Oral Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations

Key Inclusion Criteria

1. Are randomized within 120 days following nephroureterectomy, distal ureterectomy orcystectomy.
2. Have histologically or cytologically confirmed, invasive urothelial carcinoma withsusceptible FGFR3 alterations. Variant histology is allowed provided urothelialcarcinoma is predominant (>50%). Neuroendocrine (including small and large cell),sarcomatoid, and plasmacytoid variants are excluded (any component).
3. Regarding samples and documentation of FGFR3

• i. FGFR3 mutation is confirmed if: FGFR3 gene is mutated in Exon 7 (R248C,S249C), Exon 10 (G370C, A391E, Y373C), or Exon 15 (K650M/T, K650E/Q) OR
• ii. FGFR3 gene fusion or FGFR3 rearrangement is confirmed based on thefollowing genomic criteria if:
• Any fusion/rearrangement with a literature-derived known partner generegardless of strand or frame.
• Fusion/rearrangements in the same strand that are in frame with a novelpartner gene.
• Fusion/rearrangements with one breakpoint in the intron 17 - exon 18hotspot region and the other breakpoint in an intergenic region oranother gene. This rule excludes 3' duplications comprising only exon

• iii. The amino acid numbers for the FGFR3 mutations refer to the functionalFGFR3 isoform 1 (NP_000133.1) that is the NCBI Refseq ID used to reportgenetic alterations in FGFR3 by the FoundationOne® CDx test (F1CDx,Foundation Medicine, USA).
• iv. FGFR3 alteration must be confirmed by Foundation Medicine for F1CDxtesting:
• The tumor sample to be used should be from the definitive surgicalresection (cystectomy, nephroureterectomy, or distal ureterectomy), orfrom an archival biopsy of confirmed invasive urothelial carcinoma (≥pT2).

2. If status post neoadjuvant chemotherapy, pathologic stage at surgical resectionmust be Stage ≥ ypT2 and/or yN+. Prior neoadjuvant therapy is defined as at least 3 cycles of neoadjuvant cisplatin-based chemotherapy with a planned cisplatindose of 70 mg/m2/cycle. Subjects who received less than this ornon-cisplatin-based neoadjuvant treatment are not excluded.
3. If not status post neoadjuvant chemotherapy, is ineligible to receivecisplatin-based adjuvant chemotherapy based on Galsky criteria:
4. Subjects who refuse cisplatin-based chemotherapy or who are ineligible to receivecisplatin-based chemotherapy based on Galsky criteria must also meet thefollowing criteria:
5. Must have a centrally reviewed negative postoperative computed tomography (CT) (defined as lymph nodes with short axis <1.0 cm and without growth and no distantmetastases according to [RECIST v1.1 criteria or negative biopsy within 28 daysbefore randomization to confirm absence of disease at baseline.
6. Have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
7. If a woman of childbearing potential, must have a negative pregnancy test within 7days of the first dose of study drug. Sexually active males must use a condom duringintercourse while taking study drug and for 1 month after the last dose of study drugand should not father a child during this period

Key Exclusion Criteria:

1. Presence of positive invasive surgical margins following nephroureterectomy, distalureterectomy, or cystectomy. In subjects not eligible for further surgery,radiotherapy, or other efficacious treatment, microscopic positive noninvasive margins (eg, carcinoma in situ) without gross residual disease are allowed.
2. Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy forNon-Muscle Invasive Bladder Cancer (NMIBC) within the previous 30 days.
3. Are currently receiving or are planning to receive during participation in this study,treatment with agents that are known moderate or strong inducers or inhibitors ofCYP3A4 and medications which increase serum phosphorus and/or calcium concentration.Prior anticancer or other therapies are restricted as follows:
4. Prior adjuvant treatment for urothelial cancer is not allowed.
5. Prior neoadjuvant therapy (eg, chemotherapy, immunotherapy, or investigational)is allowed if inclusion criterion #4 is met. Prior neoadjuvant chemotherapy musthave been completed within a period of time that is greater than the cycle lengthused for that treatment before first dose of study drug.
6. Prior biologic, immunotherapy, or investigational therapy should have beencompleted within a period that is ≥5 half-lives or 30 days, whichever is shorter,before the first dose of study drug.
7. Have previously or currently is receiving treatment with a mitogen-activated proteinkinase (MEK) or selective FGFR inhibitor.
8. Have a history of primary malignancy within the past 3 years other than (1) invasiveUBC or UTUC (ie, disease under study), (2) noninvasive urothelial carcinoma, (3) anyadequately treated in situ carcinoma or non-melanoma carcinoma of the skin, (4) anyother curatively treated malignancy that is not expected to require treatment forrecurrence during participation in the study, or (5) an untreated cancer on activesurveillance that may not affect the subject's survival status for ≥3 years based onclinician assessment/statement and with medical monitor approval.
9. Have current evidence of corneal keratopathy or retinal disorder confirmed byophthalmic examination. Subjects with asymptomatic ophthalmic conditions assessed bythe investigator to pose minimal risk for study participation may be enrolled in thestudy.
10. Have a history and/or current evidence of extensive tissue calcification
11. Have impaired gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of oral infigratinib
12. Have current evidence of endocrine alterations of calcium/phosphate homeostasis (eg,parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis),unless well controlled.
13. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, starfruits, pomelos, or Seville oranges or products containing juice of these fruitswithin 7 days before the first dose of study drug; have taken any Chinese herbalmedicine or Chinese patent medicine treatments with anticancer activity within 14 daysof the first dose of study drug.
14. Have insufficient bone marrow function:
15. Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L).
16. Platelets <75,000/mm3 (<75 × 109/L).
17. Hemoglobin <8.5 g/dL; transfusion support is allowed if >1 week beforerandomization and hemoglobin remains stable.
18. Have insufficient hepatic and renal function:
19. Total bilirubin >1.5 × upper limit of normal (ULN) of the testing laboratory (forsubjects with documented Gilbert syndrome, direct bilirubin must be ≤1.5 × ULNand enrollment requires approval by the medical monitor).
20. AST/SGOT and ALT/SGPT >2.5 × ULN of the testing laboratory.
21. Serum creatinine >1.5 × ULN or a calculated or measured creatinine clearance of <30 mL/min.
22. Have amylase or lipase >2.0 × ULN.
23. Have abnormal calcium or phosphorus:
24. Inorganic phosphorus higher than 1.02 × ULN of the testing laboratory.
25. Total serum calcium (can be corrected) higher than 1.02 × ULN of the testinglaboratory.
26. Have clinically significant cardiac disease including any of the following:
27. New York Heart Association (NYHA) Class ≥2B; subjects with known history orcurrent symptoms of cardiac disease, or history of treatment with cardiotoxicagents, should have a clinical risk assessment of cardiac function using the NYHAclassification.
28. Uncontrolled hypertension
29. Presence of CTCAE v5.0 Grade ≥2 ventricular arrhythmias, atrial fibrillation,bradycardia, or conduction abnormality.
30. Unstable angina pectoris or acute myocardial infarction ≤3 months before thefirst dose of study drug.
31. Average QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in thefirst ECG, a total of 3 ECGs separated by ≥5 minutes should be performed. If theaverage of these 3 consecutive results for QTcF is ≤470 msec, the subject meetseligibility in this regard.
32. History of congenital long QT syndrome.
33. Have had a recent (≤3 months before the first dose of study drug) transient ischemicattack or stroke.
34. If female, are pregnant or nursing (lactating).