solid tumor

Primary objective Dose-escalation part To identify the dose-limiting toxicities (DLTs) and estimate the maximum tolerated dose (MTD) of Debio 1347 (CH5183284) based on the safety and tolerability of Debio 1347 (CH5183284) orally administered daily to patients with advanced solid malignancies, whose tumours have an alteration of the FGFR1-3 genes. Expansion part To confirm the safety profile at the RD of 80 mg once daily in a larger cohort of patients. Secondary objectives Dose-escalation part For each Debio 1347 (CH5183284) DL and overall: 1. To determine the RD for the expansion phase of Debio1347 (CH5183284). 2. To make a preliminary assessment of anti-tumour activity of Debio 1347 (CH5183284) in patients with advanced solid malignancies, whose tumours have an alteration of the FGFR1-3 genes. 3. To measure pharmacokinetic (PK) parameters of Debio1347 (CH5183284). 4. To make an assessment of biologic markers that act as PDy indicators of Debio1347 (CH5183284). Expansion part 1. To explore the anti-tumour activity of Debio 1347 (CH5183284) in patients with selected advanced solid malignancies presenting an alteration of the FGFR1-3 gene structure or expression level. 2. To measure PK parameters of Debio 1347 (CH5183284) at the RD of 80 mg once daily. 3. To make a preliminary assessment of biologic markers of Debio 1347 (CH5183284) anti-tumour activity in patients with advanced solid malignancies, whose tumours have an alteration of the FGFR1-3 gene structure or expression level.

Debio 1347 (CH5183284)

Debio 1347 (CH5183284)

tablet

錠劑 (20, 30, 50, 100 mg)、膠囊 (10, 20 mg)

Primary endpoint
Occurrence of DLTs.
Secondary endpoints
For each Debio 1347 (CH5183284) DL, formulation, and overall:
1. Incidence of treatment-emergent SAEs.
2. Incidence and severity of treatment-emergent AEs and laboratory abnormalities, graded
according to NCI-CTCAE v4.03 criteria.
3. Incidence of treatment discontinuations and treatment modifications due to AEs and
laboratory abnormalities.
4. Change in vital signs, ECG, LVEF and ECOG PS.
5. Changes in ophthalmological exams.
6. Tumour response according to RECIST version 1.1 criteria: Best overall response (BOR),
disease control rate, best change in tumour size.
7. Progression-free survival overall and rate at 6 months, 1year, and 2 years from treatment
initiation.
8. Pharmacokinetic parameters of Debio 1347 (CH5183284) in plasma (Cmax, tmax, t½, AUC0-
t, AUC, AUC∞, λz, MRT, CL/F, Vz/F, PTF, RAUC, RCmax, LI, Css av, Ctrough, as applicable)
following the single Day -9 dose (only formulation switch cycles) and
Day -2 dose and following 28 days of continuous dosing.
In addition, for the cohorts included in the formulation switch analysis:
Intra-patient relative oral bioavailability (as estimated by Debio 1347 plasma AUCτ following the
new tablet formulation vs the original capsule formulation).

1. Signed written informed consent approved before undertaking any study-specific
procedures.
2. Patients with advanced solid malignancies, whose tumours have an alteration of the
FGFR1-3 genes, confirmed by local site genetic tests on a biopsy. Archival tumour
samples obtained from primary and/or metastasis sites are acceptable. Methods and
related pre-specified cut-off points for definition of FGFR1-3 gene alterations
(amplification, mutation and translocation) are described in Section 22.1.
3. Age ≥ 18 years.
4. ECOG PS ≤ 2.
5. Histologically or cytologically confirmed advanced solid tumour that has recurred or
progressed following standard therapy, has not responded to standard therapy or for which
no standard therapy exists.
6. Patients have measurable or non-measurable disease according to RECIST version 1.1
criteria.
7. A minimum of seven up to a maximum of twenty unstained tumour biopsy slides are
available for retrospective central confirmation of FGFR status.
8. Adequate organ function as determined by the following laboratory results, within 28 days
prior to enrolment:
a. Absolute neutrophil count ≥ 1.5x109
/L;
b. Platelet count ≥ 100 x109
/L;
c. Haemoglobin ≥ 8.0 g/dL (Patients may receive erythrocyte transfusions to
achieve this haemoglobin level at the discretion of the Investigator. Only the
haemoglobin value obtained more than 1 week from the last erythrocyte
transfusion will be used for the evaluation of the patient’s eligibility);
d. Blood creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 60 mL/min
(Cockroft and Gault formula);
e. Total bilirubin ≤ 1.5 × ULN;
f. AST, ALT ≤ 2.5 × ULN (≤ 5 × ULN in patients with liver metastases);
g. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN in patients with bone
metastases), γGTP ≤ 2.5 × ULN;
h. Albumin ≥ 2.5 g/dL;
i. Corrected calcium ≤ 1.1 x ULN;
j. Phosphate ≤ 1.1 x ULN;
k. PT and/or PT-INR and/or APTT ≤ 1.3 x ULN.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures.
10. Estimated life expectancy of at least 16 weeks.

1. History of hypersensitivity to any of the excipients in the Debio 1347 (CH5183284)
formulation (lactose hydrate, microcrystalline cellulose, croscarmellose sodium,
hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate).
2. Other malignancies requiring active treatment in the last 6 months. Individuals with the
following cancers are eligible if diagnosed and treated within the past 5 years: any
carcinoma in situ, and basal cell or squamous cell carcinoma of the skin.
3. Dose-escalation part: Brain tumours and/or brain metastases unless they are
asymptomatic, stable on recent imaging (not dated more than 30 days from the inclusion
date), and have not required active treatment in the last 6 months.
Expansion part: Brain tumours (other than glioblastoma harbouring any FGFR fusion –
see expansion part inclusion criterion 3) and/or brain metastases unless they are
asymptomatic, stable on recent imaging (not dated more than 30 days from the inclusion
date) and have not required active treatment in the last 6 months.
4. History and/or current evidence of endocrine alteration of calcium-phosphate
homeostasis.
5. History of myocardial infarction or stroke within 6 months, congestive heart failure
greater than NYHA class II, unstable angina pectoris, unexplained recurrent syncope,
cardiac arrhythmia requiring treatment or family history of sudden death from
cardiac-related causes.
6. Baseline Fredericia’s corrected QT (QTcF) interval greater than 470 msec (female) or
greater than 450 msec (male), history of congenital long QT syndrome, the presence in
the screening ECG of a conduction abnormality that in the opinion of the Investigator
would preclude safe participation in this study.
7. Dose-escalation part only: Concomitant use of a drug with a known risk of QTc
prolongation (see Section 21.2).
8. Current anticoagulation therapy with therapeutic doses of warfarin (low-dose warfarin ≤
1 mg/day or low molecular-weight heparin are permitted).
9. History and or current evidence of ectopic mineralisation/calcification including but not
limited to the soft tissue, kidneys, intestine, myocardium and lung with the exception of
calcified lymph nodes and asymptomatic coronary calcification.
10. Concomitant use of a systemic steroid or any other drug that affect calcium and
phosphorus metabolism (e.g., bone/calcium metabolising drugs, such as anti-RANKL
antibody, calcitonin preparations, bisphosphonate preparations, active Vitamin D3
preparations, estrogen preparations, selective estrogen receptor modulators, Vitamin K2
preparations, calcium preparations, parathyroid hormones, phosphorus adsorbers).
Expansion part: Except for glioblastoma patients in whom administration of systemic
corticosteroids is authorised (see inclusion criterion 3 expansion part).
11. Corneal disease, such as bullous or band keratopathy, corneal desquamation, keratitis,
corneal ulcer, or keratoconjunctivitis.
12. Known infection requiring the systemic use of, for example, an antibiotic or antiviral
agent.
13. Active or HBeAg positive chronic HBV.
14. HCV infection (except cured HCV with HCV RNA test negative).
15. HIV infection.
16. Known untreated or uncontrolled acute infection, including urinary tract infection, within
7 days of study entry.
17. History of organ, bone marrow, or stem cell transplantation.
18. Pregnant or lactating woman with positive pregnancy test result within 7 days of starting
study treatment (any woman of childbearing potential who has menstruated within the
year prior to enrolment will undergo pregnancy testing).
19. Women of childbearing potential or men who are unwilling to use an appropriate method
of contraception during the study period and for 6 months after completing treatment with
Debio1347 (CH5183284). Oral or injectable contraceptive agents cannot be the sole
method of contraception.
20. Poorly controlled diabetes mellitus or hypertension (e.g., systolic > 180 mmHg or
diastolic > 100 mmHg).
21. Inability or unwillingness to swallow oral medications.
22. Clinically significant gastrointestinal abnormality that would affect the absorption of drug
such as gastrointestinal dysfunction, malabsorption syndrome, major resection of the
small bowel or total gastrectomy or inflammatory bowel disease.
23. Uncontrolled hydropericardium.
24. Chemotherapy or radiotherapy within 14 days prior to starting study treatment. In case of
monoclonal antibodies/biologics, within 28 days prior to starting study treatment.
25. Administration of investigational agents within 28 days prior to treatment initiation.
26. Major surgery and surgery for brain metastases within 28 days prior to screening start.
Intravenous port placement is not considered as a major surgery.
27. Not recovered from adverse events (AEs) or toxicities due to previous treatments to a
Grade 1 or less specified in NCI-CTCAE v4.03 excepting haemoglobin (< 8.0 g/dL),
albumin (< 2.5 g/dL) and alopecia.
28. Prior use of a selective drug targeting FGF or FGFR1-3. Patients previously treated with
medications that affect FGFR signaling as a secondary target (e.g., multi-tyrosine kinase
inhibitors that primarily inhibit VEGF, but to a lesser extent also affect FGFR1-3
signaling) can be considered after discussion with the Medical Monitor.
29. Currently under alcohol or drug abuse rehabilitation or treatment program.
30. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit
compliance with study requirements.