Solid Tumors

Primary objective To assess the efficacy of Debio 1347 in terms of objective response rate (ORR) in subjects with solid tumors harboring FGFR1-3 gene fusion/rearrangement. Secondary objectives 1. To evaluate the efficacy of Debio 1347 in terms of duration of response (DoR), DCR, progression free survival (PFS) and overall survival (OS). 2. To assess the safety of Debio 1347. 3. To assess exposure-response relationships vs efficacy and safety (notably QTcF).

Debio 1347

Debio 1347

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ORR (defined as the proportion of subjects with a BOR of partial or complete response) as centrally
measured by RECIST 1.1 criteria

1. Written informed consent given according to International Conference on Harmonisation
(ICH)/Good Clinical Practice (GCP) guidelines and local regulations.
2. Cytologically or histologically confirmed advanced solid tumor.
3. Radiographic progression on prior systemic therapy; prior localized therapy (i.e., radiation,
ablation, embolization) is allowed provided radiographic progression out-of-field or in the
treatment field is shown.
4. Male or female ≥18 years of age.
5. Locally-advanced (unresectable) or metastatic disease harboring an FGFR1-3 gene
fusion/rearrangement potentially leading to a functional FGFR aberrant protein, identified
through local and/or central molecular assay.
6. The subject must have received at least one prior line of standard therapy appropriate for their
tumor type and stage of disease (if available), and, in the opinion of the Investigator, s/he would
have been unlikely to tolerate or derive clinically meaningful benefit from further appropriate
standard of care therapy. In particular:
a. Biliary tract cancer subjects must have progressed on/after gemcitabine-based
chemotherapy (including subjects who progressed within 6 months of gemtabicine-based
adjuvant chemotherapy). Subjects can have received additional chemotherapy after
documented intolerance to gemcitabine.
b. Urothelial cancer subjects must have progressed on/after cisplatin-based or
carboplatin-based chemotherapy either given for advanced disease or within 12 months
from completion if given as neoadjuvant or adjuvant therapy and anti-PD1/PDL1 therapy
(unless not available, contraindicated for some reasons or refused by the subject).
c. NSCLC subjects must have progressed on chemotherapy and anti-PD1/PDL1 therapy
(unless contraindicated for some reasons). Subjects with known EGFR mutations, ALK
rearrangement or BRAF V600E mutation must have received the relevant target therapy
(unless not available).
d. For all other tumor types, subjects must have progressed on/after appropriate standard of
care (SOC) therapy (evidence-based level 1). Subjects who harbor genomic aberrations
for which approved target therapy is available must have received such therapy. HER2+
or ER/PR+ breast cancer subjects should have received at least one line of HER2-targeted
or ER-targeted, respectively.
7. Measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST)
criteria version 1.1.
8. Eastern Cooperative Oncology Group (ECOG) (see Appendix A) performance status (PS) of
0 to 1.
9. Screening laboratory values as follows:
a. Absolute neutrophil count (ANC) ≥ 1,000/mm3
[1.0 x 109/L].
b. Platelet count ≥ 75,000/mm3[75 x 109/L].
c. Hemoglobin ≥ 8.0 g/dL.
d. Total bilirubin ≤ 2 x upper normal limit (UNL) [biliary stent allowed]. A subject with an
isolated elevation of indirect bilirubin is eligible.
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x UNL (5 x
UNL in the presence of liver metastases).
f. Calculated or measured creatinine clearance ≥ 30 mL/min (creatinine clearance measured
based on 24-hour urine collection should be considered to help assess eligibility).
g. Serum phosphate < 1.5 x UNL.
10. Female subjects of child-bearing potential must have a negative serum pregnancy test (minimum
sensitivity of 25 mIU/mL) at screening and be willing to practice the highly effective
contraception methods listed below from the time of study entry up to 6 months after the last day
of treatment:
a. Intrauterine device (IUD)
b. Intrauterine hormone-releasing system (IUS)
c. Bilateral tubal occlusion
d. Vasectomized partner
e. Sexual abstinence if corresponds to usual and preferred lifestyle of subject.
For hormonal contraceptives see Section 7.7.1.
Of note:
- Female subjects of non-childbearing potential are defined as either pre-menopausal with a
documented tubal ligation or hysterectomy or post-menopausal with 12 months of
spontaneous amenorrhea.
- Female subjects of child-bearing potential must refrain from donating egg(s) during the
clinical study and for 6 months after Debio 1347 discontinuation.
- Male subjects must agree to use a condom from study entry and up to 6 months after the last
day of treatment. The subject’s female partner should use highly effective contraception
methods, which may include hormonal contraceptives or any of the methods outlined above,
during this period.
- Male subjects must refrain from donating sperm during the clinical study and for 6 months
after Debio 1347 discontinuation.
11. Available fresh tumor sample (preferably) or, if no fresh sample can be obtained, archived tumor
sample (slides or block) for central analysis of FGFR status or retrospective central confirmation
in case of local screening.
Of note: A "liquid biopsy", e.g., ctDNA based test is acceptable for subject eligibility but then a
pre-study treatment tissue sample is required for post-hoc confirmation of the fusion.
12. Life expectancy ≥ 3 months.

1. History of hypersensitivity to any of the excipients in the Debio 1347 formulation (lactose
hydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium
lauryl sulfate and magnesium stearate).
2. Prior treatment with a FGFR1-3 selective inhibitor.
3. History and/or current evidence of ectopic mineralization/calcification, including but not limited
to soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes, lung
nodules and asymptomatic vascular or cartilage/tendon calcifications.
4. Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic
examination.
5. Chemotherapy, radiotherapy or small molecule anti-cancer agents within 2 weeks prior to initial
dosing with Debio 1347 (3 weeks for immune checkpoint inhibitors).
6. Administration of any investigational agent within 2 weeks prior to initial dosing with
Debio 1347 (3 weeks for immune checkpoint inhibitors).
7. Surgery requiring general anesthesia, except diagnostic biopsy or local procedure, within 3 weeks
prior to initial dosing with Debio 1347 and/or if the subject has not fully recovered from the
surgery.
8. Grade > 1 (National Cancer Institute Common Terminology Criteria for Adverse Events
NCI-CTCAE v5.0) AEs or toxicities from previous treatments except:
a. Albumin (≥ 2.5 g/dL is allowed).
b. AST and ALT in subjects with liver metastases ( 5 × ULN is allowed).
c. Alkaline phosphatase (ALP) in subjects with bone metastases ( 5 × ULN is allowed).
d. Any grade of alopecia is allowed.
e. Other Grade 1-2 clinically insignificant laboratory abnormalities are allowed.
9. Symptomatic or unstable brain metastases < 1 month (Of note: Subjects with asymptomatic
stable and treated brain metastases are eligible).
10. Total corrected and/or ionized serum calcium ≥ 1.5 x UNL (corrected calcium = [0.8 x (normal
albumin - subject albumin)] + serum calcium level).
11. Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, gastric
resection, significant bowel obstruction, active ulcerative colitis, active Crohn’s disease).
12. Concomitant treatment with a prohibited medication.
13. Subjects with a known history of uncontrolled or unstable angina or myocardial infarction within
the last 6 months, unstable cardiac arrhythmias despite treatment (subjects with a history of atrial
fibrillation stabilized under treatment are allowed), unexplained recurrent syncope, family
history of sudden death from cardiac-related causes, congestive heart failure greater than New
York Heart Association (NYHA) class II, uncontrolled diabetes, uncontrolled psychiatric
disorders, severe ongoing infections or any other medical condition that might be aggravated by
the treatment on evaluation.
14. Prolongation of QTcF interval to greater than 480 msec.
15. History of congenital long QT syndrome
16. History of another malignancy other than the primary tumor within the last 2 years, with the
exception of completely resected basal or squamous cell skin cancer or any successfully treated in-situ carcinoma, or clinically insignificant prostate cancer without any treatment intent (either
treated or on active surveillance/watchful waiting). Other cancers within the last 2 years that are
considered clinically insignificant by the treating physician should be discussed with the study
Sponsor to assess eligibility.
17. Known infection requiring the systemic use of, for example, an antibiotic or antiviral agent.
18. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit
compliance with study requirements.
19. If female, pregnant or breast feeding.
20. Unable to swallow and retain oral medications.
21. Known contraindication to enhanced magnetic resonance imaging (MRI) and/or computerised
tomography (CT) scan.