| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive Urothelial Carcinoma with Susceptible FGFR3 Genetic Alterations |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 whether participants who have undergone surgery to remove invasive urothelial cancer that have a genetic abnormality (changes in tumour’s DNA) in the Fibroblast Growth Factor Receptor 3 who receive the investigational medication infigratinib for one year remain cancer free compared with those who receive placebo for one year. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the disease-free survival (DFS) including the risk of the cancer returning in participants treated with infigratinib vs placebo
- To compare metastasis-free survival (the length of time from the start of treatment for cancer that a patient is still alive and the cancer has not spread to other parts of the body) of participants treated with infigratinib vs placebo
- To compare overall survival (OS) in participa
- nts treated with infigratinib vs placebo
- To compare investigator-reviewed disease-free survival in participants treated with infigratinib vs placebo
- To understand the safety and tolerability of infigratinib when administered as postoperative adjuvant monotherapy
- Quality of life as measured by the questionnaires to be provided to the studies
- Pharmacokinetics (PK) parameters (measuring infigratinib level in your blood)
- FGFR3 alterations detected by tests such as cfDNA and/or RNA sequencing as biomarkers of disease recurrence
|
|
| 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. Have histologically or cytologically confirmed, invasive urothelial carcinoma with susceptible FGFR3 alterations within 120 days following nephroureterectomy, distal ureterectomy, or cystectomy:
• Regarding samples and documentation of FGFR3 alterations (see also Section 10.3):
• 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).
• FGFR3 gene fusion or translocation is confirmed if: gene fusion or translocation is identified.
• 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.
• Written documentation of central laboratory determination by FoundationOne CDx testing (through Foundation Medicine USA) of FGFR3 alterations is required for study eligibility in study centers outside of China. For study centres in China, confirmation is needed by a test equivalent to that of the central test.
• For patients who require molecular prescreening to confirm the presence of the FGFR3 alteration to meet the inclusion criteria, an archival tumour sample with a pathology report must be sent to Foundation Medicine USA for FoundationOne CDx testing.
• For study sites in China, written documentation of FGFR3 alterations by the contracted central laboratory is required for study eligibility
• If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be AJCC 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. Patients who received less than this or non-cisplatin-based neoadjuvant treatment will be considered as having received no neoadjuvant chemotherapy.
• • If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant chemotherapy based on Galsky et al (2011):
• Creatinine clearance ≤60 mL/minute, or
• Common Terminology Criteria for Adverse Events (CTCAE version 5.0 or later) Grade ≥2 hearing loss, or
• CTCAE Grade ≥2 neuropathy.
• If cisplatin ineligible based on Galsky et al (2011), must also meet the following criteria:
• Upper tract disease should be AJCC Stage ≥pT2 pN0-2 M0 (post-lymphadenectomy or no lymphadenectomy [pNx]).
• UBC should be AJCC Stage ≥pT3 or pN+.
• Must have a centrally reviewed negative postoperative 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 Tumours [RECIST] v1.1) or negative biopsy within 28 days before randomization to confirm absence of disease at baseline.
4. If have had AEs associated with prior surgery or neoadjuvant chemotherapy, they have stabilised or resolved to Grade ≤2 before randomisation.
5. Have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
6. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test within 7 days of the first dose of study medication. A woman is not of childbearing potential if she has undergone surgical sterilisation (total hysterectomy, or bilateral tubal ligation, or bilateral oophorectomy ≥6 weeks before taking study medication) or if she is postmenopausal and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc., for ≥12 months, with an appropriate clinical profile, and there is no other cause of amenorrhoea (e.g., hormonal therapy, prior chemotherapy).
• WOCBP and males whose sexual partners are WOCBP must agree to use barrier contraception and a second form of contraception (Clinical Trials Facilitation Group 2014) while receiving study medication and for 3 months following their last dose of study medication. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the participants. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. (Highly effective contraception methods are specified in Appendix 3 [Section 17.3] in the study Protocol.)
• Sexually active males must use a condom during intercourse while taking study medication and for 3 months after the last dose of study medication and should not father a child during this period. A condom is required to be used also by vasectomised men as well as during intercourse with a male partner to prevent delivery of the study medication via seminal fluid.
• Study participants must agree to refrain from donating sperm and eggs during the study and for 3 months following their last dose of study medication.
7. Are willing and able to comply with study visits and study procedures.
|
|
| E.4 | Principal exclusion criteria |
To be eligible for the study, a subject must not meet any of the following criteria:
1. Presence of positive surgical margins following nephroureterectomy, distal ureterectomy, or cystectomy.
2. Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy for 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 strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone. See Appendix 2 (Section 17.2).
• Prior neoadjuvant chemotherapy or immunotherapy is allowed if inclusion criterion #3 is met. Prior 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. Subjects who received biologic therapy should have completed therapy with a period that is ≥5 half-lives 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 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 surveillance that may not affect the subject’s survival status for ≥3 years based on clinician assessment/statement. For any other cancers that do not meet the criteria above, written approval is required by the Medical Monitor.
7. Have current evidence of corneal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis, 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.
12. Have used medications that are known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes (TdP) within 7 days before the first dose of study drug.
13. Have used amiodarone within 90 days before the first dose of study drug.
14. Have insufficient bone marrow function:
• Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L).
• Platelets <75,000/mm3 (<75 × 109/L).
• Hemoglobin <9.0 g/dL.
15. Have insufficient hepatic and renal function:
• Total bilirubin >1.5 × upper limit of normal (ULN) of the testing laboratory (for patients with documented Gilbert syndrome, exclusion for direct bilirubin >1.5x ULN and enrollment requires approval by the Medical Monitor).
• AST/SGOT and ALT/SGPT >2.5 × ULN of the testing laboratory.
• Calculated or measured creatinine clearance of <30 mL/min.
16. Have amylase or lipase >2.0 × ULN.
17. Have abnormal calcium-phosphate homeostasis:
• Inorganic phosphorus higher than ULN of the testing laboratory.
• Total serum calcium (can be corrected) higher than 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 |
|
| 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 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 |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| EOS is defined as 1 year after the time at which the final DFS event goal events are reached. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 25 |
| 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 |
Print
