| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008593 |
| E.1.2 | Term | Cholangiocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to determinate if treatment with infigratinib improves progression-free survival (PFS) as assessed by blinded independent central review (BICR) compared to treatment with gemcitabine with cisplatin in subjects with unresectable locally advanced or metastatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) gene fusions/ translocations. |
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| E.2.2 | Secondary objectives of the trial |
• Determinate if treatment with infigratinib improves overall survival (OS) compared to treatment with gemcitabine and cisplatin in subjects with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions/translocation
• Evaluate the efficacy of infigratinib treatment compared to gemcitabine and cisplatin in terms of investigator assessed PFS
• Further evaluate the efficacy in subjects treated with infigratinib versus gemcitabine with cisplatin by overall response rate (ORR) best overall response (BOR), duration of response and disease control rate determined by (BICR) and by the investigator
• Characterize the safety and tolerability of single agent infigratinib |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed unresectable locally advanced or metastatic cholangiocarcinoma. Subjects with gallbladder cancer or ampulla of Vater carcinoma are not eligible.
2. Have written documentation of local laboratory or central laboratory determination of FGFR2 gene fusions/translocations from a sample collected before treatment.
3. Have an archival tissue sample available with sufficient tumor for central FGFR2 fusion/translocation molecular testing. However, if an archival tissue sample is not available, a newly obtained (before randomization) tumor biopsy may be submitted instead. If written documentation of FGFR2 fusion/translocation in tumor tissue is available from the central laboratory, an additional tumor sample does not need to be submitted for central FGFR2 fusion/translocation molecular testing. Note: All enrolled subject must have determination of FGFR2 gene fusions/translocations by the central laboratory as confirmation of local laboratory testing, but this central confirmation is not required prior to enrollment in the study.
4. Have full recovery from the following permitted prior treatments (as applicable) such that the subject is reasonably expected to tolerate study treatment (gemcitabine/cisplatin or infigratinib) according to the investigator’s assessment:
a. A non-curative operation (ie., R2 resection [with macroscopic residual disease] or palliative bypass surgery only)
b. Curative surgery with evidence of unresectable disease relapse requiring systemic chemotherapy
c. Adjuvant radiotherapy (with or without radio-sensitizing low-dose chemotherapy) for localized disease provided there has been clear evidence of disease progression before inclusion in this study
d. Adjuvant or neoadjuvant chemotherapy, provided recurrence after date of completion of therapy was ≥ 6 months before trial entry
e. Photodynamic treatment provided there is clear evidence of disease progression at the local site or at a new metastatic site.
5. Are ≥ 18 years of age of either gender.
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
7. Have a life expectancy > 3 months.
8. Are able to read and/or understand the details of the study and provide written evidence of informed consent as approved by Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
9. Are able to swallow and retain oral medication.
10. Are willing and able to comply with scheduled visits, treatment plan and laboratory tests.
11. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test within 7 days of the first dose of study drug. A woman is not of childbearing potential if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before taking study drug) or if she is postmenopausal and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc., for at least 12 months, with an appropriate clinical profile, and there is no other cause of amenorrhea (eg., hormonal therapy, prior chemotherapy).
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| E.4 | Principal exclusion criteria |
1. Have received treatment with any systemic anti-cancer therapy for unresectable locally, advanced or metastatic cholangiocarcinoma. Prior neoadjuvant or adjuvant therapy is permitted if documented disease recurrence occurred ≥ 6 months after the last date of neoadjuvant or adjuvant therapy.
2. Have history of a liver transplant.
3. Have previously or currently is receiving treatment with a mitogen-activated protein kinase MEK or selective FGFR inhibitor.
4. Have neurological symptoms related to underlying disease requiring increasing doses of corticosteroids. Note: Steroid use for management of central nervous system tumors is allowed but must be at a stable dose for at least 2 weeks preceding study entry.
5. Have a history of another primary malignancy within 3 years except adequately treated in situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the study.
6. Have any other medical condition that would, in the investigator’s judgment, prevent the subject’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
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, myocardium, vascular system and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and asymptomatic coronary calcification.
9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib (eg., 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 etc.
11. 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.
12. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or products containing juice of these fruits within 7 days prior to first dose of study drug.
13. Have used medications known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes (TdP) 7 days prior to first dose of study drug.
14. Have used amiodarone within 90 days prior to first dose of study drug.
15. Have insufficient bone marrow function.
16. Have insufficient hepatic and renal function.
17. Have amylase or lipase >2.0 × ULN
18. Have abnormal calcium or phosphorus, or calcium-phosphorus product ≥55 mg2/dL2:
a. Inorganic phosphorus outside of local normal limits
b. Total corrected serum calcium outside of local normal limits
19. Have clinically significant cardiac disease.
20. Have had a recent (≤ 3 months prior to first does of study drug) transient ischemic attack or stroke.
21. CTCAE (v 5.0) Grade ≥ 2 hearing loss.
22. CTCAE (v 5.0) Grade ≥ 2 neuropathy.
23. If female, is pregnant or nursing (lactating), where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotrophin urine or blood laboratory test.
24. Have known microsatellite instability-high (MSI-H) disease and the decision is made by the treating investigator that an alternative, non-study therapy is warranted according to standard of care.
25. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents, infigratinib, or their excipients. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (from date of randomization until date of progression as determined by BICR or death due to any cause). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From date of randomization until date of progression as determined by BICR or death due to any cause. |
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| E.5.2 | Secondary end point(s) |
1. Overall survival (from date of randomization until date of death).
2. Progression-free survival (PFS) as determined by the investigator.
3. Overall response rate (ORR) assessed by BICR
according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
4. ORR assessed by the investigator according to RECIST Version 1.1.
5. Best overall response (BOR), disease control rate (partial response [PR] + complete response [CR] + stable disease [SD]), and duration of response (only for subjects who have a response) assessed by BICR and by the investigator according to RECIST 1.1.
6. Type, frequency, and severity of adverse events (AEs) and serious AEs (SAEs), laboratory abnormalities, and other safety findings.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From date of randomization until date of death every 3 months; every 3 months after disease progression
2. Every 8 weeks
3. Every 8 weeks
4. Every 8 weeks
5. Every 8 weeks
6. From randomization until 30 days after the last dose of study drug |
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| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Assessment of Biomarkers and genetic mutation |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Gemcitabine and Cisplatin |
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| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Australia |
| Belgium |
| Canada |
| China |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
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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
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| The end of trial (study) is defined as the time when at least 274 OS events have been reached (for the primary OS analysis) and the last study subject has completed study treatment |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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