| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive Urothelial Carcinoma with Susceptible FGFR3 Genetic Alterations |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046731 |
| E.1.2 | Term | Urothelial carcinoma urethra recurrent |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
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| E.2.2 | Secondary objectives of the trial |
To compare DFS including intraluminal low-risk (noninvansive, low-grade, or high-grade)recurrence in subjects treated with infigratinib vs placebo
To compare metastasis-free survival (MFS) of subjects treated with infigratinib vs placebo
To compare OS in subjects treated with infigratinib vs placebo
To compare investigator-reviewed DFS in subjects treated with infigratinib vs placebo
To characterize the safety and tolerability of infigratinib when administered as postoperative adjuvant monotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
8. Are willing and able to comply with study visits and study procedures.
For the complete list of inclusion criteria please refer to the Protocol. |
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| E.4 | Principal 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 mitogen-activated 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.
For the complete list of exclusion criteria please refer to the Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects will be evaluated at baseline within 28 days before randomization. Then the subjects will be evaluated for tumor recurrence radiographically every 3 months for the first 24 months, and annually thereafter or until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. Cystoscopy (for subjects with a bladder) and urine cytology/cfDNA will be performed at screening, 3, 6, 9, and 12 months, at C13D28 or EOT, then every 6 months up to 24 months, and then annually until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. |
|
| E.5.2 | Secondary end point(s) |
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 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Subjects will be evaluated at baseline within 28 days before randomization. Then the subjects will be evaluated for tumor recurrence radiographically every 3 months for the first 24 months, and annually thereafter or until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. Cystoscopy (for subjects with a bladder) and urine cytology/cfDNA will be performed at screening, 3, 6, 9, and 12 months, at C13D28 or EOT, then every 6 months up to 24 months, and then annually until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Taiwan |
| United States |
| Belgium |
| France |
| Portugal |
| United Kingdom |
| Bulgaria |
| Netherlands |
| Spain |
| Germany |
| Greece |
| Italy |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of study is defined as 1 year after the final number of confirmed DFS events by BICR is reached. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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