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.
- Conditions
- Cohort 1 and 2: High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) with FGFR Mutations or FusionsCohort 3 Intermediate Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) with FGFR Mutations or FusionsMedDRA version: 20.0Level: PTClassification code 10005003Term: Bladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-002449-39-DE
- Lead Sponsor
- Janssen-Cilag International NV
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 280
1. =18 yrs of age (or the legal age of consent in the jurisdiction in which the study is taking place).
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 high-grade 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.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. 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
2) OR
3) 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 one-third dose is allowed during maintenance
5. Refuses or is not eligible for cystectomy (Cohort 1 and Cohort 2 only)
6. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1
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. Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of the bladder
2. Histopathology demonstrating any small cell component, pure adenocarcinoma, pure squamous cell carcinoma, or pure squamous CIS of the bladder
3. Prior treatment with an FGFR inhibitor
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. Current central serous retinopathy or retinal pigment epithelial detachment of any grade
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. 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. 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. Not recovered from toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, neuropathy, hearing loss)
10. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
11. Major surgery within 4 weeks before Cycle 1 Day 1 (TURBT is not considered major surgery)
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. Criterion deleted per Amendment 3 from the main study. Added the Use of strong CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study drug to exclusion criteria of DDI substudy.
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.Criterion added per Amendment 3
Treatment with any other investigational agent within 3
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method