| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid tumors (other than Urothelial tumors), and FGFR gene alterations. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced solid tumors (other than Urothelial tumors), and FGFR gene alterations. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| 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 |
- Broad Panel Cohort and Core Panel Cohort:
To evaluate the efficacy of erdafitinib in terms of overall response rate (ORR) as assessed by the Independent Review Committee (IRC) in subjects with advanced solid tumors with target FGFR mutations and any gene fusions (Broad Panel Cohort), or in a pre-specified subgroup of subjects with a selected panel of FGFR markers (Core Panel Cohort), or in both cohorts
- Pediatric Cohort:
To evaluate the efficacy of erdafitinib in terms of ORR as assessed by the IRC in pediatric subjects with advanced solid tumors with FGFR mutations, any gene fusions, or FGFR internal tandem duplication (Pediatric Cohort), including adolescent subjects with target FGFR mutations and any gene fusions |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of erdafitinib, in terms of the ORR, as assessed by investigator
- To evaluate the efficacy of erdafitinib in terms of DOR
- To evaluate other measures of efficacy including DCR, clinical benefit rate (CBR), PFS, and overall survival (OS)
- To evaluate erdafitinib pharmacokinetics (PK)
- To evaluate safety and tolerability of erdafitinib
- To evaluate Health-Related Quality of Life (HRQoL) Cholangiocarcinoma Expansion Cohort
-To evaluate the efficacy and safety of erdafitinib in subjects with cholangiocarcinoma with target FGFR mutations and any gene fusions |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Criterion modified per Amendment 3
1.1 ≥6 years of age
2. Histologic demonstration of an unresectable, locally advanced, or metastatic solid tumor malignancy bearing an FGFR mutation or fusion, as determined by local* or central laboratory screening (Section 8.1.1.1).
Molecular Criteria for Broad Panel Cohort and Cholangiocarcinoma
Expansion Cohort:
*Subjects with target FGFR mutations or any** FGFR gene fusions are eligible for enrollment in the Broad Panel Cohort (The List of Target FGFR Mutations is provided in Section 10.11)
*Subjects with other FGFR mutations*** not captured in the Broad Panel Cohort are eligible for enrollment in the Exploratory Cohort.
Molecular Criteria for Pediatric Cohort:
*Subjects with any FGFR mutation*** (exclusive of FGFR valine
gatekeeper and resistance alterations defined in the Exclusion Criteria) or any** FGFR gene fusions, or FGFR internal tandem duplication**** are eligible for enrolment in the Pediatric Cohort **FGFR Fusion Specifications:
- Have a report suggesting the presence of an intact FGFR kinase domain.
- FGFR fusion with a 3-prime partner (FGFR gene is listed first, eg FGFRGENE or FGFR3-TACC3):
-The FGFR portion of the fusion must involve exon 17 or greater (≥17)
- FGFR fusion with a 5-prime partner (Partner gene is listed first and FGFR gene is second, eg GENE-FGFR or KLK2-FGFR2):
- The FGFR portion of the fusion must involve less than or equal to exon 11 (≤11)
- Have a named FGFR fusion partner gene (self-fusions or
rearrangements, eg FGFR-FGFR, are not eligible) (Broad Panel Cohort only)
-FGFR gene identifiers, canonical transcript identifiers, and kinase domain positions are provided, see Section 5.1.
3. Measurable disease according to RECIST v1.1 or RANO for primary brain tumors.
4. Subject must have received at least one prior line of systemic therapy in the advanced, unresectable, or metastatic setting; or is a child or adolescent subject with a newly-diagnosed solid tumor and no acceptable standard therapies.
5. Subject does not have standard of care options that have shown meaningful clinical benefit for the relevant underlying histology and line of therapy or the subject is unable to tolerate the therapy
6. Criterion modified per Amendment 4
6.1 Documented progression of disease, defined as any progression that requires a change in treatment, prior to full study screening. Note: Not applicable for treatment naïve pediatric subjects with no standard of care therapies.
7. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less except for alopecia, peripheral neuropathy, and Grade 2 laboratory values eligible per Inclusion Criterion 9.
8. Criterion modified per Amendment 4
8.2 For adults (≥18 years of age), ECOG performance status Grade 0 or 1 (Section 10.5)
For children and adolescents (≥6 to <16 years of age), Lansky Score of ≥ 70 (Section 10.6).
For adolescents (≥16 to <18 years of age), Karnofsky Score of ≥70 (Section 10.6).
9. Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or
erythropoiesis-stimulating agent transfusions in preceding 2 weeks):
-Absolute neutrophil count (ANC) ≥ 1,000/mm3
-Platelet count ≥ 75,000/mm3
-Hemoglobin ≥ 8.0 g/dL
b. Liver function:
-Total bilirubin ≤1.5 x institutional ULN OR direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5xULN
-Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x institutional ULN or ≤5x institutional ULN for subjects with liver metastases
c. Renal function: Creatinine clearance(CrCl) >30 mL/min calculated using the Cockcroft-Gault formula for adult subjects or the CKiD (Chronic Kidney Disease in Children)Schwartz formula for children and adolescent subjects (≥6 to <18 years of age) (Section 10.7)
d. Phosphate: <ULN within 14 days of treatment and prior to Cycle 1 Day 1 medical management allowed)
10. Must sign an ICF (or their legally acceptable representative must sign) indicating that the subject understands the nature, significance, and purpose of the study, and procedures equired for the study, and consequence of the study; and is willing to participate in the study. For children and adolescent subjects, parent(s) (preferably both if available or as per local requirements) (or their legally acceptable representative)
must sign an ICF indicating that the subject understands the purpose of, and procedures required for, the study and is willing to allow the child to participate in the study. Assent is also required of children and adolescent subjects as described in Informed Consent Process in Section 10.3.
Please refer to protocol section 5.1 for the full list of Inclusion Criteria. |
|
| E.4 | Principal exclusion criteria |
1. Has had prior chemotherapy, targeted therapy, or treatment with an investigational anticancer agent within 15 days or <5 half-lives of the agent (whichever is longer) and up to a maximum of 30 days before the first dose of erdafitinib. Has had prior monoclonal antibody or immunotherapy within 30 days before the first dose of erdafitinib and/or has an ongoing Grade ≥2 immunotherapy-related toxicity.
2. The known* presence of FGFR valine gatekeeper and resistance alterations. Mutations in the following positions: FGFR1 V561; FGFR2 V564; FGFR3 V555; FGFR4 V550; FGFR1 N546; FGFR2 N549; FGFR3 N540; and FGFR4 N535.
*Observation of a gatekeeper/resistance alteration in the local or central report. If the test does not screen for all four FGFRs, eg FGFR4, the local report remains evaluable for molecular screening.
3. For NSCLC subjects only - pathogenic somatic mutations in EGFR* or BRAF V600E, KRAS or any gene fusions in the following genes: ALK, ROS1 or NTRK.
*Assessment of these genes may be performed per institutional standard and do not have to be assessed via NGS.
3.4 For colorectal subjects only – pathogenic somatic mutations in BRAF, KRAS, NRAS and PIK3CA.
4.Criterion modified per Amendment 2
4.1 Histologic demonstration of urothelial carcinoma.
5. Hematologic malignancy (ie, myeloid and lymphoid neoplasms)
6. Active malignancies other than for disease requiring therapy
7. Symptomatic central nervous system metastases (except for subjects with primary CNS tumors)
8 Received prior selective FGFR inhibitor treatment.
9. Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients.
10. Current central serous retinopathy (CSR) or retinal pigment
epithelial detachment of any grade.
11. History of uncontrolled cardiovascular disease include:
-Unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-IV (Section 10.8) within the preceding 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months -QTc prolongation (Fridericia: QTc >480 milliseconds; or for children and adolescent subjects, Bazett: QTc >440 milliseconds)
12. Known history of AIDS (human immunodeficiency virus [HIV] infection), unless the subject has been on a stable anti-retroviral therapy regimen for the last 6 months or more, has had no opportunistic infections in the last 6 months, and has CD4 count >350.
13. . Evidence of active hepatitis B or C infection (for example, subjects with history of hepatitis C infection but normal hepatitis C virus polymerase chain reaction [PCR] test and subjects with inactive hepatitis B with positive HBsAg antibody or normal PCR are allowed)
14. Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, neuropathy, hearing loss).
15. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
16. Major surgery within 4 weeks before first dose of erdafitinib.
17. Palliative radiation to the target lesion within 2 weeks before the first dose of erdafitinib.
18. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of drug.
19. Plans to father a child while enrolled in this study or within 3 months after the last dose of drug.
20. Any condition for which, in the opinion of the investigator,
participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Examples include ongoing active infection requiring systemic therapy and uncontrolled ongoing medical conditions.
Please refer to protocol section 5.2 for the full list of Exclusion Criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Broad Panel Cohort and Core Panel Cohort:
The proportion of subjects who achieve a complete response (CR) or
partial response (PR) based on Response Evaluation Criteria in Solid
Tumors (RECIST, version 1.1) (RECIST v1.1.) or Response Assessment in Neuro-Oncology (RANO) as assessed by IRC
- Pediatric Cohort:
The proportion of subjects who achieve a CR or PR based on RECIST v1.1. or RANO as assessed by IRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The proportion of subjects who achieve a CR or PR based on RECIST v1.1. or RANO as assessed by investigator
- DOR: the duration from the date of initial documentation of a response to the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever comes first. Data from subjects who are progression-free and alive or have unknown status will be censored at the last tumor assessment
- DCR: the proportion of subjects with CR, PR or stable disease (SD)
- CBR: the proportion of subjects with CR, PR or durable SD (defined as a duration of at least 4 months)
- PFS: the duration from the date of the first dose of study drug until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever comes first. Data from subjects who are progression-free and alive or have unknown status will be censored at the last tumor assessment
- OS: measured from the date of first dose of study drug to the date of the subject's death. If the subject is alive or the vital status is unknown, the subject's data will be censored at the date the subject was last known to be alive
- PK exposure parameters.This endpoint includes pediatrics.
- Incidence and severity of AEs
- Change from baseline in patient-reported health status and physical functioning scales of the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQC30; for subjects ≥18 years of age) or Pediatric Functional Assessment Of Cancer Therapy - Brain (Peds FACT-Br for subjects <18 years of age), Patient Global Impression of Symptom Severity (PGIS), Patient Global
Impression of Change (PGIC), and European Quality of Life – 5
Dimensions-5 Levels (EQ-5D-5L).
Cholangiocarcinoma Expansion Cohort
- Key efficacy endpoints will be evaluated including ORR assessed by IRC/investigator, DOR, PFS, and OS
- Incidence and severity of AEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 |
| Biomarkers, PROs, Medical Resource Utilization |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| China |
| Japan |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The study is considered completed at the time of the end of data collection timepoint. Overall the end of data collection time point is defined as the data at which the clinical cutoff for the primary analysis has been achieved. More information in section 5.5 |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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