A Phase 3 Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Subjects With Advanced Urothelial Cancer and Selected FGFR Gene Aberrations
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 629
- 试验地点
- 642
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
The purpose of this study is to evaluate efficacy of erdafitinib versus chemotherapy or pembrolizumab in participants with advanced urothelial cancer harboring selected fibroblast growth factor receptor (FGFR) aberrations who have progressed after 1 or 2 prior treatments, at least 1 of which includes an anti-programmed death ligand 1(PD-[L]1) agent (cohort 1) or 1 prior treatment not containing an anti-PD-(L) 1 agent (cohort 2).
详细描述
A study of erdafitinib versus standard of care, consisting of chemotherapy (docetaxel or vinflunine) or anti-PD-(L) 1 agent pembrolizumab, in participants with advanced urothelial cancer and selected FGFR aberrations who have progressed on or after 1 or 2 prior treatments, at least 1 of which includes an anti-PD-(L) 1 agent (cohort 1) or 1 prior treatment not containing an anti-PD-(L) 1 agent (cohort 2). It will consist of screening, treatment phase (from randomization until disease progression, intolerable toxicity, withdrawal of consent or decision by investigator to discontinue treatment, post-treatment follow-up (from end-of-treatment to participants death, withdraws consent, lost to follow-up study completion for the respective cohort, whichever comes first). The study will have long term extension (LTE) period after clinical cutoff date is achieved for final analysis of each cohort and participants eligible in the opinion of the investigator, will continue to benefit from the study intervention. Efficacy, pharmacokinetics, biomarkers, patient reported outcomes, medical resource utilization and safety will be assessed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologic demonstration of transitional cell carcinoma of the urothelium. Minor components ( less than [<] 50 percent [%] overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable
- •Metastatic or surgically unresectable urothelial cancer
- •Documented progression of disease, defined as any progression that requires a change in treatment, prior to randomization
- •Cohort 1: Prior treatment with an anti-PD-(L) 1 agent as monotherapy or as combination therapy; no more than 2 prior lines of systemic treatment. Cohort 2: No prior treatment with an anti-PD-(L) 1 agent; only 1 line of prior systemic treatment. Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose are considered to have received systemic therapy in the metastatic setting.
- •A woman of childbearing potential who is sexually active must have a negative pregnancy test (beta human chorionic gonadotropin [beta hCG]) at Screening (urine or serum)
- •Participants must meet appropriate molecular eligibility criteria
- •Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
- •Adequate bone marrow, liver, and renal function
排除标准
- •Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to randomization
- •Active malignancies (that is, requiring treatment change in the last 24 months). The only allowed exceptions are: urothelial cancer, skin cancer treated within the last 24 months that is considered completely cured, localized prostate cancer with a gleason score of 6 (treated within the last 24 months or untreated and under surveillance) and localized prostate cancer with a gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence.
- •Symptomatic central nervous system metastases
- •Received prior fibroblast growth factor receptor (FGFR) inhibitor treatment
- •Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients
- •Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade.
- •History of uncontrolled cardiovascular disease
- •Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
研究组 & 干预措施
Cohort 2 (Arm 2B): Pembrolizumab
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (no prior treatment with anti-PD-[L] 1 agent) will receive pembrolizumab 200 mg as a 30-minute intravenous infusion once every 3 weeks, until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive the pembrolizumab until 2 years after the first dose of pembrolizumab (at start of study) or until the participant can commercially receive pembrolizumab within the local healthcare system, whichever comes first.
干预措施: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA) (Device)
Cohort 2 (Arm 2A): Erdafitinib
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (no prior treatment with anti-PD-[L] 1 agent) will swallow erdafitinib tablets orally at a starting dose of 8 mg, once daily for 21 days in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on phosphate level and observed toxicity (AEs). Participants who enter in LTE phase will continue to receive the erdafitinib tablet as per investigator's decision.
干预措施: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA) (Device)
Cohort 1 (Arm 1B): Vinflunine or Docetaxel
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-PD-[L] 1 agent) will receive vinflunine 320 milligram per meter square (mg/m^2) as a 20-minute intravenous infusion once every 3 weeks or docetaxel 75 mg/m^2 as a 1 hour intravenous infusion every 3 weeks. Treatment with either agent (choice of investigator) will be administered until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive Vinflunine or Docetaxel until the participant can commercially receive chemotherapy within the local healthcare system.
干预措施: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA) (Device)
Cohort 1 (Arm 1A): Erdafitinib
Participants will be screened based on Fibroblast Growth Factor Receptor Inhibitor Clinical Trial Assay (FGFRi CTA) to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-programmed cell death protein PD-[L] 1 agent) will swallow erdafitinib tablets orally at a starting dose of 8 milligram (mg), once daily for 21 days in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustment are based on phosphate level and observed toxicity (adverse events [AEs]). Participants who enter in Long-term extension (LTE) phase will continue to receive the erdafitinib tablet as per investigator's decision.
干预措施: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA) (Device)
Cohort 1 (Arm 1B): Vinflunine or Docetaxel
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-PD-[L] 1 agent) will receive vinflunine 320 milligram per meter square (mg/m^2) as a 20-minute intravenous infusion once every 3 weeks or docetaxel 75 mg/m^2 as a 1 hour intravenous infusion every 3 weeks. Treatment with either agent (choice of investigator) will be administered until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive Vinflunine or Docetaxel until the participant can commercially receive chemotherapy within the local healthcare system.
干预措施: Vinflunine (Drug)
Cohort 2 (Arm 2A): Erdafitinib
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (no prior treatment with anti-PD-[L] 1 agent) will swallow erdafitinib tablets orally at a starting dose of 8 mg, once daily for 21 days in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on phosphate level and observed toxicity (AEs). Participants who enter in LTE phase will continue to receive the erdafitinib tablet as per investigator's decision.
干预措施: Erdafitinib (Drug)
Cohort 1 (Arm 1A): Erdafitinib
Participants will be screened based on Fibroblast Growth Factor Receptor Inhibitor Clinical Trial Assay (FGFRi CTA) to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-programmed cell death protein PD-[L] 1 agent) will swallow erdafitinib tablets orally at a starting dose of 8 milligram (mg), once daily for 21 days in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustment are based on phosphate level and observed toxicity (adverse events [AEs]). Participants who enter in Long-term extension (LTE) phase will continue to receive the erdafitinib tablet as per investigator's decision.
干预措施: Erdafitinib (Drug)
Cohort 2 (Arm 2B): Pembrolizumab
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (no prior treatment with anti-PD-[L] 1 agent) will receive pembrolizumab 200 mg as a 30-minute intravenous infusion once every 3 weeks, until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive the pembrolizumab until 2 years after the first dose of pembrolizumab (at start of study) or until the participant can commercially receive pembrolizumab within the local healthcare system, whichever comes first.
干预措施: Pembrolizumab (Drug)
Cohort 1 (Arm 1B): Vinflunine or Docetaxel
Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-PD-[L] 1 agent) will receive vinflunine 320 milligram per meter square (mg/m^2) as a 20-minute intravenous infusion once every 3 weeks or docetaxel 75 mg/m^2 as a 1 hour intravenous infusion every 3 weeks. Treatment with either agent (choice of investigator) will be administered until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive Vinflunine or Docetaxel until the participant can commercially receive chemotherapy within the local healthcare system.
干预措施: Docetaxel (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: From randomization (3 days prior to Cycle 1 Day 1) until death due to any cause (maximum up to 51.7 months)
Overall survival was measured from the date of randomization to the date of the participant's death.
次要结局
- Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1(From randomization (3 days prior to Cycle 1 Day 1) until disease progression or relapse from CR or death (maximum up to 51.7 months))
- Objective Response Rate (ORR) Per RECIST Version 1.1(From start of the treatment (Day 1 Cycle 1) up to maximum of 51.7 months)
- Change From Baseline in Physical Functioning Scales of the Functional Assessment of Cancer Therapy - Bladder Cancer (FACT-Bl)(Baseline up to Cycle 11 (each cycle was of 21 days))
- Time Until Symptom Deterioration(Randomization (3 days prior to Cycle 1 Day 1) up to maximum of 51.7 months)
- Percentage of Participants With Shift From Baseline in Patient-Global Impression of Severity (PGIS)(Baseline, 51.7 months)
- Change From Baseline in Utility Scale of the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L)(Baseline up to Cycle 11 (each cycle was of 21 days))
- Change From Baseline in Visual Analog Scale (VAS) of the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L)(Baseline up to Cycle 11 (each cycle was of 21 days))
- Duration of Response (DOR) as Per RECIST Version 1.1(From date of first documented response to date of first documented PD or death whichever occurred first (maximum up to 51.7 months))
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From start of the treatment (Day 1 Cycle 1) up to 30 days after last dose of study drug or start of subsequent anticancer therapy (maximum up to 51.7 months))
- Number of Participants With Shift From Baseline Grade Less Than or Equal to (<=) 2 to Grade Greater Than or Equal to (>=) 3 Post-Baseline in Laboratory Parameter: Hematology(From baseline up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (maximum up to 51.7 months))
- Number of Participants With Shift From Baseline Grade <= 2 to Grade >=3 Post-Baseline in Laboratory Parameter: Chemistry(From baseline up to 30 days after last dose or start of new anticancer therapy, whichever occurred first (maximum up to 51.7 months))
- Number of Participants With Abnormalities in Electrocardiograms (ECG) Parameters(Day 1 of Cycle 2 and 4 (Each Cycle 21 days))
- Change From Baseline in Vital Signs: Weight(Baseline, 51.7 months)
- Number of Participants With Shift From Baseline to Worst Post-baseline Ophthalmologic Examination: Amsler Grid Test(From baseline up to maximum of 51.7 months)
- Number of Participants With Shift From Baseline to Worst Post-baseline Ophthalmologic Examination: Visual Acuity(From baseline up to maximum of 51.7 months)
- Number of Participants With Shift From Baseline to Worst Post-baseline Ophthalmologic Examination: Optical Coherence Tomography: Subretinal Fluid(From baseline up to maximum of 51.7 months)
- Number of Participants With Shift From Baseline to Worst Post-baseline Ophthalmologic Examination: Optical Coherence Tomography: Retinal Pigment Epithelium (RPE) Elevation(From baseline up to maximum of 51.7 months)
- Number of Participants With Shift From Baseline to Worst Post-baseline Ophthalmologic Examination: Slit Lamp Biomicroscopy: Retinal Assessment(From baseline up to maximum of 51.7 months)
- Oral Clearance (CL/F) of Erdafitinib(Day 14 of Cycle 1, Day 1 of Cycle 2: pre-dose and 2-4 hours post-dose (each cycle was of 21 days))
- Area Under the Plasma Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of Erdafitinib(Day 14 of Cycle 1, Day 1 of Cycle 2: pre-dose and 2-4 hours post-dose (each cycle is of 21 days))