A Phase 1, Open-Label, Dose-Escalation, Safety, Tolerability, and Preliminary Efficacy Study of MCLA-145 in Participants With Advanced or Metastatic Malignancies

Open-label, non-randomized, dose-escalation study with expansion cohorts for
dose confirmation/safety and preliminary efficacy. MCLA-145 will be
administered intravenously as a flat dose over 2 hours every 14 days in 28-day
cycles.

MCLA-145 is a drug that is considered an antibody. When a body*s immune system
detects something harmful, it can produce antibodies. Antibodies are proteins
that fight infection. Monoclonal antibodies are a specific type of antibody
made in a laboratory. They can attach to other molecules or cells in your body
and affect their function.

MCLA-145 interacts with proteins in your body called CD-137 (4-1BB) and
Programmed death-ligand 1 (PD-L1). Your immune system includes a type of white
blood cell called T-cells that have the ability to fight cancer. They are
often stopped by the cancer cells and this allows the cancer to grow. MCLA-145
is designed to attach to the 4-1BB protein on these T-cells and has the
potential to increase the number and enhance the function of your T-cells
making them more able to fight your cancer. A mechanism some cancer cells use
to hide from your body*s immune system is by taking control of what is called
the PD-L1/PD-1 pathway. This pathway normally reduces the amount of
inflammation that the immune system produces. MCLA-145 is designed to block
this pathway, allowing the immune system to recognize and attack the cancer
cells. By simultaneously interacting with 4-1BB and PD-L1, this interaction
may help the body*s immune system fight your cancer.

Primary:
- To determine the safety, tolerability, and dose-limiting toxicities (DLTs) of
MCLA-145 and to determine an MTD and/or the RDE in advanced or metastatic solid
tumors or B-cell lymphomas.

Secondary:
- To explore preliminary antitumor activity of MCLA-145 in participants with
advanced or metastatic solid tumors or B-cell lymphomas by assessing ORR, DCR,
PFS, and DOR.
- To evaluate the PK of MCLA-145 when given as a single agent in advanced or
metastatic solid tumors or B-cell lymphomas.
- To assess the immunogenicity of MCLA-145 when given as a single agent in
advanced or metastatic solid tumors or B-cell lymphomas.

Exploratory:
- To evaluate the receptor modulation of MCLA-145 when given as a single agent.
- To characterize the effect of MCLA-145 on tumor and immune cell infiltrate
biomarkers as predictive markers of MCLA-145 activity.
- To determine the 1-year OS of MCLA-145.
- To evaluate the clinical activity of MCLA-145 by assessing ORR, DCR, PFS, and
DOR by iRECIST (in participants with solid tumors) or RECIL 2017 (in
participants with B-cell lymphomas)

Up to 118 participants will be treated in Part 1 and Part 2, as follows:
• Part 1 will include approximately 38 participants across 10 dose levels
(starting dose = 0.4 mg).
• Part 2 will include up to 80 participants in up to 2 dose levels. The dose
levels will be determined based on safety, PK, pharmacodynamic activity, and
preliminary efficacy in Part 1.
If there are tumor specific expansions, up to 40 participants per
histology-specific cohort may be enrolled.

This is an open-label, nonrandomized, Phase 1 study to determine the safety,
tolerability, and preliminary efficacy of MCLA-145 in adult participants with
advanced or metastatic solid tumors or B-cell lymphomas that will be conducted
in 2 parts, as follows:

Part 1:
Dose escalation to determine the MTD and/or RDE of MCLA-145 in participants
with any advanced metastatic solid tumors or B-cell lymphomas, regardless of
PD-L1 expression. During dose escalation, cohorts of participants will be
treated with MCLA-145 until the MTD is reached or a lower recommended dose(s)
is established. The dose escalation will be guided by an adaptive BLRM
following the escalation with overdose control principle.
* A maximum of 5 participants with a given tumor type may be enrolled across
all dose levels in Part 1, unless the medical monitor approves additional
enrollment in that tumor type.

Part 2:
Dose expansion to confirm the dose of MCLA-145 through further evaluation of
safety, tolerability, PK, preliminary antitumor activity, and functional target
engagement.
* Participants with the following advanced or metastatic tumors, regardless of
PD-L1 expression, may be enrolled:
* Anti-PD-1 therapy relapsed or refractory melanoma.
* Anti-PD-1 therapy relapsed or refractory HNSCC.
* Anti-PD-1 therapy relapsed or refractory urothelial carcinoma.
* Immunotherapy-naive TNBC.
* Any tumor histology from Part 1 for which preliminary efficacy was observed
with MCLA-145.
* Up to 2 confirmatory dose levels may be explored. Confirmatory dose levels
will be selected based on PK, antitumor and pharmacodynamic activity including
receptor modulation, safety, and tolerability.

All medicinal products can have side effects. The side effects in humans are
not known. Even if previous animal studies have shown that Study Drug was
well-tolerated when tested and did not show any adverse effects related to a
specific organ system, the subject may still experience side effects. These may
go away after the Study Drug is stopped, but in rare cases they may be serious,
long lasting, and/or permanent and may even cause death.


a. Side effects
Study Drug works through the immune system; therefore, possible symptoms or
adverse effects that could occur may be immune-related effects such as
• inflammation of the skin or mucosa (e.g., itching, redness, rash)
• inflammation of the lungs (e.g. cough)
• inflammation of the bowels (e.g., diarrhea).
• endocrine (hormone) dysfunction
• liver injury
• fatigue or lack of energy.

Although adverse effects related to immunotherapies are generally mild and
reversible, serious immune-related adverse effects do occur.

Reactions to the Study Drug infusion could also occur. Possible reactions
include
• nausea
• vomiting
• abdominal pain
• headache
• low blood pressure
• fever
• tremor
• allergic reactions

b. Discomforts related to biopsy, bone marrow biopsy and/or aspirate, Computed
Tomography (CT)-scan, Magnetic Resonance Imaging (MRI)-scan, Positron Emission
Tomography (PET)/CT scan, Electrocardiogram: for more details see appendix D
Informed Consent Form.