

Secondary
• To characterize the safety and tolerability of petosemtamab
• To evaluate preliminary antitumor activity
• To characterize the PK of petosemtamab
• To characterize the immunogenicity of petosemtamab
• To correlate biomarkers in tumor samples relevant to EGFR and LGR5 as well as
the early tumor response profile of petosemtamab

Exploratory
• To explore additional biomarkers in tumor and blood samples (circulating free
deoxyribonucleic acid [DNA], cancer cells and proteins) predictive of response
or resistance to therapy.
• To evaluate the mutational status and other genetic alterations or gene
expression status of a panel of genes on (archival) tumor biopsies as potential
selection biomarkers for patient stratification.
• To evaluate potential pharmacodynamics (PD) biomarkers in response to therapy
• To evaluate further biomarkers to investigate the drug (ie,
mode-of-action-related effect and/or safety) and/or the pathomechanism of the
disease

Dose Expansion Single agent
Primary
• To determine the ORR per RECIST 1.1 (per investigator review)
Secondary
• To evaluate antitumor activity in terms of PFS and DOR per RECIST 1.1 (per
investigator review)
• To evaluate antitumor activity in terms of ORR and DOR per RECIST 1.1 in
expansion cohorts with preliminary antitumor activity observed (per central
review)
• To evaluate OS
• To characterize safety and tolerability of single-agent petosemtamab and
confirm the RP2D
• To characterize the PK of petosemtamab
• To characterize the immunogenicity of petosemtamab
• To correlate biomarkers in tumor samples relevant to EGFR and LGR5 as well as
the early tumor response profile of petosemtamab

Exploratory
• To explore additional biomarkers in tumor and blood samples (circulating free
nucleic acids, cancer cells, and proteins) predictive of response or resistance
to therapy
• To evaluate the mutational status and other genetic alterations or gene
expression status of a panel of genes on (archival) tumor biopsies as potential
selection biomarkers for patient stratification
• To evaluate potential PD biomarkers in response to therapy
• To evaluate further biomarkers to investigate the drug (ie,
mode-of-action-related effect and/or safety) and/or the pathomechanism of the
disease

Dose Expansion Combination
Primary
• To determine the ORR per RECIST 1.1 (per investigator review)
• To characterize safety and tolerability for combinations
Secondary
• To evaluate antitumor activity in PFS and DOR per RECIST 1.1 (per
investigator review)
• To evaluate antitumor activity in terms of ORR and DOR per RECIST 1.1 (per
central review)
• To evaluate OS
• To characterize safety and tolerability of petosemtamab in combination with
pembrolizumab as well as to further evaluate RP2D
• To characterize the PK of petosemtamab in combination with pembrolizumab
• To characterize the immunogenicity of petosemtamab
• To correlate biomarkers in tumor samples relevant to EGFR and LGR5 as well as
the early tumor response profile of petosemtamab

Exploratory
• To explore additional biomarkers in tumor and blood samples (circulating free
nucleic acids, cancer cells, and proteins) predictive of response or resistance
to therapy
• To evaluate the mutational status and other genetic alterations or gene
expression status of a panel of genes on (archival) tumor biopsies as potential
selection biomarkers for patient stratification
• To evaluate potential PD biomarkers in response to therapy
• To evaluate further biomarkers to investigate the drug (ie,
mode-of-action-related effect and/or safety) and/or the pathomechanism of the
disease

Dose expansion (combination, 2L mCRC cohort)
• To characterize safety and tolerability for petosemtamab in
combination with FOLFIRI/FOLFOX

This is a FIH phase 1/2 open-label multicenter study combining an initial dose
escalation part with a dose expansion part (in both single-agent and
combination cohorts). The initial dose escalation part was completed, and the
preliminary RP2D was established at 1500 mg Q2W (see Section 3.1.1).
At the time of implementation of this amendment, patients who are already on
treatment or in follow up will continue to follow assessments in protocol
amendment v 6.0 (dated 04 MAY 2023), while new patients treated under this
amendment will be governed by this protocol amendment.
Single-agent or combination cohorts of selected solid tumor indications for
which there is evidence of EGFR dependency and potential sensitivity to EGFR
inhibition will be evaluated in a dose expansion part of the study. The
eligible solid tumor indications are specified in the petosemtamab development
section above.

Tumor samples will be analyzed in central laboratories (unless otherwise
stated), using a Sponsor-approved test in accordance with local clinical
testing regulations, for potential biomarkers retrospectively and by
immunohistochemistry (IHC) if available at the investigational site. Patients
must sign a screening informed consent form (ICF) before the sample is
submitted for analysis

When the ICF is signed, a screening period of 28 days will start (see Section
3.3). All screening procedures should take place within 28 days prior to the
patient's first dose, including the baseline tumor biopsy (see Section 12.2.1).
Petosemtamab will be administered IV as a flat dose over an infusion period of
2 to approximately 6 h, Q2W, with 4-week cycles (28 days). As of 22 January
2021, 1500 mg Q2W is the primary dose level under investigation in the dose
expansion cohorts with demonstration of clinical activity.
Approximately 567 patients will be assigned to 1 of 7 possible dose expansion
treatment arms: 4 arms using petosemtamab as a single agent and 3 arms using
petosemtamab in combination with other agents as shown in the above diagram and
explained further in Section 3.1.1.
Safety, PK, immunogenicity, and antitumor activity of single-agent petosemtamab
will be characterized in all cohort patients, and retrospective biomarker
analyses including EGFR and LGR5 status will be performed.
A Safety Monitoring Committee (SMC) composed of the principal investigators,
the Sponsor*s medical expert(s), and safety and PK representatives, will review
data according to the SMC charter at designated timepoints throughout the study
and advise on DLTs, addition of extra patients at a given dose, and dose
escalation or de-escalation. The SMC or Sponsor may propose opening dose
expansion cohorts and advise on safety decisions, including the modification of
dosing increments, de-escalations, and dosing frequency (see Sections 3.1.6 and
9.14).
The Sponsor will monitor safety on an ongoing basis, and instruct sites on
measures for monitoring IRRs.
Dose escalation safety evaluation
The planned dose escalation part of the study has been completed. Allometric
scaling of a nonclinical PK model was used to predict petosemtamab exposure in
humans. The petosemtamab starting dose was 5 mg (flat dose) IV, Q2W, with
4-week cycles. Up to 11 dose levels were investigated: 5, 20, 50, 90, 150, 225,
335, 500, 750, 1100 and 1500 mg (flat dose), Q2W. The administered dose, dose
increments, and frequency of dosing for each patient and each cohort was
subject to change based on patient safety, PK and PD data, and upon
recommendation of the SMC.
An accelerated Simon design was implemented to evaluate safety during dose
escalation.
To be evaluable for a DLT, patients had to receive the intended petosemtamab
dose for the first 28-day cycle, or experience a DLT. Patients not evaluable
for DLT were replaced (see Section 3.1.4.1).
Dose expansion and combination safety evaluation
For the dose expansion (both single-agent and combination) cohorts, safety
evaluation will follow the guidelines

INVESTIGATIONAL THERAPY AND REGIMEN MCLA-158: IV infusion every 2 weeks, with a
starting dose of 5 mg (flat dose). The following dose levels were planned: 5,
20, 50, 90, 150, 225, 335, 500, 750, 1100 and 1500 mg (flat dose). Dose
escalation was halted once the RP2D to investigate further in the expansion
part was selected. The administered dose, dose increments, and frequency of
dosing for each patient and each cohort is subject to change based on patient
safety, PK and PD data, and upon recommendation of the SMC. As of 22 January
2021, 1500 mg Q2W is the dose level under investigation in the expansion part
with demonstration of clinical activity. Infusions must be administered over a
minimum of 4 hours during Cycle 1. Details of MCLA-158 administration over the
minimum 4 hours are provided in separate Study Specific Dosing Instructions.
Subsequent infusions after Cycle 1 can be reduced to 2 hours at the
investigator*s discretion and in the absence of IRRs. A mandatory premedication
regimen (dexamethasone, antihistamines, paracetamol) is administered for all
infusions in Cycle 1, initiated within 24 hours prior to each infusion with
optional premedication with dexamethasone for subsequent infusions in the
absence of severe IRRs. A cycle is considered 4 weeks. For each patient, a
6-hour observation period will be implemented following infusion start for the
initial MCLA-158 infusion, a 4-hour period for the second infusion, and a
minimum of 2 hours for all subsequent administrations, corresponding to at
least the duration of the infusion. Treatment adaptation • MCLA-158 infusion
will be interrupted immediately in the event of an infusion-related reaction
(IRR) and symptomatic treatment will be administered. For mild to moderate
events (grade 1-2) after marked clinical improvement, the infusion can be
resumed at a 50% infusion rate. For grade 3 events, it is up to the
investigator*s judgment whether to resume the infusion at the 50% rate or to
stop MCLA-158. For grade 4 events, MCLA-158 must be stopped definitively. •
Dose reductions, interruptions and symptomatic treatment will be implemented in
the event of dermatologic toxicities, diarrhea/vomiting, hypomagnesemia,
thrombocytopenia, and neutropenia (see protocol section 5.3.3). • MCLA-158
administration can be delayed to manage AEs for a maximum of 2 infusions (i.e.,
up to 6 weeks between two consecutive infusions). Treatment duration Study
treatment will be administered until confirmed progressive disease (as per
RECIST 1.1), unacceptable toxicity, withdrawal of consent, patient
non-compliance, investigator decision (e.g., clinical deterioration), or
MCLA-158 interruption >6 consecutive weeks. Patients will be followed up for
safety for at least 30 days following the last MCLA-158 infusion and until
recovery or stabilization of all related toxicities, and for disease
progression and survival status for 12 months. In protocol version 5 a
combination cohort with Pembrolizumab and MCLA-158 is added. Patients with
HNSCC in first lmine will be treated in this cohort.

· Risk of infusion-related reactions (IRRs) and/or hypersensitivity
Antibodies like petosemtamab can cause a reaction when given by infusion. These
are called IRRs. IRRs can include hypotension (low blood pressure), shortness
of breath, skin redness, nausea, headache, fever, chills, tremor, excessive
sweating, itching, tachycardia, and/or vomiting. These reactions might be mild,
moderate, or serious. Out of the 79 patients treated, 72% experienced an IRR.
Most of these IRRs were mild to moderate with 6 patients discontinuing
treatment due to their IRR. IRRs typically occur during or after the first
infusion of the therapeutic antibodies, and may improve or stop altogether on
later infusions.
· Skin side effects
Study drugs like petosemtamab, which target an area on cells called the EGFR
receptor, can cause skin related side effects. Out of the 79 patients treated,
35% experienced rash, 25% dermatitis acneiform, 19% redness, 14% itching, 10%
dry skin and skin fissures, 8% bumps around your hair follicles (which may
become sores), 6% skin toxicity and 5% excessive sweating. Most of these events
were mild to moderate with 1 out of 79 patients experiencing severe dermatitis
acneiform, bumps around hair follicles, skin toxicity and excessive sweating.
· Gastrointestinal side effects
Study drugs like petosemtamab, which target an area on cells called the EGFR
receptor, can also cause side effects affecting the gastrointestinal system.
Out of the 79 patients treated 18% experienced nausea, 9% diarrhea and
inflammation of the mucous membranes of the mouth and 5% vomiting. All these
events were mild to moderate. 1 out of 79 patients experienced severe abdominal
discomfort.
· Other side effects
Out of the 79 patients treated, 17% experienced a decrease in blood magnesium
levels, 8% skin infections around the nail, 6% decrease in white blood cells,
weakness and fatigue. 5% had patches of red bumps with pus and 5% experienced a
syncope.

Other potential risks seen in drugs that target the EGFR receptor are shown
below:
· Other EGFR-related risks
Other potential risks seen include conjunctivitis (*pink eye*), swelling of the
eyelids, increased tear production (*watery eyes*), decrease of potassium
levels in the blood, and respiratory symptoms such as scarring in the lungs or
other related lung conditions. To date, some of these risks have been observed,
and assessed as related, in patients treated at 1500mg Q2W. Events included dry
eye (3 patients) and lacrimation increased, eye pruritus, scleral hyperemia,
vision blurred and keratopathy in 1 patient each.
· LGR5-related risks
As described previously, petosemtamab also attaches to an area on cells called
the LGR5 receptor, which is part of a system called the WNT pathway. There is
not enough information available about side effects caused by antibodies
targeting the LGR5 in humans so the likelihood of side effects is difficult to
predict. As LGR5 is present on both tumoral and normal intestinal stem cells,
as well as other cells that may be critical for normal tissue function,
targeting LGR5 cells as a therapeutic anticancer strategy may also impact
normal tissue functioning. Concerns of effects on intestinal stem cells
(Gastrointestinal toxicity), bone turnover (risk of bone fracture) and
hematopoiesis (myelosuppression) will be taken into consideration in clinical
studies with petosemtamab.


Pregnancy and Reproductive Risks

The potential risks of MCLA-158 on human reproductive function and on the human
fetus have not yet been studied. Women must not therefore become pregnant or
breast-feed while participating in the study. As a result, if you (or your
sexual partner) are of child-bearing potential, you must use an effective
method of contraception throughout the clinical study and for 6 months after
the last dose of MCLA-158. Effective methods of contraception include: true
abstinence, or a sole partner who is vasectomized, or a combination of two of
the following: intrauterine device/system, a condom with spermicidal
foam/gel/film/cream/suppository, and an occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam, gel, film, cream or suppository.
The use of hormonal methods of contraception are not considered effective
enough for this clinical study.

If you do become pregnant during the clinical study, you must inform your
investigating doctor and you will no longer be able to take part in this
clinical study. If you or your partner becomes pregnant during the trial or
within six (6) months of stopping treatment, your trial team will discuss all
the options available to you. The outcome and progress of any pregnancy will be
followed by your trial team, and you will be asked questions about the
pregnancy and baby, if appropriate.

As MCLA-158 is a new drug being developed there may be other side effects that
are not yet known.
5. Other side effects associated with medical procedures used during the
clinical study
Blood draws, where samples of your blood are taken to run laboratory tests, are
standard practice in your illness and are not specific to this clinical study.
However, there may be more blood draws than usual which may make you more
susceptible to side effects (pain, bruising, inflammation and swelling of the
vein, bleeding or even an infection at the puncture site).
CT scans, magnetic resonance imaging (MRI) and bone scans are normally carried
out to diagnose and assess your disease and those done in this clinical study
are not expected to be different. However, there may be more of these
procedures than you are used to.
A CT scan is a series of x-rays put together by a computer. CT scans will
expose you to small amounts of radiation. Although repeated radiation may
damage body tissues and slightly increase chances of having cancer, the risk
from the imaging being done for this clinical study is not considered to be
significant.
Magnetic resonance imaging (MRI) is a technique that uses a magnetic field and
radio waves to create detailed images of the organs and tissues within your
body.
CT scans and MRI scans involve dyes (called *contrast medium*) being injected
into one of your veins to help the organs in your body and your cancer to show
up on the scans. There is a risk that you may have an allergic reaction to the
dye. This reaction may be mild (such as a skin rash or hives) or severe (such
as breathing difficulties and shock). In rare instances, severe or fatal
allergic reactions have been reported (0.001-0.0002% of cases).
Both CT and MRI scans mean lying still in a confined space for a period of
time, so you should consider this, if you suffer from claustrophobia.
A bone scan is a nuclear medicine test which helps find cancer that has started
in or has spread to the bones. This means that the procedure uses a very small
amount of a radioactive substance, called a tracer. The tracer is injected into
a vein. The tracers in the radioactive dye used in a bone scan produce very
little radiation exposure. Even the risk of having an allergic reaction to the
tracers is low. Bone scans will only be performed if your cancer has spread to
your bones.
A multigated acquisition (MUGA) scan is a nuclear medicine imaging test that
checks how well the heart is pumping during rest or exercise. A MUGA scan uses
a radioactive material (radiopharmaceutical) that targets the heart, along with
a gamma camera and a computer, to create images of the blood flowing through
the heart.
A MUGA scan is also called nuclear ventriculography, radionuclide angiography
or cardiac blood pool scan.
The dose of x-rays or radioactive materials used in nuclear medicine imaging
can be different for every test. The dose depends on the type of procedure and
body part being examined. In general, the dose of radioactive material given is
small and you are exposed to low levels of radiation during the test. The
benefit