A phase 1, first-in-human, multicenter, open-label, dose-escalation study to characterize the safety and tolerability of MP0317 in patients with relapsed/refractory advanced solid tumors

There is a clear need for a significant improvement to cancer immunotherapy.
Introduction of immune checkpoint inhibitors to cancer therapy has demonstrated
the potential of enhancing antitumor immunity to improve patient outcome but
has also shown that checkpoint inhibition alone is ineffective in many cases.
CD40 agonism has potential to improve cancer immunotherapy but agonist
molecules evaluated to-date have had disappointing efficacy due to extratumoral
CD40 activation and resultant dose-limiting peripheral immunotoxicities.

In the Sponsor*s opinion, this could be overcome by strict targeting of CD40
agonistic activity to the tumor - as intended with MP0317. MP0317 (FAPxCD40) is
a tri-specific FAP-targeting DARPin® molecule designed to combine high potency
for CD40 activation with tumor-targeting and tumor-restricted receptor
engagement and immune cell activation. By localizing and restricting the
agonistic effect of CD40 to the tumor site, MP0317 is expected to limit the
risk of potential systemic side effects (such as cytokine release syndrome
[CRS]) and to increase the therapeutic window of CD40 activation.

The tumor types selected for the proposed phase 1 monotherapy study represent
good benefit/risk potential for clinical study explorations. Firstly, the
advanced solid tumor types are known to express medium to high levels of FAP
and secondly, study patients with the selected tumor types are those for whom
approved therapies have been exhausted or who are ineligible or unable to
tolerate other treatments.

Due to the expected markedly higher level of FAP in tumors than in healthy
tissues, the FAP-targeted CD40 agonist MP0317 is expected to have a better
safety profile, in particular with respect to CRS and liver toxicity, than the
untargeted CD40 agonist monoclonal antibodies that are currently in clinical
development.

Future clinical development will focus on MP0317 in combination with other
treatment modalities (e.g. checkpoint inhibitors, chemotherapy, radiation
therapy).

Primary Objectives:
• To determine the Recommended Dose of Expanion or the MTD for MP0317 as
monotherapy in patients with advanced solid tumors (dose-escalation part only)
• To characterize the safety and tolerability of MP0317 as monotherapy in
patients with advanced solid tumors

Secondary Objectives:
• To describe the PK of MP0317 as monotherapy in patients with advanced solid
tumors
• To evaluate preliminary antitumor activity of MP0317 as monotherapy in
patients with advanced solid tumors
• To evaluate preliminary clinical benefit of MP0317 as monotherapy in patients
with advanced solid tumors

Exploraty Objective:
• To evaluate pharmacodynamic effects of MP0317 as monotherapy in peripheral
blood and tissue in patients with advanced solid tumors
• To evaluate the immunogenicity of MP0317 as monotherapy in patients with
advanced solid tumors

This is a phase I, first in human, multi-center, open-label, dose-escalation
study, followed by a safety expansion part to evaluate the safety,
tolerability, PK, pharmacodynamics and preliminary antitumor activity of study
medication MP0317 in adult subjects with advanced solid tumors.

The dose-escalation part is designed to determine the recommended dose for
expansion (RDE) or maximum tolerated dose (MTD) for MP0317 mono-therapy. The
safety expansion part is designed to confirm safety in a larger population. The
dose-escalation scheme will use an adaptive study design following a Bayesian
Logistic Regression Model (BLRM). A dose-escalation review committee (DERC)
will monitor safety and govern all cohort dosing decisions.
The sponsor in consultation with the DERC may advise on the opening of cohorts
with alternative dosing schedules (e.g. every week; q1w). Such additional
cohorts may be opened concurrently with the initial dosing schedule cohorts,
during dose escalation as well as during safety expansion phase.

Once the RDE (or MTD) has been determined, the safety expansion cohort(s) will
be opened and up to 15 additional patients will be treated with MP0317
monotherapy at this dose.

The first doses between the first two patients in any cohort must be separated
by a minimum of 7 days.

Study treatment will be administered until progressive disease (PD),
unacceptable toxicity, withdrawal of consent or other reasons to discontinue
treatment occur, whichever comes first. Treatment beyond PD will be allowed as
per Immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST).

Paired (pre and on/post-treatment) tumor and skin biopsies will be mandatory
for all subjects.
Biomarkers that may potentially correlate with antitumor activity or
immunomodulatory effects of MP0317 may be explored during the study.

For each subject, the assigned dose of MP0317 will be based on the available
cohort as recommended by the dose escalation review committee (DERC).
For the dose-escalation study part on q3w schedule, the starting dose is 0.03
mg/kg q3w and up to 6 q3w dose levels are planned. A treatment cycle will last
3 weeks (21 days), with DLT evaluation period of 4 weeks after first study drug
administration.
The doses to be evaluated on a q1w schedule in the dose-escalation part starts
with 0,50 mg/kg q1w and up to 3 q1w dose levels are planned.

The IMP is provided in 10 mL vials at a nomial concentration of 15 mg/mL.
The IV solution stabilizer (IVSS) is supplied in identical vials, but with
differently colored flip-off caps.
Both solutions are stored at -20 °C ± 5 °C.

The prepared IMP is administered as IV solution.
The infusion duration should be at least 50 minutes and no longer than 2 hours.
Subjects who receive the IMP will remain under observation for at least 24
hours after their first and secnd IMP administration.
After the third to fifth cycle, subjects should remain under medical
supervision for at least 4 hours, and from the sixth cycle onward for at least
1 hour.

The study population consists of cancer patients with advanced solid tumors,
which have been known to express medium to high levels of FAP and for whom
approved therapies have been exhausted or who are ineligible or unable to
tolerate other treatments.

Due to the expected markedly higher level of FAP in tumors than in healthy
tissues, the FAP-targeted CD40 agonist MP0317 is expected to have a better
safety profile, in particular with respect to CRS and liver toxicity, than the
untargeted CD40 agonist monoclonal antibodies that are currently in clinical
development.

MP0317 will be administered as an IV solution.
The effect of MP0317 on humans is unknown. MP0317 may cause side effects.
Side effects with other similar drugs and therefore, potential risks from
MP0317 to patients include:
• Reactions to the infusion (infusion related reactions), occurring during or
shortly after the infusion, including hypersensitivity (allergic) reactions.
• Late onset hypersensitivity (allergic) reactions manifesting as rash
accompanied by joint or body pain, starting 10-20 days after receiving the
drug
• Cytokine release syndrome is a form of systemic inflammatory response to
immunotherapy treatment.
• Tumor lysis syndrome
• Liver toxicity
• Autoimmune diseases

Risks related to study procedures:

Blood draws can cause pain, bruising, inflammation and swelling of the vein,
bleeding or even an infection at the puncture site.

MUGA: The radioactive agent will stay in the subject's blood for several hours
but will not interact with body tissues. The agent is passed out of the body
through the urine usually within 24 hours after the test is completed. The
radioactive agent used during the MUGA scan is a diagnostic dose.

ECG: Skin reactions to the sticky pads may occur, such as redness, itching or
discomfort. Some hair loss may be associated with the glue at the placement
sites of the ECG pads.

CT scan: This is normally painless but is performed in a tunnel which may the
subject feel uncomfortable, especially if suffering from claustrophobia. If a
contrast agent is used for the imaging procedure, allergic reactions and
infusion related side effects may be observed.

MRI scan. This is normally painless but is performed in a tunnel which may feel
uncomfortable, especially if suffering from claustrophobia. Certain people with
metal inside their body cannot have this scan, including those with pacemakers
and cardiac defibrillators, joint replacements, heart and vessel coils and
others. Pregnant women should not have an MRI during their first trimester
unless they absolutely need the test. The first trimester is when the child's
organs develop. Subjects also should not receive contrast agent if they have
had an allergic reaction to it in the past or if the subject has severe kidney
disease.

Tumor biopsy. During and after the tumor biopsy procedure, the subject may have
mild pain, bruising and bleeding at the biopsy site. Occasionally these
complications are significant.

Skin biopsy. During and after the skin biopsy procedure, the subject may feel a
sting transiently. After the procedure, a suture or dressing may be applied to
the site of the biopsy.

The following procedures are performed:
- Physical examination - at screening and pre-dose at each cycle;
- Vital signs measurement and pulse oximetry - at screening, 11x at cycle 1, 7x
at cycle 2 - 5 and 4x at cycle 6 and further;
- ECG - at screening, 3x at cycle 1 - 2 and 1x at cycle 3 and further;
- Blood draws (local safety lab, including urinalysis, PKs, immunogenicity,
biomarkers) - screening, 9x at cycle 1, 5x at cycle 2 - 5 and 2x at cycle 6 and
further;
- Pregnancy test (for women of childbearing potential only): at screening and
at the pre-dose at each cycle;
- Skin biopsy - 1x at screening, 1x 3 days after screening, 1x at cycle 1 day 5
and 1x at cycle 1 day 8;
- Tumor biopsy - 1x at screening, 1x at cycle 2 day 8 and, optional, 1x at time
of progressive disease or response.

The amount of blood drawn during each cycle study arm A:
Cycle 1 148 mL
Cycle 2 124 mL
Cycle 3 71 mL
Cycle 4 89 mL
Cycle 5 65 mL
Cycle 6 25 mL
Cycle 7 and following cycles 28 mL
Follow-up visit 52 mL
If an immune reaction occurs 10 mL

The amount of blood drawn during each cycle study arm B:
Cycle 1 160 mL
Cycle 2 123 mL
Cycle 3 43 mL
Cycle 4 82 mL
Cycle 5 37 mL
Cycle 6 53 mL
Cycle 7 and following cycles 29 mL
Follow-up visit 52 mL
If an immune reaction occurs 10 mL