A Phase 2 Study of Erdafitinib in Subjects with Advanced Solid Tumors and FGFR Gene Alterations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen Cilag International

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Dec 2019 → 28 Feb 2026

Decision date (initial)

2024-03-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Janssen Research & Development LLC

External identifiers

EU CT number

2023-510301-18-00

EudraCT number

2019-002113-19

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Others, Safety

Primary Objective (Broad Panel Cohort and Core Panel Cohort): To evaluate the efficacy of erdafitinib in terms of 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.
Primary Objective (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

Conditions and MedDRA coding

Advanced solid tumors (other than Urothelial tumors), and FGFR gene alterations.

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Criterion modified per Amendment 3 1.1 ≥6 years of age.
2. 2. Criterion modified per Amendment 1 2.1 Criterion modified per Amendment 2 2.2 Criterion modified per Amendment 3 2.3 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. 3. Measurable disease according to RECIST v1.1 or RANO for primary brain tumors.
4. 4. Criterion modified per Amendment 2 4.1 Criterion modified per Amendment 3 4.2 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. 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. 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. 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. 8. Criterion modified per Amendment 3 8.1 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 <18 years of age), Karnofsky Score of ≥70 (Section 10.6)
9. 10. Criterion modified per Amendment 3 10.1 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 required 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. Assentis also required of children and adolescent subjects as described in Informed Consent Process in Section 10.3, Regulatory, Ethical, and Study Oversight Considerations
10. 9. Criterion modified per Amendment 1,Amendment 2 and Amendment3 9.3 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) greater than or equal to 1,000/mm3 -Platelet count greater than or equal to 75,000/mm3 -Hemoglobin greater than or equal to 8.0 g/dL b. Liver function: -Total bilirubin less than or equal to 1.5 x institutional ULN OR direct bilirubin less than or equal to ULN for subjects with total bilirubin levels greater than 1.5xULN -Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5x institutional ULN or less than or equal to 5x institutional ULN for subjects with liver metastases c. Renal function: Creatinine clearance (CrCl) greater than 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 (greater than or equal to 6 to less than 18 years of age) (Section 10.7) d. Phosphate: less than ULN within 14 days of treatment and prior to Cycle 1 Day 1 (medical management allowed)

Exclusion criteria 20

1. Any potential subject who meets any of the following criteria will be excluded from participating in the study: 1. Criterion modified per Amendment 2 1.1 Criterion modified per Amendment 3 1.2 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. 2. Criterion modified per Amendment 2 2.1 Criterion modified per Amendment 3 2.2 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 local test does not screen for all four FGFRs, eg FGFR4, the local report remains evaluable for molecular screening.
3. 3. Criterion modified per Amendment 1 3.1 Criterion modified per Amendment 2 3.2 Criterion modified per Amendment 3 3.3 Criterion modified per Amendment 4 3.4 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. For colorectal subjects only – pathogenic somatic mutations in BRAF, KRAS, NRAS and PIK3CA.
4. 4. Criterion modified per Amendment 2 4.1 Histologic demonstration of urothelial carcinoma.
5. 5. Hematologic malignancy (ie, myeloid and lymphoid neoplasms).
6. 6. Active malignancies other than for disease requiring therapy.
7. 7. Symptomatic central nervous system metastases (except for subjects with primary CNS tumors).
8. 8 Criterion modified per Amendment 2 8.1 Received prior selective FGFR inhibitor treatment
9. 9. Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients.
10. 10. Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade
11. 11. Criterion modified per Amendment 1 11.1 Criterion modified per Amendment 2 11.2. Criterion modified per Amendment 3 11.3 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. 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. 13. Criterion modified per Amendment 1 13.1 Criterion modified per Amendment 2 13.2. 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. 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. 15. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
16. 16. Major surgery within 4 weeks before first dose of erdafitinib
17. 17. Criterion modified per Amendment 2 17.1 Palliative radiation to the target lesion within 2 weeks before the first dose of erdafitinib.
18. 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. 19. Plans to father a child while enrolled in this study or within 3 months after the last dose of drug.
20. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. For 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.
2. Pediatric Cohort: The proportion of subjects who achieve a CR or PR based on RECIST v1.1 or RANO as assessed by IRC

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Janssen Cilag International

Sponsor organisation

Janssen Cilag International

Address

Turnhoutseweg 30

City

Beerse

Postcode

2340

Country

Belgium

Scientific contact point

Organisation

Janssen Cilag International

Contact name

CTIS Point of Contact

Public contact point

Organisation

Janssen Cilag International

Contact name

CTIS Point of Contact

Third parties 1

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications