A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two Different Dose Regimens of a Pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects With Metastatic or Surgically Unresectable Urothelial Cancer With FGFR Genomic Alterations
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 239
- 试验地点
- 105
- 主要终点
- Main Study: Percentage of Participants With Best (Overall) Objective Response
研究概览
简要总结
The purpose of this study is to evaluate the objective response rate (complete response [CR]+ partial response [PR]) of the selected dose regimen in participants with metastatic or surgically unresectable urothelial cancers that harbor specific FGFR genomic alterations.
详细描述
This is a multicenter, open-label study (participants will know the identity of study drugs administered) to evaluate the efficacy and safety of erdafitinib in participants with urothelial cancer. The study comprises a 30-days Screening Phase, a Treatment Phase comprised of 28-day treatment cycles that will continue until disease progression or unacceptable toxicity occurs in a long-term extension (LTE) phase, and a post-treatment Follow-up Phase that will extend from the End-of-Treatment Visit until the participant has died, withdraws consent, is lost to follow-up, or the end of the study, whichever comes first. The end of study is defined as the date when all participants have completed the study treatment (Regimens 1 to 3) and all participants enrolled under the drug-drug interaction (DDI) substudy are no longer receiving treatment with erdafitinib. The purpose of DDI sub-study is to evaluate the interaction of repeated doses of erdafitinib with a sensitive cytochrome 450 (CYP) 3A substrate (midazolam) and with an organic cation transporter 2 (OCT2) probe substrate (metformin). Safety will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Must have histologic demonstration of metastatic or surgically unresectable urothelial cancer. Minor components of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable
- •Must have measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) at baseline
- •Must have an Eastern Cooperative Oncology Group (ECOG) performance status score 0, 1, or 2
- •Must have adequate bone marrow, liver, and renal function as described in protocol
- •Negative pregnancy test (urine or serum beta human chorionic gonadotropin [b-hCG]) at Screening for women of child bearing potential who are sexually active
- •Must have shown disease progression according to RECIST, version 1.1, following prior chemotherapy for metastatic or surgically unresectable urothelial cancer. Participants who received neoadjuvant or adjuvant chemotherapy and showed disease recurrence or progression according to RECIST, version 1.1, within 12 months of the last dose are considered to have received chemotherapy in the metastatic setting. These participants will be referred to as chemo-refractory participants. (Participants who have shown disease progression according to RECIST, version 1.1 following prior treatment with anti-Programmed death-ligand 1 (anti PDL1/PD1) antibodies are also eligible) For DDI substudy
- •Disease progression following prior chemotherapy for metastatic or surgically unresectable urothelial cancer. Participants who received neoadjuvant or adjuvant chemotherapy and showed disease recurrence or progression within 12 months of the last dose are considered to have received chemotherapy in the metastatic setting
排除标准
- •Received chemotherapy, targeted therapies, definitive radiotherapy, or treatment with an investigational anticancer agent within 2 weeks (in the case of nitrosoureas and mitomycin C, within 6 weeks; in the case of immunotherapy, within 4 weeks) before the first administration of study drug. Localized palliative radiation therapy (but should not include radiation to target lesions) and ongoing bisphosphonates and denosumab, are permitted
- •Has persistent phosphate level greater than upper limit of normal (ULN) during screening (within 14 days of treatment and prior to Cycle 1 Day 1) and despite medical management
- •Has a history of or current uncontrolled cardiovascular disease
- •Females who are pregnant, breast-feeding, or planning to become pregnant within 3 months after the last dose of study drug and males ho plan to father a child while enrolled in this study or within 5 months after the last dose of study drug
- •Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, or Grade 1 neuropathy)
研究组 & 干预措施
Erdafitinib (8 milligram)
Prior to interim analysis 1 (IA1), there were 2 treatment regimens: Regimen 1 (10 milligram [mg] once daily, 7 days on/7 days off); and Regimen 2 (6 mg once daily for 28 days). Following IA1, Regimen 1 is closed for further enrollment and starting dose of Regimen 2 is increased to 8 mg once daily for 28 days on a 28-day cycle (referred to as Regimen 3). Participants who enrolled in DDI substudy will receive pretreatment with single doses of midazolam (Day -2) and metformin (Day -1). Participants enrolled in DDI substudy will receive 8 mg erdafitinib treatment from Day 1 to Day 15, single doses of midazolam 2.5 mg (Day 13) and metformin 1000 mg (Day 14) and erdafitinib treatment will continued until disease progression. Participants who completed the DDI substudy and continue to benefit from erdafitinib treatment, will continue to receive erdafitinib in long-term extension (LTE) phase.
干预措施: Metformin (Drug)
Erdafitinib (8 milligram)
Prior to interim analysis 1 (IA1), there were 2 treatment regimens: Regimen 1 (10 milligram [mg] once daily, 7 days on/7 days off); and Regimen 2 (6 mg once daily for 28 days). Following IA1, Regimen 1 is closed for further enrollment and starting dose of Regimen 2 is increased to 8 mg once daily for 28 days on a 28-day cycle (referred to as Regimen 3). Participants who enrolled in DDI substudy will receive pretreatment with single doses of midazolam (Day -2) and metformin (Day -1). Participants enrolled in DDI substudy will receive 8 mg erdafitinib treatment from Day 1 to Day 15, single doses of midazolam 2.5 mg (Day 13) and metformin 1000 mg (Day 14) and erdafitinib treatment will continued until disease progression. Participants who completed the DDI substudy and continue to benefit from erdafitinib treatment, will continue to receive erdafitinib in long-term extension (LTE) phase.
干预措施: Midazolam (Drug)
Erdafitinib (8 milligram)
Prior to interim analysis 1 (IA1), there were 2 treatment regimens: Regimen 1 (10 milligram [mg] once daily, 7 days on/7 days off); and Regimen 2 (6 mg once daily for 28 days). Following IA1, Regimen 1 is closed for further enrollment and starting dose of Regimen 2 is increased to 8 mg once daily for 28 days on a 28-day cycle (referred to as Regimen 3). Participants who enrolled in DDI substudy will receive pretreatment with single doses of midazolam (Day -2) and metformin (Day -1). Participants enrolled in DDI substudy will receive 8 mg erdafitinib treatment from Day 1 to Day 15, single doses of midazolam 2.5 mg (Day 13) and metformin 1000 mg (Day 14) and erdafitinib treatment will continued until disease progression. Participants who completed the DDI substudy and continue to benefit from erdafitinib treatment, will continue to receive erdafitinib in long-term extension (LTE) phase.
干预措施: Erdafitinib (Drug)
结局指标
主要结局
Main Study: Percentage of Participants With Best (Overall) Objective Response
时间窗: From Cycle 1 Day 1 up to 6 years 2 months
Percentage of participants with best (overall) objective response were reported. Best objective response is defined as the best (overall) objective response a participants achieved during the study in the order of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), where CR and PR were confirmed as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. As per RECIST version 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in the short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responders are participants with BOR of CR or PR.
Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose
Cmax is the maximum observed plasma concentration of midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
Cmax is the maximum observed plasma concentration of 1-OH-Midazolam (midazolam metabolite) alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Metformin Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
Cmax is the maximum observed plasma concentration of metformin alone or in combination with erdafitinib
Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Midazolam Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
Tmax is the time to reach the maximum observed plasma concentration of midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
Tmax is the time to reach the maximum observed plasma concentration of 1-OH-Midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Metformin Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
Tmax is the time to reach maximum observed plasma concentration of metformin alone or in combination with erdafitinib
Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC[0-last]) of Midazolam Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
AUC(0-last) is the area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration of midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC[0-last]) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
AUC(0-last) is the area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration of 1-OH-Midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC[0-last]) of Metformin Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
AUC(0-last) is the area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration of metformin alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Infinite Time (AUC[0-Infinity]) of Midazolam Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
AUC(0-Infinity) is the area under the plasma concentration versus time curve from time 0 to the infinite time of midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Infinite Time (AUC[0-Infinity]) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
AUC(0-Infinity) is the area under the plasma concentration versus time curve from time 0 to the infinite time of 1-OH-Midazolam alone or in combination with erdafitinib.
Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Infinite Time (AUC[0-Infinity]) of Metformin Alone or in Combination With Erdafitinib
时间窗: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
AUC(0-Infinity) is the area under the plasma concentration versus time curve from time 0 to the infinite time of metformin alone or in combination with erdafitinib
次要结局
- Main Study: Progression-free Survival (PFS)(From screening up to 6 years 2 months)
- Main Study: Duration of Response (DoR)(From screening up to 6 years 2 months)
- Main Study: Overall Survival(From screening up to 6 years 2 months)
- Main Study: Percentage of Participants With Treatment-emergent Adverse Event (TEAEs)(From Day 1 up to 6 years 2 months)
- Main Study: Plasma Concentration of Erdafitinib at 2 Hours (C2h)(Cycle 1 Days 1 and 21: Pre-dose up to 2 hours post-dose (each cycle length=28 days))
- Main Study: Plasma Concentration of Erdafitinib at 4 Hours (C4h)(Cycle 1 Days 1 and 21: Pre-dose up to 4 hours post-dose (each cycle length=28 days))