| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
•Stage IIIB/IV NSCLC patients with activating FGFR alteration after the failure of ≥ 1st line standard therapy
•Activating FGFR alteration as defined by FIND Molecular Board
•ECOG performance status score 0, 1, or 2.
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| E.1.1.1 | Medical condition in easily understood language |
| Pat.with advanced NSCLC and FGFR alterations,in good clinical condition(ECOG 0-2),with acc. lab. results,after standard treatment and consenting for a fresh frozen biopsy will be considered eligible |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 |
| To evaluate the efficacy of erdafitinib in NSCLC with FGFR genetic alteration |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the tolerability of erdafitinib (endpoints: assessment of adverse events (AEs) according to CTC-AE V5.0)
•To evaluate the clinical efficacy of erdafitinib descriptively (endpoints: progression-free survival (PFS), overall survival (OS))
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Age > 18 years
•Stage IIIB/IV NSCLC patients with activating FGFR alteration after failure on standard treatment, or in the opinion of the investigator no effective standard therapy exists, is appropriate, tolerated, or is considered equivalent to study treatment
•Activating FGFR alteration as approved by FIND Molecular Board
•ECOG performance status score 0, 1, or 2.
•Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
•Clinical laboratory values and cardiovascular measurements at screening:
Hematology
Hemoglobin 8 g/dL (5 mmol/L) (must be without red blood cell [RBC] transfusion within 7 days prior to the laboratory test; recombinant human erythropoietin use is permitted)
Platelets 75×109/L
Absolute Neutrophil Count (ANC) 1.5×109/L (prior growth factor support is permitted more than 7 days prior to the laboratory test)
Chemistry
AST and ALT ≤2.5 × upper limit of normal (ULN) or
≤5 × ULN for patients with liver metastases
Creatinine clearance 40 mL/min based upon CKD-EPI formula
Total bilirubin ≤1.5 × ULN; except in patients with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5 × ULN is required)
Cardiovascular
Corrected QT interval according to Fridericia (QTcF) ≤480 msec based on the average of triplicate assessments performed approximately 5 minutes apart
ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; GFR=glomerular filtration rate; QTcF=QT corrected interval by the Fridericia’s formula; ULN=upper limit of normal
•Disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for cohort 1 and 2.
•A woman of childbearing potential (WOCBP) who is sexually active must have a negative pregnancy test (beta- human chorionic gonadotropin [beta-hCG]) at Screening (urine or serum, minimum sensitivity 25 IU/L or equivalent units of beta-HCG) within 24 hours prior to the start of erdafitinib.
•WOCBP and men who are sexually active with WOCBP must use appropriate method(s) of contraception with a failure rate of less than 1% per year before study entry, during the study and until 5 months after taking the last dose of study drug.
Note: Appropriate methods of contraception are:
Total abstinence, if it is the appropriate lifestyle, female sterilization or tubal ligation (at least 6 weeks prior to the start of the study treatment), male sterilization (at least 6 months prior to the start of the study treatment) and/or a combination of a hormonal method of contraception with a barrier method or/and an intrauterine device or system are considered as highly effective methods of contraception.
•Sexually active men must use a condom to prevent delivery of the drug via seminal fluid
•Women must not be breastfeeding.
•Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception.
•Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 5 months after the last dose of study drug
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| E.4 | Principal exclusion criteria |
•Pathogenic somatic alterations in the following genes: EGFR, BRAF, ALK ROS1 and NTRK (Please note that molecular testing might be reduced in heavy smokers with NSCLC. If discrepancies occur, please contact the sponsor). •Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 30 days or 5 half-life times (whichever is longer) prior to recruitment.
•Treatment with small molecules or chemotherapy within 7 days prior to C1D1
•Treatment with monoclonal antibodies within 28 days prior to C1D1.
•Any other ongoing malignancy that would potentially interfere with the interpretation of erdafitinib efficacy.
•Symptomatic central nervous system metastases.
•Received prior FGFR inhibitor treatment or if the patient has known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients
•Any corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.:
a.History of or current evidence of central serous retinopathy (CeSR) or retinal vascular occlusion (RVO)
b.Active wet, age-related macular degeneration (AMD)
c.Diabetic retinopathy with macular edema (non-proliferative)
d.Uncontrolled glaucoma (per local standard of care)
e.Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration.
•Has persistent phosphate level >ULN during screening (on 2 consecutive assessments at least 1 week apart, within 14 days prior to Cycle 1 Day 1) and despite medical management
•Has a history of current uncontrolled cardiovascular disease including:
a.unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes tachycardia, cardiac arrest, or known congestive heart failure NYHA Class III-V within the preceding 3 months (Appendix 3); cerebrovascular accident or transient ischemic attack within the preceding 3 months.
b.QTcF prolongation as confirmed by triplicate assessment at screening (QTcF >480 milliseconds).
•Pulmonary embolism or other VTE (venous thromboembolism) within the preceding 2 months
•Known human immunodeficiency virus (HIV) infection, testing is mandatory (a-HIV 1/2)
•Patients with acute or chronic Hepatitis B infection (tests should include assessment of HBsAg and HBc IgG antibody. If one parameter is positive, determine HBV-DNA to confirm acute infection. Patients with positive results for HBsAg and/or HBV-DNA are considered positive for acute or chronic infection)
•Patients with acute or chronic Hepatitis C infection (determine HCV-RNA. Patients with positive result for HCV-RNA are considered positive for acute or chronic infection)
•Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, Grade 1 neuropathy, Grade 1-2 hearing loss)
•Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
•Major surgery within 2 weeks of the first dose, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 2 weeks after the last dose of study drug administration. (Note: patients with planned surgical procedures to be conducted under local anesthesia may participate).
•Any serious underlying medical condition, such as:
a. Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection requiring current systemic treatment
b. Psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status
•Any other issue that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (i.e., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) per RECIST 1.1 under erdafitinib treatment in NSCLC with genetic alteration in FGFR |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•Assessment of adverse events (AEs) according to CTC-AE V5.0)
•Progression-free survival (PFS), overall survival (OS)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 |
| Biomarker by drug resistance |
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| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| 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 |
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