A Randomized Phase 2 Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in Subjects Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) and FGFR Mutations or Fusions

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen Cilag International

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Aug 2020 → 28 Feb 2025

Decision date (initial)

2024-06-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Janssen Research & Development LLC

External identifiers

EU CT number

2023-510306-40-00

EudraCT number

2019-002449-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Others, Pharmacodynamic, Safety, Efficacy

Cohort 1 only:
-To evaluate RFS in subjects treated with erdafitinib vs Investigator's
Choice, for subjects with high-risk NMIBC who harbor FGFR mutations or
fusions, and who recurred after BCG therapy

Conditions and MedDRA coding

Cohort 1 and 2: High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) with FGFR Mutations or Fusions Cohort 3 Intermediate Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) with FGFR Mutations or Fusions

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. ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
2. 2. Histologically confirmed, recurrent, non-muscle-invasive urothelial carcinoma of the bladder. a. Histopathology: any urothelial cell carcinoma (UCC) variant (ie, UCC with squamous and/or glandular differentiation, micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid) are allowed. Presence of any lymphovascular invasion (LVI) will be considered as evidence of high risk. b.Papillary disease (Cohort 1) must be high-risk disease, defined highgrade disease Ta/T1 lesion. Additionally, subjects must have all visible tumor resected completely prior to randomization and documented at baseline cystoscopy. Negative cytology for high-grade urothelial carcinoma is required before randomization. c.CIS (Cohort 2) is not expected to be completely excised, but concurrent papillary disease must be completely excised before enrollment and documented at baseline cystoscopy. Urine cytology is not expected to be negative for malignant cells. d.Marker Lesion (Cohort 3) must have recurrent intermediate-risk disease with all previous tumors being low grade (G1-G2), Ta or T1, and no previous CIS. Additionally, subjects must have a risk of progression less than 5% in the next 2 yrs and a risk of recurrence greater than 50%, calculated using the EORTC risk calculator. All tumors must be removed except for a single untouched 5 to 10 mm lesion (Marker Lesion).
3. 3.Criterion modified per Amendment 2 3.1 Criterion modified per Amendment 3 3.2 At least 1 of the following tumor FGFR mutations or fusions as determined by local or central testing : see table in protocol
4. 4. Criterion modified per Amendment 1. 4.1. 4a. BCG-unresponsive. BCG-unresponsive subjects must meet at least one of the following: i. Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary disease/tumor invades the subepithelial connective tissue) disease within 12m of completion of adequate BCG therapy (Cohort 2 only) ii. Recurrent high-grade Ta/T1 disease within 6m of completion of adequate BCG therapy iii. T1 high-grade at the first disease assessment following an induction BCG course Adequate BCG (Minimum Treatment Requirements) 1) At least 5 of 6 full doses of an initial induction course plus at least 1 maintenance (2 of 3 weekly full doses) in a 6m period OR 2) At least 5 of 6 full doses of an initial induction course plus at least 2 of 6 full doses of a second induction course. 4b BCG Experienced. BCG experienced subjects must meet the following: i. Recurrent high-grade Ta/T1 disease within 12m of completion of BCG therapy Prior BCG (Minimum Treatment Requirements) 1) At least 5 of 6 full doses of an initial induction course OR 2) At least 5 of 6 full doses of an initial induction course plus at least 1 maintenance (2 of 3 weekly doses) in a 6m period. One-half dose or onethird dose is allowed during maintenance
5. 5. Refuses or is not eligible for cystectomy (Cohort 1 and Cohort 2 only)
6. 6. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1
7. 7.Criterion modified per Amendment 2 7.1 Criterion modified per Amendment 4 7.2 Adequate bone marrow, liver, and renal function: a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding 2wks): i. Absolute neutrophil count (ANC) ≥1,000/mm3 ii. Platelet count ≥75,000/mm3 iii. Hemoglobin ≥8.0 g/dL b. Liver function: i. Total bilirubin ≤1.5 x institutional ULN OR direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5xULN ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x institutional ULN c. Renal function: Creatinine clearance >30 mL/min calculated using the Cockcroft-Gault formula. d. Phosphate: less than ULN within 14 days before the first dose of study drug on Cycle 1 Day 1 (medical management allowed)
8. 8. 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
9. 9. A woman of childbearing potential must have a negative pregnancy test (β-hCG) (urine or serum) within 7 days before randomization (Cohort 1) or the first dose of study drug (Cohort 2 and Cohort 3).
10. 10.Criterion modified per Amendment 2 10.1. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. a. For women of childbearing potential (defined as: fertile, following menarche and until becoming postmenopausal unless permanently sterile) -> see protocol b. For men who are sexually active with women of childbearing potential: -> see protocol

Exclusion criteria 15

1. 1. Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of the bladder
2. 2. Histopathology demonstrating any small cell component, pure adenocarcinoma, pure squamous cell carcinoma, or pure squamous CIS of the bladder
3. 3. Prior treatment with an FGFR inhibitor
4. 4. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are: a. skin cancer treated within the last 24 months that is considered completely cured b. adequately treated lobular carcinoma in situ (LCIS) and ductal CIS c. history of localized breast cancer and receiving antihormonal agents, or history of localized prostate cancer (N0M0) and receiving androgen deprivation therapy
5. 5. Current central serous retinopathy or retinal pigment epithelial detachment of any grade
6. 6. History of uncontrolled cardiovascular disease including: a. any of the following in the preceding 3 months: unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, cerebrovascular accident, or transient ischemic attack. b. QTc prolongation as confirmed by ECG assessment at screening (Fridericia; QTc >480 milliseconds). c. Pulmonary embolism or other venous thromboembolism within the preceding 2 months.
7. 7. Criterion modified per Amendment 1. 7.1. Known human immunodeficiency virus (HIV) infection, unless the subject has been on a stable anti-retroviral therapy regimen for the last 6 months or more and has had no opportunistic infections and a CD4 count >350 in the last 6 months.
8. 8. Criterion modified per Amendment 1. 8.1. 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 test and subjects with hepatitis B with positive HBsAg antibody are allowed).
9. 9. Not recovered from toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, neuropathy, hearing loss)
10. 10. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
11. 11. Major surgery within 4 weeks before Cycle 1 Day 1 (TURBT is not considered major surgery)
12. 12. Criterion modified per Amendment 2 12.1 Severe hypocalcemia (corrected serum calcium of <7 mg/dl), acute and unhealed bone fractures, known underlying bone disease, or at an increased risk of bone fracture. In addition,any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subjects (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.
13. 13. Criterion deleted per Amendment 3
14. 14.Criterion added per Amendment 2 As determined by the investigator, contraindications to the use of gemcitabine or MMC/hyperthermic MMC (Cohort 1) per local prescribing information
15. 15.Criterion added per Amendment 3 Treatment with any other investigational agent within 30 days prior to randomization.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Recurrence-free survival (RFS)

Investigational products

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

Test 3

Comparator 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 4

Locations

3 EU/EEA countries · 4 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 31 files

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

Application history

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