Urinary Bladder Neoplasms
Conditions
Keywords
Non muscle invasive bladder cancer (NMIBC), Bacillus calmette- guerin (BCG) failure, BCG unresponsive
Brief summary
The purpose of this study is to evaluate recurrence-free survival (RFS) in participants treated with erdafitinib vs Investigator's Choice, for participants with high-risk non-muscle-invasive bladder cancer (NMIBC) who harbor fibroblast growth factor receptor (FGFR) mutations or fusions, and who recurred after bacillus calmette-guerin (BCG) therapy.
Detailed description
This study enrolls participants with high risk NMIBC and FGFR mutations or fusions. Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) 1-4 inhibitor with demonstrated clinical activity in participants with solid tumors, including urothelial carcinoma, with alterations in the FGFR pathway. In Cohort 1, participants will be randomized to erdafitinib or to Investigators Choice (intravesical gemcitabine or intravesical mitomycin C \[MMC\] or hyperthermic MMC). The study consists of screening period, treatment phase, follow-up phase, and long-term extension phase.
Interventions
DRUGErdafitinib
Participants will receive erdafitinib orally beginning on Cycle 1 Day 1 until 2 years of treatment have been completed, disease recurrence, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurs first. Each cycle is of 28 days.
DRUGInvestigator Choice (Gemcitabine)
Investigator's Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly maintenance for at least 6 months.
DRUGInvestigator Choice (Mitomycin C)
Investigator's Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly maintenance for at least 6 months.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, recurrent, non-muscle-invasive urothelial carcinoma of the bladder. Variant pathology are allowed * Tumor with specified fibroblast growth factor receptor (FGFR) mutations or fusions * Bacillus Calmette- Guerin (BCG)-unresponsive after adequate BCG therapy or BCG experienced participants * Refuses or is not eligible for cystectomy (Cohort 1 and Cohort 2 only) * Eastern Cooperative Oncology Group (ECOG) performance status Grade 0-1 * 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 * A woman of childbearing potential must have a negative pregnancy test (beta-human chorionic gonadotropin \[beta-hCG\]) (urine or serum) within 7 days before randomization (Cohort 1) or the first dose of study drug (Cohort 2 and Cohort 3) * Adequate bone marrow, liver, and renal function as specified in the protocol
Exclusion criteria
* Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of the bladder * Histopathology demonstrating any small cell component, pure adenocarcinoma, pure squamous cell carcinoma, or pure squamous CIS of the bladder * Prior treatment with an FGFR inhibitor * Active malignancies 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 * Current central serous retinopathy or retinal pigment epithelial detachment of any grade
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Recurrence-Free Survival (RFS) | From randomization (Cycle 1 Day 1, pre-dose) up to 48.2 months | RFS was defined as the time from the date of randomization until the date of the reappearance of high-risk disease (high-grade Ta, T1 or carcinoma in situ \[CIS\]), or death, whichever was reported first. Recurrence was assessed using cystoscopy, bladder mapping, urine cytology, and computed tomography (CT)/ magnetic resonance imaging (MRI) urogram. Participants who were recurrence-free and alive or had unknown status were censored at the last tumor assessment. The Kaplan-Meier method was used to estimate the distribution of overall RFS for each treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Recurrence-Free Survival Rate at 6 Months and 12 Months | At Month 6 and Month 12 | RFS rate was the proportion of participants who were recurrence-free and alive based on Kaplan-Meier estimates. RFS was defined as the time from the date of randomization until the date of the reappearance of high-risk disease (high-grade Ta, T1 or CIS), or death, whichever was reported first. Recurrence was assessed using cystoscopy, bladder mapping, urine cytology, and CT/ MRI urogram. Participants who were recurrence-free and alive or had unknown status were censored at the last tumor assessment. |
| Cohort 1: Time to Progression | From randomization (Cycle 1 Day 1, pre-dose) up to 48.2 months | Time to progression (TTP) was defined as the time from the date of randomization until the date of first documented evidence of any of the following: disease progression (PD) or death. PD included development of or increase in stage to lamina propria invasion (for example- increase from Ta to T1), development of or increase in stage to muscle-invasive disease (stage greater than or equal to \[\>=\] T2), development of or increase in stage to lymph node (N+) or distant metastasis (M1) disease (participants must have previously been diagnosed with N0 and/or M0 disease), increase in tumor grade from low to high (including CIS). |
| Cohort 1: Overall Survival | From randomization (Cycle 1 Day 1, pre-dose) up to 48.2 months | Overall survival was defined as the time from the date of randomization to the date of the participant's death due to any cause. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From start of treatment (Day 1) up to 25.2 months | An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs were the events between first dose of study drug and up to 30 (+7 days) days after last dose or before start of subsequent anticancer therapy, whichever occurred first. All TEAEs including serious and non-serious events were reported in this outcome measure (OM). |
| Plasma Concentrations of Erdafitinib | All cohorts: Pre-dose on Cycle 1 Day 14, pre-dose and 3 hours post-dose on Cycle 2 Day 1 (each cycle was of 28 days) | Plasma concentrations of erdafitinib were reported. Plasma samples were analyzed using liquid chromatography/mass spectrometry method. |
Countries
Argentina, Australia, Belgium, Brazil, China, Czechia, France, Germany, India, Italy, Japan, Poland, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Pre-assignment details
Results are presented till final database lock date of 07 August 2024. Cohort 2 and Cohort 3 participants were involved in exploratory efficacy endpoints analysis and thus no efficacy data were reported in outcome measures section for Cohort 2 and 3. With implementation of Protocol Amendment 6 (dated 13 July 2023), long term extension (LTE) phase was added in study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Erdafitinib Participants with high-risk non-muscle-invasive bladder cancer (NMIBC) presenting as papillary tumor only (carcinoma in situ \[CIS\], absent), with disease recurrence after bacillus Calmette- Guerin (BCG) therapy and who either refused or were not eligible for cystectomy received erdafitinib tablets orally, at a dose of 6 milligrams (mg) once daily starting from Day 1 through Day 28 in each subsequent 28-day cycle starting from Day 1 of Cycle 1 up to disease recurrence or progression, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurred first (up to 2 years). With the implementation of Protocol Amendment 6 (dated 13 July 2023), participants who benefited from the study drug, as determined by investigator, continued to receive study drug in the LTE phase. The participants who did not enter LTE phase discontinued the study. | 49 |
| Cohort 1: Investigator's Choice Participants with high-risk NMIBC presenting as papillary tumor only (CIS, absent), with disease recurrence after BCG therapy and who either refused or were not eligible for cystectomy received the investigator's choice of treatment: either gemcitabine intravesical instillation (4 induction doses: 2000 mg once weekly on Days 1, 8, 15 and 22 of Cycle 1 followed by monthly maintenance dose on Day 1 of Cycle 2 to 7, each cycle of 28 days) or either mitomycin C (MMC) or hyperthermic MMC as an intravesical instillation at the dose of 40 mg/40 milliliter (mL). Additional doses of induction or maintenance were allowed per local standard of care. The choice of drug was determined by the investigator and treatment continued until its completion, disease recurrence, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurred first (up to 2 years). Participants with locally confirmed high-risk recurrence on Investigator's Choice were offered an option to crossover treatment with erdafitinib until protocol amendment 6 (dated 13 July 2023). With the implementation of Protocol Amendment 6 (dated 13 July 2023), participants who benefited from the study drug, as determined by investigator, continued to receive study drug in the LTE phase. The participants who did not enter LTE phase discontinued the study. | 24 |
| Cohort 2: Erdafitinib Participants with high-risk, BCG- unresponsive NMIBC presenting as CIS with or without concurrent papillary tumor and who either refused or were not eligible for cystectomy received erdafitinib tablets orally, at a dose of 6 mg once daily starting from Day 1 through Day 28 in each subsequent 28-day cycle starting from Day 1 of Cycle 1 up to disease recurrence or progression, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurred first (up to 2 years). With the implementation of Protocol Amendment 6 (dated 13 July 2023), participants who benefited from the study drug, as determined by investigator, continued to receive study drug in the LTE phase. The participants who did not enter LTE phase discontinued the study. | 16 |
| Cohort 3: Erdafitinib Participants with intermediate-risk NMIBC presenting as papillary disease only (low grade \[Grade 1- Grade 2\], Ta or T1, with no previous CIS) received erdafitinib tablets orally, at a dose of 6 mg once daily starting from Day 1 through Day 28 in each subsequent 28-day cycle starting from Day 1 of Cycle 1 up to disease recurrence or progression, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurred first (up to 2 years). With the implementation of Protocol Amendment 6 (dated 13 July 2023), participants who benefited from the study drug, as determined by investigator, continued to receive study drug in the LTE phase. The participants who did not enter LTE phase discontinued the study. | 18 |
| Total | 107 |
Baseline characteristics
| Characteristic | Cohort 1: Erdafitinib | Total | Cohort 3: Erdafitinib | Cohort 2: Erdafitinib | Cohort 1: Investigator's Choice |
|---|---|---|---|---|---|
| Age, Continuous | 68.3 Years STANDARD_DEVIATION 10.89 | 66.6 Years STANDARD_DEVIATION 11.04 | 61.6 Years STANDARD_DEVIATION 9.05 | 66.7 Years STANDARD_DEVIATION 12.37 | 67 Years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 19 Participants | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 70 Participants | 12 Participants | 11 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 18 Participants | 3 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 25 Participants | 1 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 2 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 27 Participants | 63 Participants | 15 Participants | 9 Participants | 12 Participants |
| Region of Enrollment Argentina | 2 Participants | 8 Participants | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Australia | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Belgium | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Brazil | 7 Participants | 11 Participants | 0 Participants | 1 Participants | 3 Participants |
| Region of Enrollment China | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment France | 5 Participants | 12 Participants | 1 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Germany | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment India | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Italy | 5 Participants | 9 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Japan | 6 Participants | 11 Participants | 0 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Korea, South | 8 Participants | 10 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Poland | 2 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Spain | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 10 Participants | 3 Participants | 4 Participants | 0 Participants |
| Region of Enrollment United States | 6 Participants | 17 Participants | 10 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 12 Participants | 28 Participants | 9 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 37 Participants | 79 Participants | 9 Participants | 14 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 49 | 0 / 24 | 0 / 9 | 1 / 16 | 0 / 18 |
| other Total, other adverse events | 49 / 49 | 19 / 23 | 9 / 9 | 16 / 16 | 18 / 18 |
| serious Total, serious adverse events | 13 / 49 | 2 / 23 | 3 / 9 | 4 / 16 | 1 / 18 |
Outcome results
Primary
Cohort 1: Recurrence-Free Survival (RFS)
RFS was defined as the time from the date of randomization until the date of the reappearance of high-risk disease (high-grade Ta, T1 or carcinoma in situ \[CIS\]), or death, whichever was reported first. Recurrence was assessed using cystoscopy, bladder mapping, urine cytology, and computed tomography (CT)/ magnetic resonance imaging (MRI) urogram. Participants who were recurrence-free and alive or had unknown status were censored at the last tumor assessment. The Kaplan-Meier method was used to estimate the distribution of overall RFS for each treatment group.
Time frame: From randomization (Cycle 1 Day 1, pre-dose) up to 48.2 months
Population: Intent-to-Treat (ITT) analysis set included all randomized participants. Participants in Cohort 1 were primarily analyzed by the treatment to which they were assigned, regardless of the actual treatment received. Data for this outcome measure was planned to be collected and analyzed for specified arms only as planned in protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Erdafitinib | Cohort 1: Recurrence-Free Survival (RFS) | NA Months |
| Cohort 1: Investigator's Choice | Cohort 1: Recurrence-Free Survival (RFS) | 11.60 Months |
p-value: =0.000795% CI: [0.13, 0.61]Unstratified Log rank
Secondary
Cohort 1: Overall Survival
Overall survival was defined as the time from the date of randomization to the date of the participant's death due to any cause.
Time frame: From randomization (Cycle 1 Day 1, pre-dose) up to 48.2 months
Population: ITT analysis set included all randomized participants. Participants in Cohort 1 were primarily analyzed by the treatment to which they were assigned, regardless of the actual treatment received. Data for this outcome measure was planned to be collected and analyzed for specified arms only as planned in protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Erdafitinib | Cohort 1: Overall Survival | NA Months |
| Cohort 1: Investigator's Choice | Cohort 1: Overall Survival | NA Months |
Secondary
Cohort 1: Recurrence-Free Survival Rate at 6 Months and 12 Months
RFS rate was the proportion of participants who were recurrence-free and alive based on Kaplan-Meier estimates. RFS was defined as the time from the date of randomization until the date of the reappearance of high-risk disease (high-grade Ta, T1 or CIS), or death, whichever was reported first. Recurrence was assessed using cystoscopy, bladder mapping, urine cytology, and CT/ MRI urogram. Participants who were recurrence-free and alive or had unknown status were censored at the last tumor assessment.
Time frame: At Month 6 and Month 12
Population: ITT analysis set included all randomized participants. Participants in Cohort 1 were primarily analyzed by the treatment to which they were assigned, regardless of the actual treatment received. Data for this outcome measure was planned to be collected and analyzed for specified arms only as planned in protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Erdafitinib | Cohort 1: Recurrence-Free Survival Rate at 6 Months and 12 Months | 6-month survival rate | 0.96 Proportion of participants |
| Cohort 1: Erdafitinib | Cohort 1: Recurrence-Free Survival Rate at 6 Months and 12 Months | 12-month survival rate | 0.79 Proportion of participants |
| Cohort 1: Investigator's Choice | Cohort 1: Recurrence-Free Survival Rate at 6 Months and 12 Months | 6-month survival rate | 0.73 Proportion of participants |
| Cohort 1: Investigator's Choice | Cohort 1: Recurrence-Free Survival Rate at 6 Months and 12 Months | 12-month survival rate | 0.44 Proportion of participants |
Secondary
Cohort 1: Time to Progression
Time to progression (TTP) was defined as the time from the date of randomization until the date of first documented evidence of any of the following: disease progression (PD) or death. PD included development of or increase in stage to lamina propria invasion (for example- increase from Ta to T1), development of or increase in stage to muscle-invasive disease (stage greater than or equal to \[\>=\] T2), development of or increase in stage to lymph node (N+) or distant metastasis (M1) disease (participants must have previously been diagnosed with N0 and/or M0 disease), increase in tumor grade from low to high (including CIS).
Time frame: From randomization (Cycle 1 Day 1, pre-dose) up to 48.2 months
Population: ITT analysis set included all randomized participants. Participants in Cohort 1 were primarily analyzed by the treatment to which they were assigned, regardless of the actual treatment received. Data for this outcome measure was planned to be collected and analyzed for specified arms only as planned in protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Erdafitinib | Cohort 1: Time to Progression | NA Months |
| Cohort 1: Investigator's Choice | Cohort 1: Time to Progression | NA Months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs were the events between first dose of study drug and up to 30 (+7 days) days after last dose or before start of subsequent anticancer therapy, whichever occurred first. All TEAEs including serious and non-serious events were reported in this outcome measure (OM).
Time frame: From start of treatment (Day 1) up to 25.2 months
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Erdafitinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 49 Participants |
| Cohort 1: Investigator's Choice | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 19 Participants |
| Cohort 2: Erdafitinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 16 Participants |
| Cohort 3: Erdafitinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 18 Participants |
Secondary
Plasma Concentrations of Erdafitinib
Plasma concentrations of erdafitinib were reported. Plasma samples were analyzed using liquid chromatography/mass spectrometry method.
Time frame: All cohorts: Pre-dose on Cycle 1 Day 14, pre-dose and 3 hours post-dose on Cycle 2 Day 1 (each cycle was of 28 days)
Population: Pharmacokinetic (PK) evaluable analysis set: all randomized (Cohort 1) or treated (Cohort 2 and 3) participants who had received at least 1 dose of erdafitinib and had at least 1 PK sample obtained post-treatment. 'N' (overall number of participants analyzed): number of participants evaluable for this OM, 'n' (number analyzed): participants analyzed at specified time points. Data for this outcome measure was not planned to be collected and analyzed for 'Cohort 1: Investigator's Choice' arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Erdafitinib | Plasma Concentrations of Erdafitinib | Cycle 2 Day 1: 3 hours post dose | 750 Nanograms per milliliter (ng/mL) | Standard Deviation 367 |
| Cohort 1: Erdafitinib | Plasma Concentrations of Erdafitinib | Cycle 2 Day 1: Predose | 635 Nanograms per milliliter (ng/mL) | Standard Deviation 335 |
| Cohort 1: Erdafitinib | Plasma Concentrations of Erdafitinib | Cycle 1 Day 14: Predose | 592 Nanograms per milliliter (ng/mL) | Standard Deviation 252 |
| Cohort 1: Investigator's Choice | Plasma Concentrations of Erdafitinib | Cycle 2 Day 1: 3 hours post dose | 739 Nanograms per milliliter (ng/mL) | Standard Deviation 337 |
| Cohort 1: Investigator's Choice | Plasma Concentrations of Erdafitinib | Cycle 1 Day 14: Predose | 525 Nanograms per milliliter (ng/mL) | Standard Deviation 227 |
| Cohort 1: Investigator's Choice | Plasma Concentrations of Erdafitinib | Cycle 2 Day 1: Predose | 603 Nanograms per milliliter (ng/mL) | Standard Deviation 350 |
| Cohort 2: Erdafitinib | Plasma Concentrations of Erdafitinib | Cycle 2 Day 1: 3 hours post dose | 709 Nanograms per milliliter (ng/mL) | Standard Deviation 220 |
| Cohort 2: Erdafitinib | Plasma Concentrations of Erdafitinib | Cycle 2 Day 1: Predose | 685 Nanograms per milliliter (ng/mL) | Standard Deviation 246 |
| Cohort 2: Erdafitinib | Plasma Concentrations of Erdafitinib | Cycle 1 Day 14: Predose | 605 Nanograms per milliliter (ng/mL) | Standard Deviation 171 |