Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial of Infigratinib for the Adjuvant Treatment of Subjects with Invasive Urothelial Carcinoma with Susceptible FGFR3 Genetic Alterations (PROOF 302)
- Conditions
- Invasive Urothelial Carcinoma with Susceptible FGFR3 Genetic Alterationsbladder cancerUrothelial Carcinoma10046447
- Registration Number
- NL-OMON55032
- Lead Sponsor
- QED Therapeutics, Inc.
- Brief Summary
Trial ended prematurely
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 5
1. Are >=18 years of age (>=20 years of age in Taiwan) of either sex.
2. Have signed informed consent.
3. Are randomized within 120 days following nephroureterectomy, distal
ureterectomy, or cystectomy. Note: at the time of definitive surgery,
lymph node dissection (LND) should be performed in cases of suspected
lymph node invasion based on preoperative imaging or intraoperative
findings. In other cases, LND is to be performed in accordance with
surgeon preferences/local standard practices. Additional details on
recommended standards for LND are provided in the protocol.
4. 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):
a. Regarding samples and documentation of FGFR3 alterations:
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:
(1) Any fusion/rearrangement with a literature-derived known partner
gene regardless of strand or frame.
(2) Fusion/rearrangements in the same strand that are in frame with a
novel partner gene.
(3) 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. Written documentation of central laboratory determination by F1CDx
testing of FGFR3 alterations is required for study eligibility.
v. For subjects who require molecular prescreening to confirm the
presence of the FGFR3 alteration to meet the inclusion criteria, a tumor
sample with a pathology report must be sent to Foundation Medicine
USA for F1CDx testing. (Instructions for optimal tumor specimens are
provided in the protocol).
(1) The tumor sample to be used should be from the definitive surgical
resection (cystectomy, nephroureterectomy, or distal ureterectomy).
(2) An archival biopsy of confirmed invasive urothelial carcinoma (>=pT2)
can be used if (1) tissue from definitive surgery cannot be submitted, (2)
the biopsy sample is not older than 4 months prior to surgery date and
(3) the subject did not receive any type of systemic anticancer treatment
since the biopsy was obtained. If more than one biopsy is available, the
most recent one is to be sent.
b. 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 enrolled, they will be stratified as having
received no neoadjuvant chemotherapy.
c. If not status post neoadjuvant chemotherapy, is
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 nonmuscle 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. Subjects are not permitted to
receive enzyme-inducing antiepileptic drugs, including carbamazepine,
phenytoin, phenobarbital, and primidone. Prior anticancer or other
therapies are restricted as follows:
a. Prior adjuvant treatment for urothelial cancer is not allowed.
b. 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
the first dose of study drug.
c. 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. Are planning to receive other systemic therapies intended to treat
invasive urothelial carcinoma while on this study.
5. Have previously or currently is receiving treatment with a mitogenactivated
protein kinase (MEK) or selective FGFR inhibitor.
6. 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. For any other cancers that do not meet the criteria
above, and for which the natural history or treatment do not have the
potential to interfere with the safety or the efficacy assessments of the
study, written approval is required by the medical monitor.
7. Have current evidence of corneal keratopathy or retinal disorder
including, but not limited to, bullous/band keratopathy, inflammation or
ulceration, keratoconjunctivitis, macular degeneration, or diabetic
retinopathy, 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, vasculature, myocardium, and lung with the exception of
calcified lymph nodes, minor pulmonary parenchymal calcifications,
small renal cyst or stone calcifications, and asymptomatic coronary
calcification.<
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary endpoints: Centrally reviewed DFS, from date of randomization to<br /><br>local/regional or contralateral invasive or metastatic recurrence, or death due<br /><br>to any cause, whichever occurs earlier</p><br>
- Secondary Outcome Measures
Name Time Method