A Phase 1 Study to Determine the Safety, and Pharmacokinetics of the Selective MET kinase Inhibitor, DO-2 in Patients With Advanced or Refractory Solid Tumours

In biochemical assays, DO-2 bound to recombinant wild type MET kinase with a kd
of 0.2nM. DO-2 had binding affinities of 1.4nM versus the 1250T and 4.4nM
versus the 1235D MET mutants. The next kinase to which DO-2 bound with high
affinity, in a panel of more than 450 kinases, was PIP5K2C with a binding
affinity of 650nM representing a margin of more than 3000 fold relative to
MET. In a panel of cancer cells, the growth of the HS746T gastric cancer cell
line, carrying an exon 14 skipping mutation and MET amplification was inhibited
with an IC50 of 21nM. The other cell lines not carrying MET mutations or
amplifications had IC50 values greater than 10*M representing a margin of more
than 475 fold.
DO-2 has been shown to have potent in vivo tumour inhibitory activity including
the complete regression of large established exon 14 skipping and MET
amplification positive Hs746T gastric cancer xenografts resulting in no
measureable tumours even 28 days after stopping dosing. Significant growth
delay or regression of a range of MET amplification positive lung and gastric
cancer xenografts, U87-MG glioblasoma, lung renal and pancreatic patient
derived xenografts were also seen. The minimum effective dose (MED) (NCI
guidelines) determined in a panel of in vivo models has been defined as
0.16mg/kg of DO-2 (Cmax 78ng/ml : AUC 683ng.h/ml).
1.25mg/kg (Cmax 573ng/ml : AUC 5339ng.h/ml) has been found to cause tumour
regression and to drive efficacy to a similar degree as higher doses, with no
improvement in activity observed with increasing dose to 10mg/kg (Cmax
4585ng.ml AUC 42710ng.h/ml) or in a limited number of studies using 50mg/kg
(Cmax 22925ng/ml AUC 213550ng.h/ml).
Complete responses were seen following 16 days of dosing (seen in 8/8 animals
carrying the Hs746T xenograft at a dose of 3mg/kg (Cmax1376ng/ml AUC
12813ng.h/ml)) with no tumours regrowing 40 days after stopping dosing.
Daily dosing of mice for 21 days with the highest dose tested thus far (50mg/kg
(Cmax 22925ng/ml AUC 213550ng.h/ml) was well tolerated with no observation of
clinical signs of toxicity in the mice, hence no MTD in mice has yet been
determined. The low MED and the highest dose of 50mg/kg showing no clinical
signs of toxicity leads to a very large safety margin in mice.
Efficacy of DO-2 in a nude rat model was also evaluated at a dose of 10mg/kg
(Cmax 4923ng/ml, AUC0-24 30158ng.h/ml). Both MET amplified SNU5 and the HGF
autocrine U87MG glioblastoma models were found to regress at this dose. Lower
doses were not tested.
The mean Kp,uu,brain of DO-2 was estimated to be 0.3, meaning that on average,
30% of unbound DO-2 in plasma crosses the BBB. Kp,uu,brain value of 0.3 from
in vivo rodent assessment is often used as an arbitrary cut-off to judge if a
drug candidate has good BBB penetrability as most CNS drugs have Kp,uu,brain >
0.3 . In this regard, DO-2 can be considered a CNS-penetrant compound with
brain penetrability of DO-2 being higher than many other tyrosine kinase
inhibitors (TKI) that are marketed or in the clinical development stage, as
reflected by their rat Kp,uu,brain values measured using a similar approach .
The nonclinical toxicity of the non-deuterated version (JNJ-38877605) has been
studied extensively in a full GLP safety package in rats and dogs. Toxicity
studies of up to 28 days and the core battery of safety pharmacology studies,
demonstrated a benign safety profile that supported initation of the Phase I
clinical trial.
For the deuterated compound DO-2, a 14 day dose finding toxicity study in male
rats demonstrated similar toxicity for both DO-2 and JNJ-38877605. The study
identified 40mg/kg/day as the NOAEL for DO-2 (Cmax 31253ng/ml (+/- 6970ng/ml)
AUC0-24 251328ng.h/ml (+/- 109571ng.h/ml). A dose of 160 mg/kg/day was
considered non-severley toxic for both deuterated and non-deuterated forms.
A 28 day GLP toxicology study of DO-2 was conducted in New Zealand white
rabbits which are considered metabolically relevant as they possess the AOX-1
enzyme present in patients. In this study, the highest dose tested
(40mg/kg/day) was considered to be the NOAEL (Cmax 5023ng/ml : AUC
9434ng.h/ml).

This study has been transitioned to CTIS with ID 2023-504897-39-00 check the CTIS register for the current data.

Primary Objectives:

To determine the safety and tolerability of DO-2 (adverse event profile, dose
limiting toxicity and the maximum tolerated dose).

Secondary Objectives:

To determine the pharmacokinetic (PK) profile of DO-2 and its primary
metabolite, DO-5 and investigate the potential impact of food on the PK profile.

To measure antitumour activity in response to administration of DO-2, according
to RECIST 1.1.

Exploratory objectives:

Alternative ef*cacy endpoints to support antitumour effectiveness have been
explored in the literature for evaluating signs of clinical bene*t in small
patient populations. An example is the growth modulation index (GMI), which
is de*ned as the ratio of time to progression (TTP2) on current therapy to TTP1
on the most recent prior therapy, within the same patient. GMI will also be
assessed in the current study. This ratio (GMI) can be used to determine
whether current therapy is providing clinical bene*t, and was originally
proposed as a novel surrogate endpoint in the context of non-cytotoxic drug
trials (such as the current agent DO-2), where a GMI endpoint is more
appropriate than measuring tumour shrinkage. Considering that molecularly
targeted agents may generate signi*cant clinical bene*ts aside from the tumour
shrinkage [partial response (PR) or complete response (CR)] evaluated by
RECIST, GMI has since been applied in early development settings to assess the
bene*t of targeted therapies selected by molecular pro*ling in patients with
advanced refractory cancers. The bene*t of using GMI for an intra-patient
analysis is that patients act as their own controls, allowing the direct
comparison of different treatments within the same patient over time, and this
could be one approach to generate comparative ef*cacy data for a drug developed
in single-arm trials.

Study Design: This study comprises of two parts: Part 1 to determine the
maximum tolerated dose (dose escalation) and recommended dose for further
studies, and Part 2 dose expansion and food effect assessment.
In Part 1, a Simon Design 3 accelerated titration design with 2 stages, will be
followed. One patient will be enrolled per cohort, until grade 2 toxicity is
observed. Three sequential patients per cohort will be enrolled thereafter,
with a minimum of 1 week between first dose administration in the first patient
and the subsequent ones, in those latter cohorts. Patients in each cohort will
attend an inpatient visit at Cycle 1 from Day -1/Day 1 before their dose until
24 h after dosing. Following appropriate assessments on Day 2, the patients
will be discharged.
For Part 1, cycles 1 and 2, patients will attend outpatient visits on Day 8,
15, 22 and for any subsequent cycles Day 1. All patients will return for a
follow-up visit 28 days after their last dose. DO-2 will initially be
administered once a day orally (fasted), in cycles of 28 days. Patients will be
provided with DO-2 as capsules. The starting dose will be 5 mg. All
subsequent doses will be selected by the Safety Evaluation Team (SET). Dose
escalation decisions will be made on the basis of safety evaluations and
pharmacokinetic data obtained in Cycle 1 at each dose level (the *DLT period*
of the study).
Part 2 will not start until the SET have confirmed satisfactory safety,
tolerability and PK data from Part 1. Patients will be treated in 3 cohorts at
the recommended Part 2 dose and schedule, allowing further exploration of
different doses or schedules. Patients will attend outpatient and inpatient
visits as per Part 1 with the exception of the food effect cohort, for which
some patients will also attend an inpatient visit on Day 3. The potential
impact of food on the PK profile of DO-2 will be investigated during this phase
in a total of 20 evaluable patients or as a determined by the SET. Patients
will be provided with DO-2 as capsules.

Assessments:
Safety and tolerability
Safety evaluations will include an assessment of adverse events, clinical
laboratory data, (including specific renal function assessments such as
creatinine clearance, and cystatin C clearance, urinary protein, -albumin),
electrocardiogram, vital signs measurements, physical examination findings and
Eastern Oncology Cooperative Group (ECOG) performance status will be completed
from screening until the subject*s last visit.
Pharmacokinetics
Blood samples for assay for DO-2, DO-5 and M3 will be taken before, during and
frequently up to 24 h after dosing on Day 1. In addition, for Part 1 only,
pre-dose Day 8 and 15 PK blood samples will be taken, and on day 22 pre-dose
and up to 8-10 h thereafter.
For the Part 2 food effect cohort only, blood samples for assay for DO-2, DO-5
and M3 will be taken before, during and frequently up to 24 h after dosing on
Day 1 and 3.

Not applicable

Please be referred to section 1.2 of the Protocol