An open label, dose escalation followed by dose expansion, safety and tolerability trial of CAN04, a fully humanized monoclonal antibody against IL1RAP, in subjects with solid malignant tumors.

CAN04 is a monoclonal antibody targeting the Interleukin 1 Receptor Accessory
Protein (IL1RAP) and has been engineered by grafting the Complementarity
Determining Regions of a murine IL1RAP monoclonal antibody into the human IgG1
and modified for ADCC enhancement, thus providing a dual MoA (as explained in
*trial rationale* below). CAN04 is a first-in-class molecule whose mode of
action is to modulate the tumor microenvironment and more specifically tumor
inflammatory processes.
The present trial is the first in human trial of CAN04 and is divided into two
parts. The aim of the first part (Part I) was to define the Maximum Tolerated
Dose/ Recommended Phase 2 Dose (MTD/ RP2D) of CAN04 in subjects with relapsed
or refractory Non-Small Cell Lung Cancer (NSCLC), Pancreatic Ductal
Adenocarcinoma (PDAC), Triple Negative Breast Cancer (TNBC) or Colorectal
Cancer (CRC).
In the second part of the trial (Part II) two different schedules of CAN04 were
planned to be investigated; once per week (Q1W) at the RP2D determined in Part
I (10 mg/kg) and Q1W during the initial 6 weeks followed by once every two
weeks (Q2W) treatment (week 7 onwards) at 10 mg/kg (the RP2D determined in Part
I) or at 15 mg/kg.
Part II consists of five treatment arms where the safety and tolerability of
CAN04 will be determined, as monotherapy (arms A, B and E) and in combination
with standard chemotherapy regimen (arms C and D) in subjects with either NSCLC
or PDAC. Preliminary signs of efficacy will also be investigated. More
specifically, Part II will adopt a basket trial non-randomized, parallel-arm
design where subjects with NSCLC or PDAC who would be otherwise eligible to
receive standard of care chemotherapy, will receive it in combination with
CAN04.

At the time of protocol version 7.0, the evaluation of the complete CAN04
information from Part I, Part II Arms A and B and the initial escalation in
Arms C and D, concluded that 5 mg/kg can be considered as a provisional
Pharmacologically Active Dose (PAD) suitable as an adequate dose in combination
with standard of care chemotherapy. At this dose, CAN04 produced in humans an
exposure well-above those required to produce maximal IL-1 pathway target
inhibition and maximal antibody-dependent cell cytotoxicity (ADCC) in
preclinical models. Based on this, it was decided not pursuing dose escalation
above 5 mg/kg in combination with chemotherapy as it was originally planned and
discontinuing Arm E (at 15 mg/kg as single agent).

Primary Objectives
Part I
- To define the Maximum Tolerated Dose (MTD) or Recommended Phase 2 dose (RP2D)
of CAN04 once weekly (Q1W) in subjects with relapsed or refractory NSCLC, PDAC,
TNBC or CRC.
Part II
- To determine the safety and tolerability of CAN04 in subjects with NSCLC or
PDAC tumors, when given as monotherapy or in combination with chemotherapy.

Secondary Objectives (for both parts of the study)
- To assess pharmacokinetic (PK) parameters of CAN04.
- To assess anti-drug antibody (ADA) formation against CAN04.
- To determine preliminary signs of clinical efficacy of CAN04 as a single
agent.
Additional secondary objectives for Part II
- To assess quality of life.
- To determine preliminary signs of clinical efficacy of CAN04 when given in
combination with standard of care therapies

Exploratory objective (for both parts of the study)
- To assess disease-related, inflammatory, immune or microenvironment-related
parameters related to the trial drug, in the circulation and in tumor tissue.
- To assess levels of C-Reactive Protein.
- To assess volumetric size of tumor.
- To evaluate mechanisms behind infusion related reactions (IRRs)

The trial is a combined phase I/IIa, open-label, dose-escalation followed by
dose expansion, safety and tolerability clinical trial, in subjects with solid
tumors. It consists of two parts.

In Part I (Dose Escalation - DE), the intention was to include subjects with
any of the four solid tumor types including, NSCLC, PDAC, TNBC or CRC. In this
part of the trial safety and tolerability were documented and the MTD/RP2D were
determined. Cohorts of 3 subjects received Q1W treatment with CAN04. The Dose
Limiting Toxicity (DLT) observation period for each dose level was the first 21
days of treatment with CAN04.

The decision to escalate to the next dose level was taken by the Dose
Escalation Committee (DEC) after reviewing safety data (including DLTs) from
all subjects who entered the previous dose cohort and completed the 21-day DLT
observation period, i.e. safety data collected up to Visit 4 (V4) according to
the Schedule of Assessments. In Part I of the study, the DEC comprised of the
Coordinating Investigator, participating Investigators or designees of them,
the Medical Monitor and Sponsor representative.

Subjects stayed on CAN04 treatment until disease progression, unacceptable
toxicity, or discontinuation for any other reason.
In Part I, in case of Progressive Disease (PD) according to Immune Related
Response Criteria (irRC), subjects could have their dose escalated to the
highest safe dose, in accordance with the dose modification criteria.

In Part I, subject replacement was allowed for subjects who dropped out for any
reason during the DLT observation period, except for DLTs. No subject
replacement would occur for subjects who withdrew later. After the first drug
administration (V1), subjects were required to stay at the clinic for at least
8 hours for safety monitoring. Subjects could be admitted to the hospital for
24 hours after the first administration, where this was the local practice.
Visits were scheduled every 7 days (+/- 1 day), and then continued with weekly
dosing visits until disease progression (according to irRC).

After completion of Part I, all results were evaluated by the Part I DEC.
Results included safety, efficacy and other clinical data, as well as
pharmacokinetic data and any available biomarker data from all subjects
included in Part I of the trial and who completed at least 21 days of
treatment. The Committee confirmed the RP2D of 10 mg/kg CAN04 in a monotherapy
setting (no MTD was reached). After completion of Part I, a data package
supporting the choice of the CAN04 dose of 10 mg/kg as RP2D for monotherapy was
prepared and submitted to appropriate regulatory authorities.

In Part II (Expansion Cohort - EC) of this trial, safety and tolerability, as
well as early signs of efficacy will be further evaluated for CAN04 monotherapy
and as part of combination treatment regimes, as follows:
* Arm A: subjects with squamous or non-squamous NSCLC or PDAC who have relapsed
on or are refractory to standard therapy or for whom there is no standard
therapy will receive CAN04 monotherapy at 10 mg/kg administered Q1W. This arm
was already completed at the time of protocol version 7.0.
* Arm B: subjects with squamous or non-squamous NSCLC or PDAC who have relapsed
on or are refractory to standard therapy or for whom there is no standard
therapy will receive CAN04 monotherapy at 10 mg/kg administered Q1W for the
first 6 weeks followed by Q2W treatment. This arm was already completed at the
time of protocol version7.0.
* Arm C: CAN04 at 5 mg/kg in combination with cisplatin/gemcitabine in subjects
with histologically or cytologically confirmed diagnosis of stage IIIB or stage
IV squamous or non-squamous NSCLC who are candidates for 1st line of standard
chemotherapy regimen with cisplatin/gemcitabine or who relapsed after 1st line
with pembrolizumab monotherapy and are candidates for 2nd line of standard
chemotherapy regimen with cisplatin/gemcitabine. CAN04 will be administered Q1W
for the first 6 weeks followed by Q2W treatment.
* Arm D: CAN04 at 5 mg/kg in combination with nab-paclitaxel/gemcitabine, in
previously untreated subjects with histologically confirmed, unresectable,
locally advanced or metastatic (stage III or stage IV) PDAC. CAN04 will be
administered Q1W for the first 6 weeks followed by Q2W treatment. Prior to the
decision to use the 5 mg/kg dose as a PAD, 8 subjects were dosed with 7.5 mg/kg
CAN04.
* Arm E: subjects with squamous or non-squamous NSCLC or PDAC who have relapsed
on or refractory to standard therapy or for whom there is no standard therapy
were initially planned to receive CAN04 monotherapy at 15 mg/kg administered
Q1W for the first 6 weeks followed by Q2W treatment. Enrollment to this arm has
been discontinued due to the selection of 5 mg/kg as a provisional PAD.

Subjects will stay on treatment until disease progression, unacceptable
toxicity, or discontinuation for any other reason.

Arm C and D
At the time of protocol version 7.0, a decision was made that the PAD dose of
CAN04 for Arms C and D will be 5 mg/kg, based on the evaluation of the complete
CAN04 information from Part I, Part II Arms a and B, and the initial escalation
in Arms C and D.

Subjects in Arm C should continue CAN04 treatment until disease progression
even if the planned maximal cisplatin dose (between 4 and 6 cycles in the
absence of progressive disease or toxicity) has been reached. In Arm C and D,
besides the Medical Monitor and Sponsor representative, the DEC and,
subsequently, the Safety Review Committee (SRC), assessing safety of CAN04
treatment, also included three investigators per indication (three NSCLC and
three PDAC specialists), who were selected from among the Coordinating and
other participating Investigators or designees of them. The Medical Monitor is
responsible for appointing and assembling the DECs/SRCs and
moderating/facilitating its meetings.

In Arm C and D of Part II, subject replacement was allowed only during the
run-in phase and for subjects who drop out for any reason, except Treatment
Limiting Toxicities (TLTs) that occur during the TLT observation period
(defined as the period between initiation of CAN04 priming infusion to the day
the subject is scheduled to receive the second cycle of chemotherapy: Visit 5
for Arm C and Visit 6 for Arm D) and upon decision of the DEC/SRC. No subject
replacement will occur for subjects enrolled in Part II Arms C and D, with the
exception of subjects discontinued due to IRR with the priming dose.

Arm E
Arm E enrollment is discontinued at the time of protocol version 7.0.
Cohorts of 3 subjects were planned to start with Q1W treatment with CAN04 and
switch to Q2W after 6 weeks of treatment. The CAN04 dose from V2 and onwards
was planned to be 15 mg/kg. The occurrence of DLTs was planned to be observed
in the first 6 subjects of Arm E during the first 21 days of treatment with
CAN04, i.e. safety data collected up to Visit 4 (V4) according to the Schedule
of Assessments. If 2 DLTs were to be found in these first 6 subjects, the
DEC/SRC would reduce the CAN04 dose to 10 mg/kg in following subjects. The
DEC/SRC in Arm E was planned to consist of the same investigators as the DEC in
Part I. Also, in Arm E, a minimum of one week (7 days) between dosing the first
two subjects in the same dose cohort is required (i.e. the second subject was
planned not to be dosed until 24h post the second dosing of the first subject).
At the time of protocol version 7.0, it was decided to discontinue Arm E.

In addition, it would be evaluated if premedication with corticosteroids could
be reduced without interfering with anticipated incidence and severity of IRRs.
To this end, subjects in Arm E would receive a lower dose of corticosteroid
than the one in use for the other cohorts, as premedication. The decision to
further reduce the dose of corticosteroid as premedication, or to adjust other
preventive measures for IRR will be taken by the DEC/SRC after reviewing safety
data (including incidence and severity of IRRs, DLTs) from all subjects who
entered the previous dose cohort and completed the first drug administration
(V1).

In Arm E, subject replacement was planned to be allowed for the first 6
subjects in case they drop out for any reason during the DLT observation
period, except for DLTs. No subject replacement would occur for later subjects
or those who withdraw later. After the first drug administration (V1), subjects
would be required to stay at the clinic for at least 8 hours for safety
monitoring. Subjects may be admitted to the hospital for 24 hours after the
first administration, where this is the local practice.

Not applicable

In this study CAN04 is being administered to humans for the first time.
Pre-clinical studies with CAN04 and studies in animals did not show any serious
side effects, but this may be different in humans. Patients will be monitored
closely for the occurrence of any significant clinical events and treatment
will only continue if it is considered safe and appropriate to do so. The
pre-clinical studies of CAN04 indicated that its use is generally safe and well
tolerated and can justify evaluation in a patient population.
These studies also indicated that CAN04 can elicit a targeted cellular immune
response and has a strong potential for anti-tumor activity.

During the first part of the study with CAN04 dose escalation, some patient had
experienced moderate to severe infusion-related reaction during the first
administration of CAN04. For this reason, from cohort 04 onwards in this study,
an adjusted low first dose of CAN04 is administered after premedication.
During the first part of the study with CAN04, some patients have also
experienced:
- Diarrhoea
- Nausea
- Vomiting
- Chills
- Fatigue
- Pyrexia
- Pruritus
In patients treated with CAN04 alone a decrease in white blood cell count can
be seen in some patients. In combination with chemotherapy more patients
experience lowered white blood cell count compared to when what is expected
with chemotherapy alone.

Moreover, there is experience with the side effects of drugs that are similar
to CAN04. Other monoclonal antibodies have been used for many years and this
class of drugs can lead to the following side effects: infusion reactions,
allergic reactions, cytokine release syndrome.

In summary, the expected benefit outweighs the expected risks for the patients.