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Advanced Solid TumorsPhase 1NCT03864042

Pharmacokinetic Drug-drug Interaction Study of Encorafenib and Binimetinib on Probe Drugs in Patients With BRAF V600-mutant Melanoma or Other Advanced Solid Tumors

A Phase 1 study testing losartan, dextromethorphan and caffeine in people with Advanced Solid Tumors and Metastatic Melanoma, run by Pfizer at 29 sites in 5 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Solid Tumors, Metastatic Melanoma
What is being tested?
losartan, dextromethorphan and caffeine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
56 participants
Where
29 sitesin 5 countries
Study dates
2 Jan 2018to 29 May 2023
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study:

  • Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors
  • Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test;
  • Evidence of measurable or non-measurable lesions
  • Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry
  • Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • Adequate bone marrow, hepatic and renal function as specified in the protocol
  • ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose.

Key Exclusion Criteria - Patients meeting any of the following criteria are not eligible for enrollment in the study:

  • Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT] demonstrating no current evidence of progressive brain metastases at screening);
  • Symptomatic or untreated leptomeningeal disease;
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
  • Clinically significant cardiac disease
  • Known hyper-coagulability risks other than malignancy (e.g., Factor V Leiden syndrome);
  • Thromboembolic event except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment.
  • Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion;
  • ARM 1 ONLY: Positive urine cotinine test at screening
  • ARM 3 ONLY:
  • History of psychosis, depression or mania;
  • History of angioedema;
  • History of mitral valve prolapse;
  • History of left ventricular hypertrophy;

Trial locations and contacts

29 sites in 5 countries.

29 sites in 5 countries

United States11 sites

  • University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

    Aurora, Colorado, 80045

  • Gabrail Cancer Center Research

    Canton, Ohio, 44718

  • University of Illinois at Chicago

    Chicago, Illinois, 60612

  • Mary Crowley Cancer Research - Medical City Hospital

    Dallas, Texas, 75230

  • Hopkins Eye Clinic

    Hopkins, Minnesota, 55343-8087

  • University of TN Medical Center

    Knoxville, Tennessee, 37920

  • Park Nicollet Eye Clinic

    Maple Grove, Minnesota, 55369

  • UC Irvine Health

    Orange, California, 92868-3201

  • Regions Cancer Care Center

    Saint Paul, Minnesota, 55101

  • HealthPartners Specialty Center-Eye Care

    Saint Paul, Minnesota, 55130

  • Utah Cancer Specialists

    West Valley City, Utah, 84119

Other trials in United States

Spain10 sites

  • Hospital del Mar

    Barcelona, 08003

  • Hospital Clinico Universitario Virgen de la Arrixaca

    El Palmar, 30120

  • Hospital Universitari Arnau de Vilanova

    Lleida, 25198

  • Hospital Beata Maria Ana

    Madrid, 28007

  • Hospital General Universitario Gregorio Marañon

    Madrid, 28007

  • Clinica Rementeria

    Madrid, 28010

  • MD Anderson Cancer Center Madrid

    Madrid, 28033

  • Hospital Universitario HM Sanchinarro - CIOCC

    Madrid, 28050

  • CERCO

    Seville, 41009

  • Hospital Universitario Virgen Macarena

    Seville, 41009

Other trials in Spain

Canada5 sites

  • Cross Cancer Institute

    Edmonton, Alberta, T6G 1Z2

  • Jewish General Hospital

    Montrea, Quebec, H3T 1E2

  • Sir Mortimer B Davis Jewish General Hospital

    Montreal, Quebec, H3T 1E2

  • McGill University Health Center

    Montreal, Quebec, H4A 3J1

  • Princess Margaret Cancer Centre

    Toronto, Ontario, M5G 2M9

Other trials in Canada

Netherlands2 sites

  • Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis

    Amsterdam, 1066 CX

  • Erasmus Medical Center

    Rotterdam, 3000 CA

Other trials in Netherlands

Belgium1 site

  • Universitair Ziekenhuis Antwerpen

    Edegem, 2650

Other trials in Belgium

About this study

Official title: 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

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.

Being tested
losartan, dextromethorphan, caffeine, omeprazole, midazolam
Keywords
solid tumor, melanoma
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • losartanDrug

    taken orally

  • dextromethorphanDrug

    taken orally

  • caffeineDrug

    taken orally

  • omeprazoleDrug

    taken orally

  • midazolamDrug

    taken orally

  • rosuvastatinDrug

    taken orally

  • bupropion immediate release (IR)Drug

    taken orally

  • encorafenibDrug

    taken orally

  • binimetinibDrug

    taken orally

  • modafinilDrug

    taken orally

Study groups in NCT03864042
Study groupRoleWhat they receive
Arm 1 - CYP Probe CocktailExperimentalPatients 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.
Receives: Drug: losartan; Drug: dextromethorphan; Drug: caffeine; Drug: omeprazole; Drug: midazolam; Drug: encorafenib; Drug: binimetinib
Arm 2 - Rosuvastatin and BupropionExperimentalPatients 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.
Receives: Drug: rosuvastatin; Drug: bupropion immediate release (IR); Drug: encorafenib; Drug: binimetinib
Arm 3 - ModafinilExperimentalPatients 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)
Receives: Drug: encorafenib; Drug: binimetinib; Drug: modafinil

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  2. Cmax of Plasma Total 1-OH Midazolam 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  3. Cmax of Plasma Free 1-OH Midazolam 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  4. Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  5. Cmax of Plasma Absolute Caffeine 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  6. Cmax of Plasma Baseline-Adjusted Caffeine 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  7. Cmax of Plasma Paraxanthine 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  8. Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  9. Cmax of Plasma 5-OH Omeprazole 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  10. Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  11. Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  12. Cmax of Plasma Hydroxybupropion 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  13. 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

    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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  14. AUClast of Plasma Total 1-OH Midazolam 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  15. AUClast of Plasma Free 1-OH Midazolam 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  16. AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  17. AUClast of Plasma Absolute Caffeine 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  18. AUClast of Plasma Baseline-Adjusted Caffeine 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  19. AUClast of Plasma Paraxanthine 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  20. AUClast of Plasma Omeprazole 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  21. AUClast of Plasma 5-OH Omeprazole in Arm 1 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  22. AUClast of Plasma Rosuvastatin 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  23. AUClast of Plasma Bupropion 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  24. AUClast of Plasma Hydroxybupropion 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  25. The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14

    Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.

    Measured: 0 to 8 hours after dosing on Days -7, 1 and 14

  26. Ae0-8 of E-3174 on Day -7, Day 1 and Day 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.

    Measured: 0 to 8 hours after dosing on Days -7, 1 and 14

  27. Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14

    Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.

    Measured: 0 to 8 hours after dosing on Days -7, 1 and 14

  28. Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 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.

    Measured: 0 to 8 hours after dosing on Days -7, 1 and 14

  29. Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  30. Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  31. AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3

    AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  32. AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3

    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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

Secondary outcomes (117)

  1. Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14

    MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight (MW), which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  2. 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

    MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUCinf (metabolite) × MW (parent)] / [AUCinf (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  3. MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14

    MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. Paraxanthine was the metabolite of caffeine.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  4. MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14

    MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  5. MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14

    MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUCinf (metabolite) × MW (parent)] / [AUCinf (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  6. MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14

    MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. Hydroxybupropion was the metabolite of bupropion.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  7. MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21

    MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  8. Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14

    MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  9. MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14

    MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. Paraxanthine was the metabolite of caffeine.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  10. MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14

    MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  11. MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14

    MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. Hydroxybupropion was the metabolite of bupropion.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  12. MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21

    MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  13. 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

    Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. E-3174 was the metabolite of losartan.

    Measured: 0 to 8 hours after dosing on Days -7, 1 and 14

  14. MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14

    Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. Dextrorphan was the metabolite of dextromethorphan.

    Measured: 0 to 8 hours after dosing on Days -7, 1 and 14

  15. Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  16. Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.

  17. Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  18. Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  19. Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  20. Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  21. Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  22. Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14

  23. Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14

  24. Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  25. Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  26. Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  27. AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  28. AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  29. AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  30. AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  31. AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  32. AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  33. AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  34. AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  35. Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  36. AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  37. AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  38. AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  39. AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  40. AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  41. AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  42. AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  43. Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  44. Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  45. Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  46. Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  47. Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  48. Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  49. Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  50. Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  51. Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.

  52. T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  53. T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  54. T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.

  55. T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  56. T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  57. T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  58. T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  59. T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  60. T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  61. Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14

    CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  62. CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14

    CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  63. Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14

    Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  64. Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14

    Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14

  65. Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14

    Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.

    Measured: Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14

  66. Fe for E-3174 on Day -7, Day 1 and Day 14

    Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. E-3174 was the metabolite of losartan.

    Measured: 0 to 8 hours postdose on Day -7, Day 1 and Day 14

  67. Fe for Dextromethorphan on Day -7, Day 1 and Day 14

    Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.

    Measured: 0 to 8 hours postdose on Day -7, Day 1 and Day 14

  68. Fe for Dextrorphan on Day -7, Day 1 and Day 14

    Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. Dextrorphan was the metabolite of dextromethorphan.

    Measured: 0 to 8 hours postdose on Day -7, Day 1 and Day 14

  69. Cmax of Encorafenib on Day 1 and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.

  70. Cmax of LHY746 on Day 1 and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  71. Cmax of Binimetinib on Day 1 and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.

  72. Cmax of AR00426032 on Day 1 and Day 14

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  73. AUClast of Encorafenib on 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.

  74. AUClast of LHY746 on 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. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  75. AUClast of Binimetinib on 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  76. AUClast of AR00426032 on 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. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  77. Tmax of Encorafenib on Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.

  78. Tmax of LHY746 on Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14

  79. Tmax of Binimetinib on Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.

  80. Tmax of AR00426032 on Day 1 and Day 14

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  81. AUCinf of Encorafenib on Day 1

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  82. AUCinf of Binimetinib on Day 1

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.

  83. AUCinf of AR00426032 on Day 1

    AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  84. T1/2 of Encorafenib on Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  85. T1/2 of LHY746 on Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  86. T1/2 of Binimetinib on Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  87. T1/2 of AR00426032 on Day 1 and Day 14

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14

  88. AUC%Extrap of Encorafenib on Day 1

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  89. AUC%Extrap of LHY746 on Day 1

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  90. AUC%Extrap of Binimetinib on Day 1

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  91. AUC%Extrap of AR00426032 on Day 1

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  92. Kel of Encorafenib on Day 1

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  93. Kel of LHY746 on Day 1

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  94. Kel of Binimetinib on Day 1

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  95. Kel of AR00426032 on Day 1

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1

  96. CL/F of Encorafenib on Day 1

    CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.

  97. CL/F of Binimetinib on Day 1

    CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.

  98. Vz/F of Encorafenib on Day 1

    Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.

  99. Vz/F of Binimetinib on Day 1

    Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.

  100. Cmax of Binimetinib on Day 14 and Day 21

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  101. Cmax of AR00426032 on Day 14 and Day 21

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  102. AUClast of Binimetinib 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.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  103. AUClast of AR00426032 on Day 14 and Day 21

    AUClast is AUC from time 0 (pre-dose) to the time of the last quantifiable concentration. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  104. Tmax of Encorafenib on Day 14 and Day 21

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  105. Tmax of LHY746 on Day 14 and Day 21

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  106. Tmax of Binimetinib on Day 14 and Day 21

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  107. Tmax of AR00426032 on Day 14 and Day 21

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  108. T1/2 of Encorafenib on Day 14 and Day 21

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  109. T1/2 of LHY746 on Day 14 and Day 21

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  110. T1/2 of Binimetinib on Day 14 and Day 21

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  111. T1/2 of AR00426032 on Day 14 and Day 21

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.

    Measured: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21

  112. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase

    An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.

    Measured: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase

  113. Number of Participants With Laboratory Abnormalities in the DDI Phase

    Laboratory parameters:hematology (hemoglobin,hematocrit,red blood cell [RBC],platelet,white blood cell count [WBC],neutrophils,eosinophils,monocytes, basophils, lymphocytes), chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, inorganic phosphate, potassium, total protein, sodium, uric acid), urinalysis (appearance, color, specific gravity, pH, ketones, protein, glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, RBC, bacteria, epithelial cells, and casts), coagulation (activated partial thromboplastin time, prothrombin time/international normalized ratio) and others. Clinically notable: worsening from baseline by at least 2 grades or to greater than or equal to (>=) Grade 3, by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.

    Measured: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase

  114. Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase

    Vital signs (temperature, pulse rate [PR]), systolic blood pressure [SBP]), and diastolic blood pressure [DBP]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP>=100 millimeters of mercury (mm Hg)/less than or equal to (<=) 50 mmHg with increase/decrease from baseline of >=15 mmHg; SBP: >=160 mmHg/<=90 mmHg with increase/decrease from baseline of >=20 mmHg; PR: >=120 beats per minute (bpm)/<=50 bpm with increase/decrease from baseline of >=15 bpm; temperature for Arms 1 and 3: >=37.5°C/<=35°C; Arms 2: >=37.5°C/<=36°C.

    Measured: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase

  115. Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase

    Triplicate 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. The criterion included: QTcF >450 - <=480 mesc, >480 - <=500 msec, >500 msec, increase from baseline >30 - <=60 msec and increase from baseline >60 msec. QT interval >450 - <=480 msec, >480 - <=500 msec, >500 msec, increase from baseline >30 - <=60 msec and increase from baseline >60 msec. Heart rate increase from baseline >25% and value >100 bpm and decrease from baseline >25% and value <60 bpm. PR interval increase from baseline >25% and value >200 msec. QRS interval increase from baseline >25% and value >110 msec. Any new post-baseline notable ECG findings in the DDI phase was collected and reported in this outcome measure.

    Measured: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase

  116. Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase

    LVEF abnormalities are defined according to CTCAE grade version 4.03. Participants was considered as having a LVEF abnormality if the worst post-baseline value was Grade 2, 3, or 4 according to the following classification: Grade 0: Non-missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and <-20%; Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal to -20%; Grade 4: LVEF lower than 20%.

    Measured: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase

  117. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase

    An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. Any significant findings in the laboratory test, physical examinations, ophthalmic examinations, vital signs, ECG tests were captured as an AE.

    Measured: After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Mar 2019
  2. Study start2 Jan 2018
  3. Primary completion11 Jul 2022
  4. Study completion29 May 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
56 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03864042
Sponsor's protocol ID
ARRAY-818-103
Other IDs
C4221003, 2019-001036-66, 2019
Status last verified
May 2024
First submitted
1 Feb 2019
Last updated
27 Sep 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.

Publications

  • Piscitelli J, Reddy MB, Wollenberg L, Del Frari L, Gong J, Matschke K, Williams JH. Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors. Cancer Chemother Pharmacol. 2024 Sep;94(3):337-347. doi: 10.1007/s00280-024-04676-2. Epub 2024 Jun 15.

    PubMed 38878209

  • Piscitelli J, Reddy MB, Wollenberg L, Del Frari L, Gong J, Wood L, Zhang Y, Matschke K, Williams JH. Clinical Evaluation of the Effect of Encorafenib on Bupropion, Rosuvastatin, and Coproporphyrin I and Considerations for Statin Coadministration. Clin Pharmacokinet. 2024 Apr;63(4):483-496. doi: 10.1007/s40262-024-01352-9. Epub 2024 Feb 29.

    PubMed 38424308

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing losartan, dextromethorphan and caffeine in people with Advanced Solid Tumors and Metastatic Melanoma, run by Pfizer at 29 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 29 sites in United States, Spain, Canada, Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 (time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14). The study lists 32 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03864042, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Sep 2024.

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