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 or cystectomy.
2. Have histologically or cytologically confirmed, invasive urothelial carcinoma with susceptible FGFR3 alterations. Variant histology is allowed provided urothelial carcinoma is predominant (\>50%). Neuroendocrine (including small and large cell), sarcomatoid, and plasmacytoid variants are excluded (any component).

   1. 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 the following genomic criteria if:

        * Any fusion/rearrangement with a literature-derived known partner gene regardless of strand or frame.
        * Fusion/rearrangements in the same strand that are in frame with a novel partner gene.
        * Fusion/rearrangements with one breakpoint in the intron 17 - exon 18 hotspot region and the other breakpoint in an intergenic region or another gene. This rule excludes 3' duplications comprising only exon 18.
      * iii. The amino acid numbers for the FGFR3 mutations refer to the functional FGFR3 isoform 1 (NP\_000133.1) that is the NCBI Refseq ID used to report genetic alterations in FGFR3 by the FoundationOne® CDx test (F1CDx, Foundation Medicine, USA).
      * iv. FGFR3 alteration must be confirmed by Foundation Medicine for F1CDx testing:

        * The tumor sample to be used should be from the definitive surgical resection (cystectomy, nephroureterectomy, or distal ureterectomy), or from an archival biopsy of confirmed invasive urothelial carcinoma (≥pT2).
   2. If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be Stage ≥ ypT2 and/or yN+. Prior neoadjuvant therapy is defined as at least 3 cycles of neoadjuvant cisplatin-based chemotherapy with a planned cisplatin dose of 70 mg/m2/cycle. Subjects who received less than this or non-cisplatin-based neoadjuvant treatment are not excluded.
   3. If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant chemotherapy based on Galsky criteria:
   4. Subjects who refuse cisplatin-based chemotherapy or who are ineligible to receive cisplatin-based chemotherapy based on Galsky criteria must also meet the following 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 distant metastases according to \[RECIST v1.1 criteria or negative biopsy within 28 days before randomization to confirm absence of disease at baseline.
3. Have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
4. If a woman of childbearing potential, must have a negative pregnancy test within 7 days of the first dose of study drug. Sexually active males must use a condom during intercourse while taking study drug and for 1 month after the last dose of study drug and should not father a child during this period

Key Exclusion Criteria:

1. Presence of positive invasive surgical margins following nephroureterectomy, distal ureterectomy, 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 for Non-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 of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration. Prior anticancer or other therapies are restricted as follows:

   1. Prior adjuvant treatment for urothelial cancer is not allowed.
   2. Prior neoadjuvant therapy (eg, chemotherapy, immunotherapy, or investigational) is allowed if inclusion criterion #4 is met. Prior neoadjuvant chemotherapy must have been completed within a period of time that is greater than the cycle length used for that treatment before first dose of study drug.
   3. Prior biologic, immunotherapy, or investigational therapy should have been completed within a period that is ≥5 half-lives or 30 days, whichever is shorter, before the first dose of study drug.
4. Have previously or currently is receiving treatment with a mitogen-activated protein kinase (MEK) or selective FGFR inhibitor.
5. Have a history of primary malignancy within the past 3 years other than (1) invasive UBC or UTUC (ie, disease under study), (2) noninvasive urothelial carcinoma, (3) any adequately treated in situ carcinoma or non-melanoma carcinoma of the skin, (4) any other curatively treated malignancy that is not expected to require treatment for recurrence during participation in the study, or (5) an untreated cancer on active surveillance that may not affect the subject's survival status for ≥3 years based on clinician assessment/statement and with medical monitor approval.
6. Have current evidence of corneal keratopathy or retinal disorder 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.
7. Have a history and/or current evidence of extensive tissue calcification
8. Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib
9. Have current evidence of endocrine alterations of calcium/phosphate homeostasis (eg, parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis), unless well controlled.
10. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, or Seville oranges or products containing juice of these fruits within 7 days before the first dose of study drug; have taken any Chinese herbal medicine or Chinese patent medicine treatments with anticancer activity within 14 days of the first dose of study drug.
11. Have insufficient bone marrow function:

    1. Absolute neutrophil count (ANC) \<1,000/mm3 (1.0 × 109/L).
    2. Platelets \<75,000/mm3 (\<75 × 109/L).
    3. Hemoglobin \<8.5 g/dL; transfusion support is allowed if \>1 week before randomization and hemoglobin remains stable.
12. Have insufficient hepatic and renal function:

    1. Total bilirubin \>1.5 × upper limit of normal (ULN) of the testing laboratory (for subjects with documented Gilbert syndrome, direct bilirubin must be ≤1.5 × ULN and enrollment requires approval by the medical monitor).
    2. AST/SGOT and ALT/SGPT \>2.5 × ULN of the testing laboratory.
    3. Serum creatinine \>1.5 × ULN or a calculated or measured creatinine clearance of \<30 mL/min.
13. Have amylase or lipase \>2.0 × ULN.
14. Have abnormal calcium or phosphorus:

    1. Inorganic phosphorus higher than 1.02 × ULN of the testing laboratory.
    2. Total serum calcium (can be corrected) higher than 1.02 × ULN of the testing laboratory.
15. Have clinically significant cardiac disease including any of the following:

    1. New York Heart Association (NYHA) Class ≥2B; subjects with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the NYHA classification.
    2. Uncontrolled hypertension
    3. Presence of CTCAE v5.0 Grade ≥2 ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction abnormality.
    4. Unstable angina pectoris or acute myocardial infarction ≤3 months before the first dose of study drug.
    5. Average QTcF \>470 msec (males and females). Note: If the QTcF is \>470 msec in the first ECG, a total of 3 ECGs separated by ≥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.
    6. History of congenital long QT syndrome.
16. Have had a recent (≤3 months before the first dose of study drug) transient ischemic attack or stroke.
17. If female, are pregnant or nursing (lactating).