To determine if treatment with infigratinib improves centrally reviewed disease-free survival (DFS) compared with placebo treatment in subjects with invasive urothelial carcinoma with susceptible FGFR3 alterations after nephroureterectomy, distal…
ID
Source
Brief title
Condition
- Other condition
- Urethral disorders (excl calculi)
Synonym
Health condition
Invasive Urothelial Carcinoma with Susceptible FGFR3 Genetic Alterations
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints: Centrally reviewed DFS, from date of randomization to
local/regional or contralateral invasive or metastatic recurrence, or death due
to any cause, whichever occurs earlier
Secondary outcome
Secondary endpoints:
Investigator-reviewed DFS including intraluminal low risk (noninvasive,
low-grade, or high-grade) recurrence, from date of randomization to any
recurrence or death due to any cause, whichever occurs earlier
Investigator-reviewed MFS, from date of randomization to metastatic recurrence
or death due to any cause, whichever occurs earlier
OS (from date of randomization to death)
Investigator-reviewed DFS, from date of randomization to local/regional or
contralateral invasive or metastatic recurrence, or death due to any cause,
whichever occurs earlier
Type, frequency, and severity of adverse events and serious adverse events,
laboratory abnormalities, and other safety findings
QOL as measured by the EQ-5D-5L and the EORTC QLQ C30
PK parameters (trough and maximum plasma concentration).
FGFR3 alterations detected by cfDNA and/or RNA sequencing as biomarkers of
disease recurrence
Background summary
There is a need for a treatment of urothelial cell carcinoma for patients who
cannot receive standard chemotherapy. In laboratory studies, infigratinib has
been shown to shrink or slow the growth of several different types of cancers
or tumors in animals whose tumor cells have a genetic abnormality in the FGFR3
gene. This genetic abnormality in the FGFR3 gene can cause cells to grow
abnormally and develop into cancer. It may be the case that infigratinib will
inhibit the abnormal FGFR3 gene, thus preventing cells from growing without
inhibition. Infigratinib may prevent or delay your tumor from coming back.
However, infigratinib is an investigational (study) drug, and its actual
ability to affect malignant cells remains unknown.
Study objective
To determine if treatment with infigratinib improves centrally reviewed
disease-free survival (DFS) compared with placebo treatment in subjects with
invasive urothelial carcinoma with susceptible FGFR3 alterations after
nephroureterectomy, distal ureterectomy, or cystectomy.
Study design
This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled
study to evaluate the efficacy of infigratinib in approximately 218 adult
subjects with invasive urothelial carcinoma with susceptible FGFR3 genetic
alterations (mutations, and gene fusions or translocations [ie,
rearrangements]; hereafter referred to collectively as *FGFR3 alterations*) who
are within 120 days following nephroureterectomy, distal ureterectomy, or
cystectomy and ineligible for cisplatin-based (neo)adjuvant chemotherapy or
with residual disease after neoadjuvant therapy. The sample size can be
increased up to a total of 328 subjects based on interim analysis result using
an adaptive design promising zone approach. Subjects with invasive urothelial
carcinoma includes subjects with invasive upper tract urothelial carcinoma
(UTUC) and urothelial carcinoma of the bladder (UBC).
Subjects will be randomly assigned (1:1) to receive oral infigratinib or
placebo administered once daily for the first 3 weeks (21 days) of each 28-day
cycle for a maximum of 52 weeks, until local/regional or contralateral invasive
or metastatic recurrence, or until other criteria specified in Section 8.1.1 is
met, whichever occurs first. Subjects will be evaluated for tumor recurrence
radiographically and by urine cytology. For subjects with UTUC (ie, subjects
with a bladder), cystoscopy will be performed. Radiography, urine cytology, and
cystoscopy will continue until metastatic recurrence by blinded independent
central review (BICR) or metastatic recurrence by investigator assessment if
local/regional or contralateral invasive recurrence by BICR has already
occurred. After that time, subjects will be followed up for survival status and
use of anticancer therapy for 1 year after the final DFS event goal is reached
(ie, End of Study).
An interim analysis for adaptation and futility for centrally reviewed DFS will
be conducted after approximately 35 centrally reviewed DFS events have been
reached. Based on the results of the interim analysis on DFS, if a sample size
increase is deemed necessary using the promising zone approach, the sample
size/centrally reviewed DFS event goal will be increased by a maximum of 50%
(328/105). If sample size is increased and event goal is adjusted, then the
subsequent analyses will be adjusted accordingly time-wise when the adjusted
event goal is reached. The details of the sample size adaptation method will be
prespecified in the adaptation plan.
Subjects will be stratified according to lymph node involvement (yes vs no),
prior neoadjuvant chemotherapy (yes vs no), AJCC Stage (pT2 vs >pT2), and
disease (UTUC vs UBC).
Intervention
Subjects randomly assigned to placebo will receive placebo matching in
appearance the investigational product (infigratinib), which will be provided
as hard gelatin capsules for oral use and will be administered once daily on a
3 weeks on (Days 1-21) /1 week off (Days 22 28) dosing schedule.
Study burden and risks
Extract from the patient information and consent form:
All drugs may cause certain side effects and discomforts. The most common side
effects and discomforts reported for the infigratinib are:
Very Common (Frequency of 10% (1 in 10) or higher) adverse events reported:
• Temporary increases in the mineral phosphate in the blood. Change to your
blood phosphate levels may not cause symptoms, or the change could lead to
calcium deposits in your body, including in your skin, heart, or blood vessels.
A blood test will determine if there have been changes in your blood phosphate
levels. If your phosphate level is high, your doctor may decrease your study
drug dose or may ask you to take medicine to lower the phosphate level.
• Temporary decreases in the mineral phosphate in your blood.
• Temporary increases in the mineral calcium in the blood. You may not have any
symptoms if you have a slight increase or decrease of the calcium level in your
blood. In severe cases of high levels of calcium, you might experience kidney
problems, irregular heartbeat, or confusion.
• Temporary changes in measurements of your kidney function which are most
frequently seen at the same time as the changes in your phosphorus blood
levels.
• Muscle weakness and/or discomfort and fatigue.
• Joint pain.
• Stomatitis (inflamed and sore mouth).
• Gastrointestinal (GI) adverse effects including constipation, diarrhea,
nausea, vomiting, abdominal pain, indigestion, changes in taste.
• Dry mouth.
• Decreased appetite and weight changes.
• Skin and nail changes, including blistering and peeling of the skin on the
hands and feet.
• Eye related adverse effects (most frequently dry eye and blurry vision) and
less frequently corneal or retinal problems, worsening cataracts, or
inflammation of the eye.
• Hair loss.
• Temporary, mild changes in blood tests that monitor the ability of your liver
to work. These changes will most likely go away when you stop taking
infigratinib.
• Decrease in the number of red blood cells, which may cause fatigue and
shortness of breath.
• Nose bleeds.
• Low sodium in the blood which can lead to weakness.
• Pain in extremity which might be at rest or with exercise.
• Headache.
Infigratinib has caused mild to moderate visual changes in some patients. While
this type of visual impairment may improve again, there is a risk that it might
be permanent after you stop taking infigratinib. Blurred vision and, in some
cases, loss of vision have been seen with similar drugs tested in other human
studies. All patients will undergo a detailed eye examination at the start of
the study and this is repeated during the study. If the results of eye exams
conducted at screening are abnormal, you will not be able to participate in
this study and you may need to discontinue from the study if abnormal changes
are found while you are on study. It is important to tell your doctor about any
pre-existing eye problems you have and visual changes that occur while taking
the study drug as your doctor may decide to change or stop your treatment with
the study drugs. It is important that you do not drive a car or work with
machinery if you begin to experience any visual changes while on the study.
Common (Frequency of 1% up to 10%) adverse events reported:
1. Injury to the cornea, which is the transparent, dome-shaped window covering
the front of the eye. These changes may be noticed as blurry vision or may only
be found by an ophthalmologist (a doctor that specializes in eye care).
2. Changes to your retina (the light sensitive portion of your eye).
3. Dehydration.
4. Changes in body*s ability to produce hormones.
5. Numbness in your fingers or toes.
6. Increases in blood levels of potassium which usually does not cause any
symptoms but can cause nausea, palpitations, and low energy.
7. Some changes to the function of your kidneys are temporary but some may
continue after you stop taking infigratinib and may impact on the ability of
your kidneys to function.
8. Increases in the digestive enzymes amylase and lipase without symptoms,
which can be related to the function of your pancreas. Changes to the function
of your liver that may continue after you stop taking infigratinib and may
impact on the ability of your liver to work.
9. Temporary worsening of measurements of the pumping ability of your heart
most often without symptoms and may go away when you stop taking infigratinib.
10. Dizziness.
8000 Marina Blvd Suite 400
Brisbane CA 94005
US
8000 Marina Blvd Suite 400
Brisbane CA 94005
US
Listed location countries
Age
Inclusion criteria
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 ineligible to receive
cisplatin-based adjuvant chemotherapy based on Galsky (2011):
i. Creatinine clearance <=60 mL/minute, or
ii. Common Terminology Criteria for Adverse Events (CTCAE version 5.0)
Grade >=2 hearing loss, or
iii. CTCAE Grade >=2 neuropathy.
d. Subjects who refuse cisplatin-based chemotherapy or who are
ineligible to receive cisplatin-based chemotherapy based on Galsky
(2011), must also meet the following criteria:
i. UTUC should be Stage >=pT2 pN0-2 (post-lymphadenectomy or no
lymphadenectomy [pNx]), or pN+, M0
ii. UBC should be Stage >=pT3 or pN+, M0.
e. 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 Response
Evaluation Criteria in Solid Tumors [RECIST] v1.1) or negative biopsy
within 28 days before randomization to confirm absence of disease at
baseline
5. If have had adverse events (AEs) associated with prior surgery or
neoadjuvant chemotherapy, they have stabilized or resolved to Grade <=2
before randomization.
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 7 days of the first dose of study drug.
For the complete list of inclusion criteria please refer to the Protocol.
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 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.
9. Have impaired gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral infigratinib (eg, active 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), unless well controlled.
11. 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.
12. Have insufficient bone marrow function:
a. Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L)
b. Platelets <75,000/mm3 (<75 × 109/L)
c. Hemoglobin<8.5 g/dL; transfusion support is allowed if >1 week
before randomization and hemoglobin remains stable
13. Have insufficient hepatic and renal function:
a. 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)
b. AST/SGOT and ALT/SGPT >2.5× ULN of the testing laboratory
c. Serum creatinine >1.5 × ULN or a calculated (using the Cockcroft-
Gault [C-G] formula [Cockcroft 1976]) or measured creatinine clearance
of <30 mL/min
For the complete list of exclusion criteria please refer to the Protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003248-63-NL |
| ClinicalTrials.gov | NCT04197986 |
| CCMO | NL73746.091.20 |