FORAGER-1: A Phase 1, Open-Label, Multicenter Study of Vepugratinib (LY3866288; LOXO-435) in Locally Advanced or Metastatic Solid Tumors Including Urothelial Cancer and Muscle Invasive Bladder Cancer With FGFR3 Alterations
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 677
- 试验地点
- 143
- 主要终点
- Phase 1a: To determine the recommended dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs)
研究概览
简要总结
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of Vepugratinib by itself or when it is combined with other medicines that treat cancer. Vepugratinib may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Study participation could last up to approximately 6 years, depending on which part of the study you join.
详细描述
This is an open-label, multi-center, phase 1 study in participants with FGFR3-altered advanced solid tumor malignancy including metastatic urothelial cancer (UC), muscle-invasive bladder cancer (MIBC), and low grade intermediate risk non-muscle-invasive bladder cancer (LG IR NMIBC). The study will be conducted in 2 phases. Phase 1a will assess safety, tolerability, and pharmacokinetics of Vepugratinib to determine the optimal dose for further expansion. Phase 1b will include dose expansion cohorts to evaluate the efficacy and safety of Vepugratinib as monotherapy or in combinations with other medicines that treat cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Cohort A2 is randomized
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
- •Cohort A1, C1, D1, and D2: Locally advanced or metastatic solid tumor malignancy with a qualifying FGFR3 alteration.
- •Cohort A2, B2, B5 and B7: Urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration.
- •Cohorts B1 and B4: Urothelial cancer that is locally advanced or metastatic and have received prior erdafitinib.
- •Cohort B6: Muscle Invasive Bladder Cancer with a qualifying FGFR3 alteration.
- •Cohort B7: Urothelial cancer that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration and expression of human epidermal growth factor receptor 2 (HER2).
- •Cohort B8: Low Grade Intermediate Risk Non-Muscle Invasive Bladder cancer and a qualifying FGFR3 genetic alteration.
- •Measurability of disease:
- •Cohort A1, D1, and D2: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1).
- •Cohorts A2, B1, B2, B4, B5, B7, and C1: Measurable disease required as defined by RECIST v1.
- •Cohort B8: Baseline disease which includes at least 1 lesion.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of:
- •0 or 1 for Cohorts A1, A2, B5, B6, B7, and B
- •Less than or equal to 2 for Cohorts B1, B2, B4, C1, DI and D
- •Cohort B6: Must be eligible for radical cystectomy plus pelvic lymph node dissection and agree to undergo curative intent standard radical cystectomy plus pelvic lymph node dissection.
排除标准
- •Participants with primary central nervous system (CNS) malignancy.
- •Untreated or uncontrolled CNS metastases.
- •Current evidence of corneal keratopathy or retinal disorder. Individuals with asymptomatic ophthalmic conditions may be eligible.
- •Any serious unresolved toxicities from prior therapy.
- •Significant cardiovascular disease.
- •Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF).
- •Active uncontrolled systemic infection or other clinically significant medical conditions.
- •Participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. Participants who have stopped breastfeeding may be enrolled.
- •Cohort D1 only:
- •Have had renal transplantation.
- •Have a known history of nephrotic syndrome.
- •Have uncontrolled fluid overload, including clinically significant ascites, pleural effusion, or peripheral edema.
- •Have uncontrolled hypertension.
- •Are on hemodialysis or similar.
- •Cohort D2 only:
- •Have a history of:
- •Ventricular tachycardia or ventricular fibrillation.
- •Hypertrophic obstructive cardiomyopathy unless managed concurrently with atrial fibrillation.
- •Wolff-Parkinson-White syndrome.
- •Second- or third-degree atrioventricular block unless a functioning pacemaker is in place.
- •Heart rate less than (<) 50 bpm.
- •Have any of these medical conditions:
- •Severe respiratory insufficiency.
- •Sleep apnea syndrome.
- •Myasthenia gravis.
- •Acute narrow-angle glaucoma.
- •Active liver disease or clinically significant hepatic impairment.
- •History of myopathy or rhabdomyolysis with any HMG-CoA reductase inhibitor.
研究组 & 干预措施
Phase 1a: Cohort A1 Vepugratinib Monotherapy Dose Escalation
Vepugratinib administered orally
干预措施: Vepugratinib (Drug)
Phase 1a: Cohort A2 Vepugratinib Monotherapy Dose Optimization
Vepugratinib administered orally
干预措施: Vepugratinib (Drug)
Phase 1b: Cohort B1, B2, B4, C1, and D1 Vepugratinib Monotherapy Dose Expansion
Vepugratinib administered orally
干预措施: Vepugratinib (Drug)
Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin
Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
干预措施: Vepugratinib (Drug)
Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin
Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
干预措施: Vepugratinib (Drug)
Experimental: Phase 1b: Cohort B7 Vepugratinib Plus Trastuzumab Deruxtecan
Vepugratinib administered orally in combination with trastuzumab deruxtecan administered IV
干预措施: Vepugratinib (Drug)
Phase 1b: NMIBC Cohort B8 Vepugratinib Monotherapy Dose Expansion
Vepugratinib administered orally
干预措施: Vepugratinib (Drug)
Phase 1b: Cohort D2 (Drug to Drug Interaction)
Vepugratinib Plus Midazolam Plus Digoxin Plus Rosuvastatin (Lead-In Only) followed by Vepugratinib Monotherapy
Vepugratinib administered orally
Midazolam with digoxin with rosuvastatin administered orally once per cycle for 2 cycles.
干预措施: Vepugratinib (Drug)
Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin
Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
干预措施: Pembrolizumab (Drug)
Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin
Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
干预措施: enfortumab vedotin (Drug)
Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin
Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
干预措施: Pembrolizumab (Drug)
Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin
Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
干预措施: enfortumab vedotin (Drug)
Experimental: Phase 1b: Cohort B7 Vepugratinib Plus Trastuzumab Deruxtecan
Vepugratinib administered orally in combination with trastuzumab deruxtecan administered IV
干预措施: Trastuzumab Deruxtecan (Drug)
Phase 1b: Cohort D2 (Drug to Drug Interaction)
Vepugratinib Plus Midazolam Plus Digoxin Plus Rosuvastatin (Lead-In Only) followed by Vepugratinib Monotherapy
Vepugratinib administered orally
Midazolam with digoxin with rosuvastatin administered orally once per cycle for 2 cycles.
干预措施: Midazolam (Drug)
Phase 1b: Cohort D2 (Drug to Drug Interaction)
Vepugratinib Plus Midazolam Plus Digoxin Plus Rosuvastatin (Lead-In Only) followed by Vepugratinib Monotherapy
Vepugratinib administered orally
Midazolam with digoxin with rosuvastatin administered orally once per cycle for 2 cycles.
干预措施: Digoxin (Drug)
Phase 1b: Cohort D2 (Drug to Drug Interaction)
Vepugratinib Plus Midazolam Plus Digoxin Plus Rosuvastatin (Lead-In Only) followed by Vepugratinib Monotherapy
Vepugratinib administered orally
Midazolam with digoxin with rosuvastatin administered orally once per cycle for 2 cycles.
干预措施: Rosuvastatin (Drug)
结局指标
主要结局
Phase 1a: To determine the recommended dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs)
时间窗: Minimum of the first 21-day cycle of LOXO-435 treatment
Number of participants with DLTs
Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR)
时间窗: Up to approximately 30 months or 2.5 years
ORR per investigator assessed RECIST v1.1
Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration
时间窗: Up to approximately 30 months or 2.5 years
A summary of TEAEs and SAEs regardless of causality, will be reported in the Reported Adverse Events module
Overall Response Rate (ORR)
时间窗: Up to Approximately 30 Months or 2.5 Years
Pharmacokinetics (PK) of Vepugratinib: Area Under the Concentration versus Time Curve (AUC)
时间窗: Up to 2 Months
PK of Midazolam, Rosuvastatin, and Digoxin Administered Alone and in the Presence of Vepugratinib: Area Under the Concentration versus Time Curve (AUC[0-inf])
时间窗: Up to 2 Months
Complete Response Rate (CRR) in Participants with Low-Grade Intermediate-Risk Non-Muscle Invasive Bladder Cancer (LG IR NMIBC)
时间窗: Up to approximately 24 months or 5 years
次要结局
- To assess the pharmacokinetics (PK) of LOXO-435: Area under the concentration versus time curve (AUC)(Up to 2 months)
- To assess the PK of LOXO-435: Minimum plasma concentration (Cmin)(Up to 2 months)
- To evaluate the preliminary antitumor activity of LOXO-435: Objective response rate (ORR)(Up to approximately 30 months or 2.5 years])
- To evaluate the preliminary antitumor activity of LOXO-435: Duration of response (DoR)(Up to approximately 30 months or 2.5 years)
- To evaluate the preliminary antitumor activity of LOXO-435: Time to response (TTR)(Up to approximately 30 months or 2.5 years)
- To evaluate the preliminary antitumor activity of LOXO-435: Progression-free survival (PFS)(Up to approximately 30 months or 2.5 years)
- To evaluate the preliminary antitumor activity of LOXO-435: Disease control rate (DCR)(Up to approximately 30 months or 2.5 years)
- To evaluate the preliminary antitumor activity of LOXO-435: Overall survival (OS)(Up to approximately 30 months or 2.5 years)
- Change from baseline in bladder-related symptoms, measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) subscale (BlCS)(Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 (28 day cycles))
- Change from baseline in physical function, measured by FACT- Physical Well-being Scale (PWB) subscale(Up to approximately 30 months or 2.5 years)
- Change from Baseline in Bladder-Related Symptoms, Measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) Subscale (BlCS)(Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 (28 Day Cycles))
- Change from Baseline in Physical Function, Measured by FACT- Physical Well-Being Scale (PWB) Subscale(Up to Approximately 30 Months or 2.5 Years)
- Event-Free Survival (EFS) in Participants with Muscle Invasive Bladder Cancer (MIBC)(Up to approximately 30 months or 2.5 years)