Cholangiocarcinoma

The primary objective is to determine if treatment with infigratinib improves centrally assessed PFS compared to treatment with gemcitabine and cisplatin in subjects with advanced/metastatic or inoperable cholangiocarcinoma with FGFR2 gene fusions/ translocations. The secondary objectives are to • Evaluate the efficacy of treatment with infigratinib versus gemcitabine and cisplatin in terms of OS for subjects with advanced/metastatic or inoperable cholangiocarcinoma with FGFR2 gene fusions/translocation • Evaluate the efficacy of infigratinib treatment compared to gemcitabine and cisplatin in terms of investigator assessed PFS. • Further evaluate the efficacy in subjects treated with infigratinib versus gemcitabine and cisplatin by ORR, best overall response (BOR), duration of response and disease control rate determined centrally and by the investigator • Characterize the safety and tolerability of single agent infigratinib.

Infigratinib(BGJ398)

Infigratinib(BGJ398)

capsule
capsule

100mg/Capsules
25mg/ Capsules

The primary endpoint is PFS (from date of randomization until date of progression as
determined by independent central read or death due to any cause)

The secondary endpoints are:
• OS (from date of randomization until date of death)
• PFS as determined by the investigator
• ORR assessed centrally according to Response Evaluation Criteria in Solid Tumors
(RECIST) Version 1.1
• ORR assessed by the investigator according to RECIST Version 1.1
• BOR, disease control rate (PR + CR + stable disease [SD]), and duration of response
(only for subjects who have a response) assessed centrally and by the investigator
according to RECIST 1.1
• Type, frequency, and severity of AEs and serious AEs (SAEs), laboratory
abnormalities, and other safety findings.

1. Have histologically or cytologically confirmed non-resectable, recurrent, or
metastatic cholangiocarcinoma. Subjects with gallbladder cancer or ampulla of Vater
carcinoma are not eligible.
2. Have written documentation of local or central laboratory determination of FGFR2
gene fusions/translocations. Note: Central confirmation is not required prior to
enrollment in study.
3. Have a representative tumor sample available for central FGFR2 fusion/translocation
molecular testing. An archival tumor sample and associated pathology report may be
submitted. However, if not available, a newly obtained tumor biopsy may be
submitted instead. Note: If available FGFR2 fusion/translocation written
documentation is from the central laboratory being used in the study, a tumor sample
does not need to be submitted for central FGFR2 fusion/translocation molecular
testing.
4. Have full recovery from the following permitted prior treatments (as applicable) such
that the subject is reasonably expected to tolerate study treatment
(gemcitabine/cisplatin or infigratinib) according to the investigator’s assessment:
a. A non-curative operation (ie, R2 resection [with macroscopic residual disease] or
palliative bypass surgery only)
b. Curative surgery with evidence of non-resectable disease relapse requiring
systemic chemotherapy
c. Adjuvant radiotherapy (with or without radio-sensitizing low-dose chemotherapy)
for localized disease provided there has been clear evidence of disease
progression before inclusion in this study
d. Adjuvant chemotherapy, provided the treatment was completed >6 months before
trial entry
e. Photodynamic treatment provided there is clear evidence of disease progression at
the local site or at a new metastatic site.
5. Are ≥18 years of age of either gender.
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
7. Have a life expectancy >3 months.
8. Are able to read and/or understand the details of the study and provide written
evidence of informed consent as approved by IRB/IEC.
9. Have recovered from AEs of previous systemic anti-cancer therapies to baseline or
Grade 1, except for alopecia.
10. Are able to swallow and retain oral medication.
11. Are willing and able to comply with scheduled visits, treatment plan and laboratory
tests.
12. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test
within 7 days of the first dose of study drug. A woman is not of childbearing potential
if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal
ligation or bilateral oophorectomy at least 6 weeks before taking study drug) or if she
is postmenopausal and has had no menstrual bleeding of any kind including menstrual
period, irregular bleeding, spotting, etc., for at least 12 months, with an appropriate
clinical profile, and there is no other cause of amenorrhea (eg, hormonal therapy,
prior chemotherapy).
WOCBP and males whose sexual partners are WOCBP must agree to use barrier
contraception and a second form of highly effective contraception (Clinical Trials
Facilitation Group 2014; see Appendix 3 [Section 17.3]) while receiving study drug
and for 3 months following their last dose of study drug. Alternatively, total
abstinence is also considered a highly effective contraception method when this is in
line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.
Sexually active males must use a condom during intercourse while taking drug and
for 3 months after the last dose of the study drug and should not father a child during
this period. A condom is required to be used also by vasectomized men as well as
during intercourse with a male partner to prevent delivery of the drug via seminal
fluid.

1. Have received treatment with any systemic anti-cancer therapy for unresectable,
recurrent, or metastatic cholangiocarcinoma. Prior neoadjuvant or adjuvant therapy is
permitted if completed >6 months prior to first dose of study drug.
2. Have history of a liver transplant.
3. Have received prior or current treatment with a MEK or selective FGFR inhibitor.
4. Have neurological symptoms related to underlying disease requiring increasing doses
of corticosteroids. Note: Steroid use for management of central nervous system
tumors is allowed but must be at a stable dose for at least 2 weeks preceding study
entry.
5. Have a history of another primary malignancy within 3 years except adequately
treated in situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any
other curatively treated malignancy that is not expected to require treatment for
recurrence during the course of the study.
6. Have any other medical condition that would, in the investigator’s judgment, prevent
the subject’s participation in the clinical study due to safety concerns or compliance
with clinical study procedures.
7. Have current evidence of corneal or retinal disorder/keratopathy including, but not
limited to, bullous/band keratopathy, corneal abrasion, inflammation/ulceration,
keratoconjunctivitis, confirmed by ophthalmic examination. Subjects with
asymptomatic ophthalmic conditions assessed by the investigator to pose minimal
risk for study participation may be enrolled in the study.
8. Have a history and/or current evidence of extensive tissue calcification including, but
not limited to, the soft tissue, kidneys, intestine, myocardium, vascular system, and
lung with the exception of calcified lymph nodes, minor pulmonary parenchymal
calcifications, and asymptomatic coronary calcification.
9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral infigratinib (eg, ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, small bowel resection).
10. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, eg,
parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis
etc.
11. Are currently receiving treatment with agents that are known strong inducers or
inhibitors of CYP3A4 and medications which increase serum phosphorus and/or
calcium concentration. Subjects are not permitted to receive enzyme-inducing antiepileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone.
See Appendix 2 (Section 17.2) for details.
12. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star
fruits, pomelos, Seville oranges or products containing juice of these fruits within 7
days prior to first dose of study drug.
13. Have used medications known to prolong the QT interval and/or are associated with a
risk of Torsades de Pointes (TdP) 7 days prior to first dose of study drug.
14. Have used amiodarone within 90 days prior to first dose of study drug.
15. Are currently using therapeutic doses of warfarin sodium or any other coumadinderivative anticoagulants or using direct thrombin inhibitors (eg, argatroban) or
Factor Xa inhibitors (eg, rivaroxaban) that are primarily metabolized by CYP3A4.
Heparin and/or low molecular weight heparins or direct thrombin inhibitors and/or
Factor Xa inhibitors that are not metabolized by CYP3A4 (eg, dabigatran, edoxaban)
are allowed.
16. Have insufficient bone marrow function:
a. Absolute neutrophil count (ANC) <1,000/mm3
(1.0 × 109
/L)
b. Platelets <100,000/mm3
(<100× 109
/L)
c. Hemoglobin <9.0 g/dL
17. Have insufficient hepatic and renal function:
a. Total bilirubin >1.5 × upper limit of normal (ULN) (unless documented Gilbert’s
syndrome with approval by the medical monitor)
b. AST/ serum glutamic-oxaloacetic transaminase (SGOT) and ALT/ serum
glutamic-pyruvic transaminase (SGPT) >2.5 × ULN (AST and ALT >5 × ULN in
the presence of liver involvement of cholangiocarcinoma)
c. Calculated or measured creatinine clearance of <45 mL/min
18. Have amylase or lipase >2.0 × ULN
19. Have abnormal calcium-phosphate homeostasis:
a. Inorganic phosphorus outside of local normal limits
b. Total corrected serum calcium outside of local normal limits
20. Have clinically significant cardiac disease including any of the following:
a. Congestive heart failure requiring treatment (New York Heart Association
Grade ≥2), LVEF <50% or local lower limit of normal as determined by MUGA
scan or echocardiogram (ECHO), or uncontrolled hypertension (refer to the
European Society of Cardiology and European Society of Hypertension
guidelines [Williams et al 2018]; see Appendix 3 [Section 17.3])
b. Presence of Common Terminology Criteria for Adverse Events (CTCAE) v4.0 or
later Grade ≥2 ventricular arrhythmias, atrial fibrillation, bradycardia, or
conduction abnormality
c. Unstable angina pectoris or acute myocardial infarction ≤3 months prior to first
dose of study drug
d. QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first
ECG, a total of 3 ECGs separated by at least 5 minutes should be performed. If
the average of these 3 consecutive results for QTcF is ≤470 msec, the subject
meets eligibility in this regard
e. Known history of congenital long QT syndrome
21. Have had a recent (≤3 months prior to first dose of study drug) transient ischemic
attack or stroke
22. CTCAE (v4.0 or later) Grade ≥2 hearing loss
23. CTCAE (v4.0 or later) Grade ≥2 neuropathy
24. If female, is pregnant or nursing (lactating), where pregnancy is defined as the state of
a female after conception and until the termination of gestation, confirmed by a
positive human chorionic gonadotrophin urine or blood laboratory test.
25. Have known microsatellite instability-high (MSI-H) disease and the decision is made
by the treating investigator that an alternative, non-study therapy is warranted
according to standard of care.