A phase 1 study of oral Debio 0123 in combination with carboplatin in patients with advanced solid tumors.

Currently, limited emerging clinical data are available with Debio 0123. The
study design has been based on the extensive nonclinical investigations in
vitro and in vivo, summarized below. Please refer to the Debio 0123
Investigator*s Brochure for a comprehensive presentation of all available data.
1. Pharmacology
Debio 0123 is a potent and highly selective WEE1 inhibitor shown to decrease
phosphorylation of WEE1 target CDK1 in cell lines and induce increased mitosis
as well as unrepaired DNA damage.
In vivo, Debio 0123 has shown a dose-dependent anti-tumoral activity as single
agent that was well tolerated. In a lung cancer xenograft model, treatment with
30 mg/kg Debio 0123 resulted in tumor regression. In an in vivo lung cancer
model, where neither Debio 0123 nor carboplatin decreased tumor growth when
administered as single agents, combination of both strongly reduced tumor
growth and was well tolerated, using several schedules of treatment. These data
supported the further clinical development of Debio 0123 in combination with
carboplatin.
2. Nonclinical pharmacokinetics and metabolism
Debio 0123 is a high permeability drug and in vitro data suggest no significant
involvement of efflux transporters such as P-gp (ABCB1), BCRP (ABCG2) or MRP2
(ABCC2) for its intestinal transport. Significant systemic exposure was
observed in animals (mice, rats, monkeys) after oral administration of Debio
0123 (oral bioavailability 66-100%), and nonclinical PK properties (half-life
of 4.5-7.5-hours [h] across the 3 species, resulting from a medium clearance
and high volume of distribution) support to start with a once-a-day (QD) dosing
regimen in this FIH study. Neither gender effect nor food effect was observed
in the rat. Debio 0123 is moderately bound to plasma proteins (92% in humans).
Extensive distribution into tissues and into the tumor (tumor:plasma ratio 9.2)
was confirmed in the mouse, with significant brain penetration (brain:plasma
ratio 0.7-1.3).

Analyses of urine from the animal PK studies showed that renal excretion is
marginal (< 1% of the dose excreted as unchanged Debio 0123 in urine), and in
vitro data suggest that Debio 0123 is mainly metabolized in the liver and
intestines by CYP3A4. Based the in vitro and in vivo metabolism studies, the
major metabolite in animals was identified as N32-desmethyl-Debio 0123 (AUC
compared to the parent compound: 7.5-23.6% in the mouse; 3.2-16.7% in the rat;
44.3-54.1% in the monkey), which retains an in vitro WEE1 inhibiting activity
similar to that of the parent drug, although less cell permeable. Although the
in vitro interspecies metabolite profiles have suggested that it may be formed
only to a lower extent in humans, the PK of this metabolite will be
investigated in the FIH study.
Based on in vitro studies evaluating the risk of drug-drug interactions, Debio
0123 has shown significant potential to inhibit CYP2C19 and CYP3A4 (and, albeit
to a lesser extent, CYP2C8), as well as transporters P-gp (ABCB1), BCRP
(ABCG2), OCT1, OCT2, MATE1 and MATE2-K. Signs of CYP3A4 induction were also
observed. In vivo significance remains to be further evaluated and will depend
on the dose administered and actual exposure achieved in humans. Nevertheless,
those data have formed the basis for recommendations regarding the use of
concomitant medications in the FIH study. Of note, PK interaction from Debio
0123 on carboplatin was not expected since carboplatin PK is neither dependent
on hepatic metabolism nor on active renal secretion.
3. Nonclinical safety
A nonclinical safety program has been conducted consisting of 7-, 14-, and/or
28-day repeat dose toxicity in two relevant species, rats and monkeys, with a
recovery phase and including exposure assessment to Debio 0123 and its major
metabolite.
In the rats, repeated administration of 50 mg/kg/day was not tolerated over 14
days in the MTD (maximum tolerated dose) study and well tolerated at 30
mg/kg/day over 28 days in the GLP (Good Laboratory Practice) study. Clinical
chemistry pointed towards regenerative anemia (decreased red cell production
and increased reticulocytes) and liver effects (enzyme elevations). In the
latter organ, histopathologic findings were limited to minimal centrilobular
hypertrophy. Adrenal cortical hypertrophy alongside thymus atrophy was
considered as stress reaction due to administration. In the lungs, alveolar
inflammatory cell infiltration was noted in both sexes and in the prostate of
males a decreased secretion, in line with a decreased organ weight. Organ
weight increases in liver, spleen and adrenal glands were considered due to
extramedullary hematopoiesis. In females, kidney and heart weights were also
increased with no histopathological correlates. Additional histopathology of
the mid- and low-dose groups and recovery animals is currently ongoing, but due
to the limited effects already seen in the high-dose animals, the Severely
Toxic Dose in 10% of the animals the Severely Toxic Dose in 10% (STD10) of the
animals was was considered to be above the highest dose level of 30 mg/kg/day
in this 28-day GLP study in rats.
In the monkeys, 30 mg/kg/day were not tolerated during a 14-day MTD study. The
animals in this group were sacrificed on Day 12 due to their body weight loss.
In the GLP study with a high-dose level of 10 mg/kg/day, treatment with Debio
0123 was well tolerated at all dose levels. The findings were limited to
hematology and clinical chemistry (regenerative anemia and liver enzyme
elevations), with low severity and showing recovery. No histopathological
observations were made. In male monkeys only, slight increases in the QTc
interval were noted from 3 mg/kg/day, but did neither increase further with 10
mg/kg/day, nor following the 2-fold increase in Cmax due to accumulation after
14 days of treatment. In addition, a minimal decrease of the respiratory rate
was noted in the monkey telemetry study at 10 mg/kg/day. In conclusion, the
Highest Non-Severely Toxic Dose (HNSTD) was not reached in this study.
Alongside the classical nonclinical safety assessment of Debio 0123, cardiac
safety was investigated extensively based on initial results on the human
Ether-a-go-go-Related gene (hERG) ion channel (IC50 9 µM) and effects on
stem-cell derived human cardiomyocytes (severe electrophysiological changes
from 3 µM). In addition to hERG, Debio 0123 inhibits to some extent the
voltage-gated L-type Calcium channel (Cav1.2 - IC50 ~30 µM) and also the
voltage-gated Sodium channel (Nav1.5 - IC50 ~30 µM). Of note, the identified
metabolite N32-demethyl-Debio 0123 showed similar IC50 values for each of the 3
ion channels. Though such concentrations will likely not be reached
systemically in vivo, the possible slight effects on these channels may
contribute to the overall cardiac effect. A monkey telemetry study showed clear
QT prolongations, but these were limited and not dose-dependent (no relevant
increase in the QT duration at dose levels above 10 mg/kg/day). Experiments in
tissues and cardiomyocytes obtained from human donor hearts confirmed the
potential of Debio 0123 to increase the QT duration but did not show
pro-arrhythmic signals. In addition, Debio 0123 showed a potential for a
negative inotropic effect. Debio 0123 was not directly mutagenic but positive
in the rat micronucleus assay, which is expected based on its mechanism of
action of interfering with cell cycle progression control.
Debio 0123 absorbs in the ultraviolet-visible spectrum and was positive in the
in vitro 3T3 Neutral Red Uptake (NRU) photosafety assay. As a consequence,
Debio 0123 may induce phototoxicity in humans. Based on these results, a
phototoxic effect of Debio 0123 cannot be excluded. Since no further data on
the accumulation of Debio 0123 in the skin is available, as a precautionary
measure, subjects must be advised to avoid excessive exposure to sunlight an

This study has been transitioned to CTIS with ID 2024-510984-52-00 check the CTIS register for the current data.

Main Objective :
- Dose escalation part: To determine the recommended phase 2 dose (RP2D) of
Debio 0123 when administered in combination with carboplatin in subjects with
solid tumors which recurred or progressed after prior cisplatin or carboplatin
containing therapy.
- Expansion part:
To characterize the safety and tolerability of Debio 0123 when administered in
combination with carboplatin at the RP2D determined during the dose escalation
part of the study and to evaluate the preliminary antitumor activity of Debio
0123 when administered in combination with carboplatin.

Secondary objectives:
- Dose escalation part :
1.To determine the dose-limiting toxicities (DLTs) of Debio 0123 when
administered in combination with carboplatin
2.To characterize the safety and tolerability of Debio 0123 when administered
as monotherapy (Arm A) and in combination with carboplatin (Arm A and Arm B)
3.To determine the pharmacokinetic (PK) profile of Debio 0123 (and of its
metabolite N32-desmethyl-Debio 0123) when administered alone (Arm A) and in
combination with carboplatin (Arm A and Arm B)
4. For Arm B, to assess the effect of food and high gastric pH (concomitant
lansoprazole) on the PK of Debio 0123
5.To evaluate the relationship between plasma concentrations of Debio 0123 (and
its metabolite) and changes in QT interval corrected using Fridericia's formula
(QTcF, C-QTcF relationship)
6.To make a preliminary assessment of anti-tumor activity of Debio 0123 when
administered in combination with carboplatin in subjects with solid tumors
progressed after prior cisplatin or carboplatin containing therapy
- Expansion part:
1. To assess additional parameters relative to the preliminary antitumor
activity of Debio0123 when administered in combination with carboplatin.
2. To confirm the PK profile Debio 0123 (and its metabolite N32-desmethyl-Debio
0123) when administered at the RP2D in combination with carboplatin

Multi-center, open-label, non-randomized, uncontrolled, study with a dose
escalation part of Debio 0123 as monotherapy and in combination with
carboplatin, in subjects with advanced solid tumors that recurred or progressed
following prior cisplatin or carboplatin-containing therapy, and for which no
standard therapy of proven benefit is available. The dose escalation part will
be followed by an expansion part of Debio-0123 in combination with carboplatin
in subjects with platinum-resistant, recurrent epithelial ovarian cancer (EOC),
primary peritoneal cancer, or fallopian tube cancer.
The dose escalation part consists of 2 arms testing each a different regiment,.
Arm A includes Debio 0123 as monotherapy (first cycle only) and in combination
with carboplatin (starting with Cycle 2 until end of treatment [EOT]), and Arm
B Debio 0123 in combination with carboplatin (starting at cycle 1 until EOT) .
The dose escalation part will follow an adaptive dose-escalation design using a
modified Continual Reassessment Method (mCRM).

The expansion part of the study will start after the recommended phase 2 dose
(RP2D) has been determined in the dose escalation part. The study population
will consist of subjects with platinum-resistant, recurrent, histologically or
cytologically confirmed high-grade (serous, clear cell, or endometrioid) EOC,
primary peritoneal cancer, or fallopian tube cancer. The subjects will receive
Debio 0123 in combination with carboplatin starting at Cycle 1 and continue
treatment until EOT.

Debio 0123 is formulated for oral administration in capsules of 20 mg, 30 mg,
60 mg, 100 mg, 130 mg and 150 mg strength (10 mg mini-tablets in hard gelatin
capsules)
Carboplatin: concentrate for solution for infusion.

When participating to the study, patients enrolled in arm A will have to visit
the study sites during the screening period (on 2 consecutive days), cycle 1
(13 times), cycle 2 (6 times), and cycles 3 and all subsequent cycles (also 6
times per cycle), for receiving the study treatments (Debio 0123 is
administered on day -3 of cycle 1, then on days 1 to 3 of each cycle.
Carboplatin is infused on day 1, starting from cycle 2 onwards).

Patients enrolled in arm B will have to visit the study sites during the
screening period , and all cycles (13 times, visits on site may be reduced up
to 7 times), for receiving the study treatments (Debio 0123 is administered on
day 1, 2, 3, 8, 9 and 10 of each cycle, Carboplatin is infused on day 1).

Patients enrolled in expansion part have to visit the study sites during the
screening, then all cycles (13 times, visit on site my be reduced), for
receiving the study treatments (Debio 0123 is administered from D1 to D3 (and
from D8 to D10 for some patients), carboplatin is infused on D1 or each cycle)
A visit for tumor assessment to be performed at cycle 3 and 5 and then once
every third cycle (from C5 anwards).
Visits of the patients at the study site will enable the monitoring of their
condition by the medical staff (e.g. cardiac function monitoring, testing of
laboratory parameters). In addition, during these visits, additional biological
samplings will be performed for pharmacokinetics, pharmacodynamics,
pharmacogenetics and biomarkers studies (samples related to pharmacokinetics
taken during all cycles, only during cycle 1 for other studies).
For patients in Arm A, starting at cycle 3 and then every 2 cycles, patients
will undergo CT-scans or MRIs on day 21 to evaluate tumor response to the study
treatment.
For patients in Arm B, at screening and EOT visit; at Day 21 of Cycles 3 and 5
and at the end of every three cycles for up to 2 years from the first drug
intake patients will undergo CT-scans or MRIs.
For patients in expansion part, patients will undergo CT-scans or MRIs at
screening, Cycle 3 D21 and Cycle 5 D21 and at D21 of every third cycle after
Cycle 5 for up to 2 years after Cycle 1 D1, EoT, and efficacy FU, every 12
weeks, if applicable.

This will also be the case at the end of treatment and then during follow-up
study visits (will be scheduled every 3 months if treatment is discontinued
before the maximum duration of 2 years for other reasons than disease
progression and until the patient is receiving another anti-cancer treatment,
and this until a maximum of two years after study treatment initiation).
Female patients will be tested for pregnancy during screening, on day -4 of
cycle 1 (baseline), then on day 21 of each subsequent cycles, and finally at
the end of treatment and 30 days after.

Moreover, participating patients will be exposed to the following main risks:
1. associated to Debio 0123 intake: QT prolongation, reduced number of red
blood cells (which can cause tiredness and shortness of breath), reduction in
the number of platelets in the blood, which increases the risk of bruising and
bleeding (thrombocytopenia), elevation of one type liver enzyme named alanine
aminotransferase and fatigue.
2. associated to carboplatin intake: hematological toxicity (leukopenia,
neutropenia, thrombocytopenia and anemia), myelosuppression, hepatic and/or
renal insufficiency, allergic reactions, neurotoxicity, ototoxicity and tumor
lysis syndrome.
3. associated to the combination of Debio 0123 and carboplatin, even if an
increased risk of side effects when both treatments are combined is not
expected. However, because it has not been proved in humans yet, this cannot
not be excluded. For this reason, special precaution will be taken when Debio
0123 and carboplatin will be administered in combination, to monitor the
presence of the following side effects: Cardiotoxicities, hematological and
gastro-intestinal toxicities.
4. Risks associated to lansoprazole are specified in the product label
5. associated to study procedures:
a. Venipuncture may cause local swelling, pain, redness, bruising, and seldom
infection.
b. Use of contrast agents for echocardiograms, CT-scans, MRIs, may cause
allergic or cardiopulmonary reactions.
c. Exposure to higher levels of radiation compared to natural environment when
undergoing CT-scans, however with a low risk of harmful effects.
d. Skin punch or tumor biopsies: invasive procedures may cause pain, bleeding,
infection, damage to nearby tissue or nerves, reaction to local anesthetic,
irritation and swelling at the site, bruising, scarring, moving cancer cells
into unaffected areas (very rare).
Based on preclinical results, development of a similar compound and medical
need for these patients, we evaluate the potential benefit as the following:
Debio 0123 exhibited a potent anti-tumoral activity as a single agent and
showed promising synergistic effects when combined with a DNA damaging agent
like carboplatin. In addition, the mechanism of action of Debio 0123 within the
cell cycle and preliminary clinical results with a similar molecule (the WEE1
inhibitor AZD1775), support the likelihood that patients may benefit from the
treatment combining Debio 0123 and carboplatin, particularly in the absence of
a standard therapy of proven benefit.
Because of the urgent medical need of these recurrent solid tumors, the
strategy of this FIH study is to create an appropriate balance between
potential risks and benefit of Debio 0123. Although there is no evidence that
the experimental drug will be providing benefit to the patients, it is in the
interest of these patients to provide them with a drug that might contribute to
improve their life expectancy.