Oral Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations
Bladder Cancer
Unknown Primary
18 Years and older, Male and Female
QBGJ398-302 (primary)
NCI-2020-00610
2019-003248-63
Summary
This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate
the efficacy of infigratinib (an oral targeted FGFR1-3 inhibitor) versus placebo, as adjuvant
treatment following surgery in adult subjects with invasive urothelial carcinoma and
susceptible FGFR3 genetic alterations (mutations, and gene fusions or rearrangements) who
have disease that is considered at high risk for recurrence with surgery alone. The study
enrolls subjects with either bladder cancer post radical cystectomy or upper tract urothelial
cancer post distal ureterectomy and/or nephrectomy. Study treatment is randomized 1:1 between
infigratinib or placebo with treatment up to 1 year or until invasive local, distal, or
metastatic disease recurrence confirmed by independent imaging reviewer.
Eligibility
- Are randomized within 120 days following nephroureterectomy, distal ureterectomy or cystectomy.
- 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).
- 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
- - 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).
- 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.
- If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant chemotherapy based on Galsky criteria:
- 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:
- 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.
- Have Eastern Cooperative Oncology Group (ECOG) performance status of =2.
- 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
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