An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-Administered With Encorafenib and Binimetinib in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Pfizer
- 入组人数
- 56
- 试验地点
- 29
- 主要终点
- Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14
研究概览
简要总结
This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.
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
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: losartan (Drug)
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: dextromethorphan (Drug)
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: caffeine (Drug)
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: omeprazole (Drug)
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: midazolam (Drug)
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: encorafenib (Drug)
Arm 1 - CYP Probe Cocktail
Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:
- 25 mg losartan oral tablet
- 30 mg dextromethorphan oral capsule
- 50 mg caffeine oral liquid
- 20 mg omeprazole oral capsule
- 2 mg midazolam oral syrup
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: binimetinib (Drug)
Arm 2 - Rosuvastatin and Bupropion
Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14:
- 10 mg rosuvastatin oral tablet
- 75 mg bupropion immediate release (IR) oral tablet
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: rosuvastatin (Drug)
Arm 2 - Rosuvastatin and Bupropion
Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14:
- 10 mg rosuvastatin oral tablet
- 75 mg bupropion immediate release (IR) oral tablet
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: bupropion immediate release (IR) (Drug)
Arm 2 - Rosuvastatin and Bupropion
Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14:
- 10 mg rosuvastatin oral tablet
- 75 mg bupropion immediate release (IR) oral tablet
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: encorafenib (Drug)
Arm 2 - Rosuvastatin and Bupropion
Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14:
- 10 mg rosuvastatin oral tablet
- 75 mg bupropion immediate release (IR) oral tablet
encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
All drugs will be taken within 10 minutes.
干预措施: binimetinib (Drug)
Arm 3 - Modafinil
Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
then receive continuous treatment of modafinil on Day 15 through Day 21:
- 400 mg modafinil tablet once daily (QD)
干预措施: encorafenib (Drug)
Arm 3 - Modafinil
Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
then receive continuous treatment of modafinil on Day 15 through Day 21:
- 400 mg modafinil tablet once daily (QD)
干预措施: binimetinib (Drug)
Arm 3 - Modafinil
Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1:
- 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
- 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)
then receive continuous treatment of modafinil on Day 15 through Day 21:
- 400 mg modafinil tablet once daily (QD)
干预措施: modafinil (Drug)
结局指标
主要结局
Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.
Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.
Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.
Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is area under the concentration-time profile (AUC) from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Paraxanthine was the metabolite of caffeine.
AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. 5-OH Omeprazole was the metabolite of omeprazole.
AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Ae0-8 of E-3174 on Day -7, Day 1 and Day 14
时间窗: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. E-3174 was the metabolite of losartan.
AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Hydroxybupropion was the metabolite of bupropion.
The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14
时间窗: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14
时间窗: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14
时间窗: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. Dextrorphan was the metabolite of dextromethorphan.
Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3
时间窗: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.
次要结局
- Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14(0 to 8 hours after dosing on Days -7, 1 and 14)
- MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14(0 to 8 hours after dosing on Days -7, 1 and 14)
- Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.)
- Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14)
- Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14)
- Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.)
- T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.)
- T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14)
- Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14(Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14)
- Fe for E-3174 on Day -7, Day 1 and Day 14(0 to 8 hours postdose on Day -7, Day 1 and Day 14)
- Fe for Dextromethorphan on Day -7, Day 1 and Day 14(0 to 8 hours postdose on Day -7, Day 1 and Day 14)
- Fe for Dextrorphan on Day -7, Day 1 and Day 14(0 to 8 hours postdose on Day -7, Day 1 and Day 14)
- Cmax of Encorafenib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.)
- Cmax of LHY746 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- Cmax of Binimetinib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.)
- Cmax of AR00426032 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- AUClast of Encorafenib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.)
- AUClast of LHY746 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- AUClast of Binimetinib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- AUClast of AR00426032 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- Tmax of Encorafenib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.)
- Tmax of LHY746 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14)
- Tmax of Binimetinib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.)
- Tmax of AR00426032 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- AUCinf of Encorafenib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- AUCinf of Binimetinib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.)
- AUCinf of AR00426032 on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- T1/2 of Encorafenib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- T1/2 of LHY746 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- T1/2 of Binimetinib on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- T1/2 of AR00426032 on Day 1 and Day 14(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14)
- AUC%Extrap of Encorafenib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- AUC%Extrap of LHY746 on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- AUC%Extrap of Binimetinib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- AUC%Extrap of AR00426032 on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- Kel of Encorafenib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- Kel of LHY746 on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- Kel of Binimetinib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- Kel of AR00426032 on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1)
- CL/F of Encorafenib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.)
- CL/F of Binimetinib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.)
- Vz/F of Encorafenib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.)
- Vz/F of Binimetinib on Day 1(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.)
- Cmax of Binimetinib on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Cmax of AR00426032 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- AUClast of Binimetinib on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- AUClast of AR00426032 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Tmax of Encorafenib on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Tmax of LHY746 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Tmax of Binimetinib on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Tmax of AR00426032 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- T1/2 of Encorafenib on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- T1/2 of LHY746 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- T1/2 of Binimetinib on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- T1/2 of AR00426032 on Day 14 and Day 21(Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase(After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase)
- Number of Participants With Laboratory Abnormalities in the DDI Phase(After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase)
- Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase(After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase)
- Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase(After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase)
- Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase(After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase(After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase)