A modular, multi-arm, multi-part, first time in patient study to evaluate the
safety and tolerability of OMO-1, alone and in combination with anti-cancer
treatments, in patients with locally advanced, unresectable or metastatic
solid malignancies

This study is the first study of OMO-1 in patients with solid tumour cancer. It
is sponsored by OCTIMET Oncology NV, a biotechnology company, developing drugs
to treat cancer.
The purpose of this study is to find out the tolerability, safety and potential
benefits of OMO-1 in patients who have solid tumour cancer. It will help to get
more knowledge about how OMO-1 affects the human body, and which dose is able
to treat cancer and has an acceptable side effect profile
The study drug is called OMO-1. It is a small chemical that stops the activity
of the MET receptor tyrosine kinase, a protein that causes tumour growth which
is present in solid tumour cancer.
The MET gene has been shown to be responsible for some hereditary types of
cancer. In addition, inappropriate MET activation has been shown in most types
of solid tumours, often correlating with poor prognosis (Maulik 2002; Peruzzi
2006). The role of MET signalling in cancer stem cells is also a field of
increasing interest since it is known that the MET pathway has been found to
play a crucial role in the field of stem cell biology. In addition, it has
recently been proposed that invasive growth, such as that regulated by MET, is
a characteristic feature of stem cells as well as progenitor cells and may be
usurped by cancer stem cells (Boccaccio 2006). We assume that MET inhibition
may be a route to targeting cancer stem cells thereby offering a potential for
cure.

Core:
Core Primary Objective:
* To investigate the safety and tolerability of OMO-1 when given orally to
patients with locally advanced, unresectable or metastatic solid malignancies,
alone or in combination with anti-cancer treatments, and define the doses and
schedules for further clinical evaluation
Core Secondary Objectives:
* To characterise the PK and pharmacodynamics (PDc) of OMO 1, following a
single dose and/or at steady state after multiple dosing, when given orally
alone or in combination with anti-cancer treatments.
* To assess the preliminary efficacy of OMO-1 by Response Evaluation Criteria
In Solid Tumours (RECIST) 1.1. locally*.
*Note: Scans will also be collected for potential future central review.
Core Exploratory Objectives:
* To explore the relationship between dose and PK, efficacy, safety, and/or
blood borne and tissue biomarkers.
* To collect and store an optional pre-dose plasma and serum sample and/or
analyse blood or tissue including patient specific archival tumour tissue, if
available, for potential future exploratory research into factors that may
influence the development of agents to treat human disease and/or response to
OMO 1 (where response is defined broadly to include efficacy, tolerability or
safety). This may include the analysis of tumour specific and circulating
biomarkers, such as tumour deoxyribonucleic acid (DNA), messenger ribonucleic
acid (mRNA), proteins or metabolites. In the event that additional tumour
molecular profiling is required to understand further any response to OMO 1, a
sample of the most recent tumour biopsy for additional research may be
requested.
* To collect and store pharmacogenetics (PGx) samples, for potential future
exploratory research into factors that may influence the development of agents
to treat human disease and/or response to OMO 1 (where response is defined
broadly to include efficacy, tolerability or safety).
* To collect and store plasma circulating free tumour DNA (cftDNA) for future
exploratory research into genes/genetic variation that may influence response
(i.e., distribution, safety, tolerability and efficacy) to OMO 1 treatment.
* To investigate predictive markers and acquired resistance to OMO-1 that may
be observed in tumour or cftDNA from patients treated with OMO-1.
* To investigate the per-patient concordance between potential patient
selection biomarkers (and/or other molecular aberrations) and PDc biomarkers as
determined either by OCTIMET Oncology NV or local test methods, in comparison
to potential patient selection biomarkers and PDc biomarkers levels obtained by
central laboratory tests.
In addition to the core objectives, module specific objectives include:
Module 1:
Primary Objectives:
* Parts A and B: To assess the safety and tolerability of OMO-1 when given
alone in patients with locally advanced, unresectable or metastatic solid
malignancies.
* Part B: To assess the preliminary efficacy of OMO-1 given orally as a single
agent in patients with selected locally advanced, unresectable or metastatic
solid malignancies.
Secondary Objectives:
* Part A: To determine the recommended dose and schedule of OMO-1 to take
forward into Part B of the study module.
* Part A: To determine the dose(s) and schedule(s) of OMO-1 with which to begin
to explore dose escalation of OMO-1 in combination with anti-cancer agents in
further study modules.
* Part B: To refine the choice of tumour indications for controlled Phase 2
trial(s).
Exploratory Objectives:
* To assess the effects of modulation of mesenchymal-epithelial transition
(MET)/organic cation transporter 2 (OCT 2) pathways signalling in surrogate
and/or tumour tissue, including but not limited to hepatocyte growth factor
(HGF) protein levels, phosphorylated MET (pMET), shedMET, total MET (tMET),
phosphorylated extracellular regulated kinase (pERK), phosphorylated GAB2
(pGAB2), immune-phenotype, tumour infiltrating lymphocyte (TIL) population.
* To assess the effects of dual modulation of OCT 2 and MET, including but not
limited to the measurement of the plasma levels of tryptophan and kynurenine
and serum creatinine.
* To measure tumour cell response biomarkers, including but not restricted to
markers of cell proliferation and apoptosis.
Module 2
Primary Objectives:
* Parts A and B: To assess the safety and tolerability of OMO-1 when given in
combination with a small molecule EGFR-TKI in patients who have MET amplified
tumours and whose disease is progressing on current EGFR TKI treatment.
* Part B: To assess the preliminary evidence of efficacy activity of OMO-1 when
given in combination with a small molecule EGFR-TKI in patients who have MET
amplified tumours and whose disease is progressing on current EGFR TKI
treatment.
Secondary Objective:
* Part A: To determine the recommended dose and schedule of OMO-1 to take
forward into Part B of the study module.
Exploratory Objectives:
* To assess the effects of modulation of MET pathway signalling in surrogate
and/or tumour tissue, including but not limited to HGF protein levels, pMET,
pERK, pGAB2, immune-phenotype, TIL population.
* To measure tumour cell response biomarkers, including but not restricted to
markers of cell proliferation and apoptosis.

This is a modular, first time in patient, open-label, multicentre study of
OMO-1, administered orally, alone and in combination with anti-cancer
treatments, in patients with locally advanced, unresectable or metastatic solid
malignancies.
The study will consist of a number of study modules * the first of which is
Module 1. Module 2 follows subsequent to the initiation of Module 1.
Study modules will consist of a Part A (dose finding) and an optional Part B
(cohort expansion). The option to start Part B and add further modules will be
the decision of the SRC, based on emerging preclinical anti-tumour data and,
safety and tolerability information from the study as a whole.
The initial dosing schedule and/or sequence of OMO-1 in each module may be
subsequently changed between patient cohorts in response to emerging safety, PK
and PDc findings. The maximum tolerated dose (MTD) of OMO-1 for individual
modules may therefore differ based on the emerging safety profile for each
combination.
Once a MBAD of OMO-1 for a module has been identified from Part A of that
module, the SRC may decide to commence Part B. The optional Part B will include
approximately 30 patients and a maximum of 40 patients in specific patient
groups to explore preliminary efficacy or the effect of food or particular drug
combinations on drug PK. Single arm cohorts would provide reasonable estimation
of safety and efficacy against a well-defined background knowledge of the class
effect of cMET inhibitors.
For all modules, Parts A or B may be expanded by additional paired biopsy
sub-groups (sequential biopsy cohorts) of up to 12 additional patients at doses
(at or above the MBAD) that have been confirmed to be tolerated. These patients
will have mandatory serial biopsies to assess the tumour for relevant PDc
biomarkers, and to explore further the tolerability, safety and PK activity at
these doses.
In all combination modules, the dose of each combination agent investigated
will not exceed their current recommended dose. The starting dose of OMO-1 in
combination modules will be one dose level below the recommended Phase 2 dose
(RP2D) in Module 1 (monotherapy). For cohorts in which OMO-1 is dosed in
combination with cytotoxic chemotherapy, dosing of OMO-1 will discontinue once
the course of chemotherapy has been completed.
Module 1:
Module 1 will consist of Part A which will assess the safety and tolerability
of multiple ascending doses of OMO-1 given as monotherapy in patients with
locally advanced, unresectable or metastatic malignancy, providing a starting
dose(s) and schedule(s) for the initiation of further modules. An optional Part
B will assess preliminary signs of monotherapy efficacy activity of OMO-1. If
eligible (e.g. having disease measurable according to RECIST 1.1), these
patients will be included within the clinical response assessment for Part A.
Dose-escalation within Part A will commence at a dose level (Cohort 1) of 100
mg BD taken with food; with 4-5 hours between the OMO-1 doses on a single day,
apart from on PK sampling days when there must be 4 hours between OMO-1 doses.
Cohorts of patients will be recruited in a 3+3 design. A normal treatment cycle
will consist of 21 days (3 weeks). Subsequent indicative cohort dose levels are
200 mg (Cohort 2), 400 mg (Cohort 3), 600 mg (Cohort 4*s dose level was changed
from 600 mg BD to 250 mg BD based on SRC recommendation following review of
data) and 350 mg BD (Cohort 5); doses and schedules are subject to SRC
recommendations based upon emerging PK, tolerability and PDc data. Additional
PK samples will be collected in Part A (including the sequential biopsy
cohorts) at specific time points in all of patients who are admitted overnight
on Cycle 1 Day 1 (C1D1). Treatment with OMO-1 will continue until stopping
criteria are met.
Initially patients will be recruited irrespective of the MET status of their
tumour. Once a MBAD of OMO-1 has been achieved in Module 1, the following will
occur:
* Patients will continue to be recruited into the dose escalation cohorts of
Part A, irrespective of the MET status of their tumour.
* Parallel sequential biopsy cohorts of patients, who have confirmed MET
amplified or mutated tumours, may be recruited into Part A at doses that have
been confirmed to be tolerated. Sequential tumour biopsies will be mandated to
further explore drug-on-target effects within the tumour, and to explore
further the tolerability, safety and PK activity at these doses.
* Part B may be initiated in parallel at doses that have been confirmed to be
tolerated.
* Subsequent modules may be initiated in parallel (following substantial
amendment approval).
In the optional Part B, patients will be recruited into cohort expansions of
OMO-1 monotherapy as confirmed by the SRC. Treatment will continue until
individual stopping criteria are met. Cohort expansions of specific patient
groups, may include, but not be restricted to:
* Any patient with MET amplified/mutated tumours.
* Locally advanced or metastatic MET amplified/mutated non-small cell lung
cancer (NSCLC) (squamous and non-squamous).
* Locally advanced or metastatic MET amplified/mutated squamous cell carcinoma
of the head and neck (SCCHN).
* Locally advanced or metastatic MET amplified/mutated gastric carcinoma.
* Locally advanced or metastatic MET overexpressing/amplified/mutated papillary
renal cell carcinoma (PRCC).
* Locally advanced or metastatic MET amplified/mutated gastro-oesophageal
junction (GEJ) carcinoma.
Cohorts of other tumour types or specific phenotypic/genotypic subtypes of
tumours may be expanded depending upon emerging data.
The expected duration of the trial (Module 1) for each patient is 18 weeks (6
cycles). The clinical cut-off for Module 1 is 3 months following the
recruitment of the last patient or the last patient last visit, whichever is
sooner. All patients still receiving treatment at that time will continue to
receive OMO-1 until the stopping criteria are met. Data collection may be
reduced after the clinical cut-off date. The specific changes will be based on
a review of the data summarized at that time. All patients still receiving
treatment at the time of end of study will continue to receive OMO-1 based on
clinical benefit and until the stopping criteria are met.
Module 2:
Module 2 will consist of 2 parts: Part A will assess the safety and
tolerability of OMO-1 when given orally in combination with a small patients
who have MET amplified tumours and whose disease is progressing on current
EGFR-TKI treatment. The optional Part B will assess preliminary signs of
efficacy activity of OMO-1 when given orally in combination with a small
molecule EGFR-TKI. If eligible (e.g. having disease measurable according to
RECIST 1.1), these patients will be included within the clinical response
assessment in Part A.
* Part A: Dose finding: Dose escalation of OMO-1 given in combination with a
small molecule EGFR-TKI.
* Part B: Optional cohort expansion: OMO-1 given in combination with a small
molecule EGFR-TKI.
Combination therapy cohorts in Parts A or B may be expanded by additional
sequential biopsy cohorts at doses that have been confirmed to be tolerated.
Sequential tumour biopsies will further explore drug-on-target effects within
the tumour, and to explore further the tolerability, safety and PK activity at
these doses. The option to start Part B and to include sequential biopsy
cohorts will be the decision of the SRC.
For Parts A and B, the primary endpoint is an assessment of the safety and
tolerability of OMO-1 when given orally in combination with a small molecule
EGFR-TKI.
Part A (dose finding):
1. Dose escalation: OMO-1 given in combination with a small molecule EGFR-TKI
(gefitinib/erlotinib, afatinib and osimertinib). OMO-1 administered from a dose
(as defined by the SRC) which will be at or above the monotherapy MBAD (defined
from Module 1 Part A);
For Part A: Dose escalation:
Patients will be treated with OMO-1 in combination with a small molecule
EGFR-TKI. Patients will be treated in 3 parallel treatment cohorts (OMO-1 +
gefitinib/erlotinib, afatinib or osimertinib).
Dose escalation within Part A will commence at an OMO-1 dose and schedule
sequence defined by the SRC, depending upon data generated from Module 1 Part A
of the study; OMO-1 dose levels will not be weight-adjusted and doses and
schedules are subject to SRC recommendations based upon emerging safety, PK,
tolerability and PDc data
A normal combination treatment cycle will consist of 21 days (3 weeks). Safety
will be monitored on an ongoing basis; dose-limiting toxicities (DLTs) will be
assessed during C1 of the combination therapy. Patients will be recruited in a
3+3 design to a planned OMO-1 dose level within a combination therapy.
Once a MTD/maximum feasible dose (MFD) dose of OMO-1 in combination with a
small molecule EGFR-TKI has been identified, the SRC may decide to commence
Part B of Module 2.
Part B: Cohort expansion:
The initiation of the cohort expansion with the recommended dose and schedule
of OMO-1 in combination with a small molecule EGFR-TKI will be based on an
adequate safety and tolerability profile of the combination from Part A of
Module 2. Part B will consist of cohort expansions in which patients will be
followed for objective response rate (ORR) and duration of response (DoR). The
SRC will define the recommended dose(s) and schedule(s) for OMO-1 to be
explored in Part B from Part A of Module 2.
The expected duration of the trial (Module 2) for each patient is 18 weeks (6
cycles). The clinical cut-off for Module 2 is 3 months following the
recruitment of the last patient or the last patient last visit, whichever is
sooner. The EGFR-TKI will be administered as per the relevant package insert.
All patients still receiving treatment at that time will continue to receive
study treatment until the stopping criteria for either study treatment are met.
Data collection may be reduced after the clinical cut-off date. The specific
changes will be based on a review of the data summarized at that time. All
patients still receiving treatment at the time of end of study will continue to
receive study treatment based on clinical benefit and until the stopping
criteria for either study treatment are met.

Module 1:
Starting dose of 100 mg twice daily (BD) taken with food; with 4 5 hours
between the OMO-1 doses on a single day, apart from on pharmacokinetic (PK)
sampling days when there must be 4 hours between OMO 1 doses.
Doses and schedules for the subsequent cohorts will be defined by the safety
review committee (SRC).
Module 2:
* Dose finding: OMO-1 given in combination with a small molecule EGFR TKI
(gefitinib/erlotinib, afatinib and osimertinib). OMO 1 administered at the
monotherapy recommended Phase 2 dose (RP2D; defined from Module 1 Part A).
Doses and schedules for the subsequent cohorts will be defined by the SRC).
The dosage and administration of the EGFR-TKIs as per the package insert for
the relevant EGRF TKI, or recognised dose reduction in the case of afatinib.

As with all medicines, there is a risk that OMO-1 may cause unwanted effects
(side-effects).
OMO-1 has generally been relatively well tolerated in a recent healthy
volunteer clinical study.
Laboratory Tests
Laboratory tests performed could be uncomfortable or painful but are necessary
to monitor the patient's health status.
Biopsy
Whenever a biopsy is done, there is a risk of bleeding (haemorrhage) during the
procedure. The study doctor will monitor the amount of bleeding. In rare cases,
the bleeding can be major.
Risk of MRI (magnetic resonance imaging)
MRI looks at the internal organs by using a large magnet, radio waves and
computer equipment to produce pictures, or images, of the human body. During a
MRI, the patient will lie on their back motionless in a big machine. This may
produce anxiety. At certain times during the scan, loud tapping noises can be
heard. The MRI scan does not cause any pain and does not expose the patient to
X-ray radiation.
Risk of CT scan
A CT scan is a commonly used diagnostic procedure. The test exposes the patient
to a small dose of radiation. All radiation is cumulative over their lifetime.
The radiation risk in this study has been assessed as insignificant, taken in
the context of their current condition.
Pregnancy avoidance
Patients must ensure they avoid pregnancy by undergoing highly effective
contraceptive methods.

The safety and welfare of the patients has been considered and will continue to
be paramount during the course of the research study. Safety of the
participants in the study will be monitored by qualified and appropriately
trained clinical staff, including nurses, physiologists and research physicians.

It is not known for certain that you will have any clinical benefit by taking
part in the study. The chances of success with experimental treatments are low
(it is possible that no benefit results from treatment with OMO-1). However,
the information we get from this study may help us to treat future patients
with locally advanced, unresectable or metastatic solid tumours.