Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

• ClinicalTrials.gov Identifier: NCT02621047
• Recruitment Status: Completed
• First Posted: December 3, 2015
• Results First Posted: August 24, 2018
• Last Update Posted: August 24, 2018
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: December 1, 2015
• First Posted Date: December 3, 2015
• Results First Submitted Date: November 7, 2017
• Results First Posted Date: August 24, 2018
• Last Update Posted Date: August 24, 2018
• Actual Study Start Date: December 4, 2015
• Actual Primary Completion Date: December 8, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 7, 2017)

• Maximum Observed Plasma Concentration (Cmax) of Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
• Cmax of Unbound Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
• Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) for Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. AUC 0-inf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
• AUC 0-inf for Unbound Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
• Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measureable Concentration (AUC 0-last) for Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
• AUC 0-last for Unbound Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]

Original Primary Outcome Measures (submitted: December 1, 2015)

• Total and unbound maximum observed plasma concentration (Cmax) for alectinib [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Total and unbound area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC 0-inf) for alectinib [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Total and unbound area under the plasma concentration-time curve from time 0 to the last measureable concentration (AUC 0-last) for alectinib [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]

Current Secondary Outcome Measures (submitted: November 7, 2017)

• Cmax of Total Metabolite of Alectinib (M4) [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total M4 = unbound M4 plus M4 bound to plasma proteins
• Cmax of Unbound M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
• Cmax of Total Combined Alectinib and M4 (Alectinib + M4) [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
• Cmax of Unbound Alectinib + M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
• AUC 0-inf of Total M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total M4 = unbound M4 plus M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
• AUC 0-inf of Unbound M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
• AUC 0-inf of Total Alectinib + M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
• AUC 0-inf of Unbound Alectinib + M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.
• AUC 0-last of Total M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total M4 = unbound M4 plus M4 bound to plasma proteins
• AUC 0-last of Unbound M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
• AUC 0-last of Total Alectinib + M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins
• AUC 0-last of Unbound Alectinib + M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
• Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins
• Tmax for Total M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total M4 = unbound M4 plus M4 bound to plasma proteins
• Apparent Terminal Half-life (t1/2) of Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. t1/2 = the time measured for the plasma concentration to decrease by one half.
• t1/2 of Total M4 [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total M4 = unbound M4 plus M4 bound to plasma proteins. t1/2 = the time measured for the plasma concentration to decrease by one half.
• Apparent Oral Clearance (CL/F) of Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability.
• CL/F of Unbound Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the oral bioavailability.
• Apparent Volume of Distribution (Vz/F) for Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
• Vz/F for Unbound Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
• Fraction of Drug Unbound (fu) of Total Alectinib [ Time Frame: Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1) ]
  Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. fu = ratio of unbound alectinib to total alectinib multiplied by 100.

Original Secondary Outcome Measures (submitted: December 1, 2015)

• Total and unbound Cmax of metabolite of alectinib (M4) and of combined alectinib and M4 (alectinib + M4) [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Total and unbound AUC 0-inf of M4 and of combined alectinib and M4 (alectinib + M4) [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Total and unbound AUC 0-last of M4 and of combined alectinib and M4 (alectinib + M4) [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Time to reach maximum observed plasma concentration (Tmax) for alectinib and M4 [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Apparent terminal half-life (t1/2) of alectinib and M4 [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Total and unbound apparent oral clearance (CL/F) of alectinib [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Total and unbound apparent volume of distribution (Vz/F) for alectinib [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Fraction of drug unbound (fu) [ Time Frame: Pre-dose, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-dose ]
• Percentage of participants with at least one adverse event (AE) [ Time Frame: Up to Day 21 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib
• Official Title: The Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib: A Multiple-Center, Open-Label Study Following Single Oral Dosing of Alectinib to Subjects With Hepatic Impairment and Matched Healthy Subjects With Normal Hepatic Function
• Brief Summary: This is a multicenter, non-randomized, single-dose, open-label study conducted in male and surgically sterile or post-menopausal female participants with stable chronic hepatic impairment and in healthy participants matched by age, gender, and body weight to assess the effect of hepatic impairment on the pharmacokinetics of alectinib.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hepatic Impairment

Intervention

Drug: Alectinib

Participants will receive alectinib as per the dosage schedule mentioned in arm description.

Study Arms

• Experimental: Alectinib: Moderate Hepatic Impairment
  Participants with moderate hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 milligrams (mg) on Day 1.
  Intervention: Drug: Alectinib
• Experimental: Alectinib: Severe Hepatic Impairment
  Participants with severe hepatic impairment (based on Child-Pugh score) will receive alectinib at a single oral dose of 300 mg on Day 1.
  Intervention: Drug: Alectinib
• Experimental: Alectinib: Normal Hepatic Function
  Participants with normal hepatic function will receive alectinib at a single oral dose of 300 mg on Day 1.
  Intervention: Drug: Alectinib

• Publications *: Morcos PN, Cleary Y, Sturm-Pellanda C, Guerini E, Abt M, Donzelli M, Vazvaei F, Balas B, Parrott N, Yu L. Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib. J Clin Pharmacol. 2018 Dec;58(12):1618-1628. doi: 10.1002/jcph.1286. Epub 2018 Jul 27.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 27, 2017): 28
• Original Estimated Enrollment (submitted: December 1, 2015): 48
• Actual Study Completion Date: December 8, 2016
• Actual Primary Completion Date: December 8, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

All Participants

• Body mass index between 18 to 35 kilograms per square meter (kg/m^2) inclusive and weight greater than (>) 50 kilograms (kg)
• Female participants must be surgically sterile or post-menopausal
• Male participants and their partners of child-bearing potential must be willing to use 2 effective methods of contraception, one of which must be a barrier method

Participants with Hepatic Impairment

- Documented chronic stable liver disease (Child-Pugh Class A, B or C)

Exclusion Criteria:

All Participants

• Pregnant or lactating women, males with female partners who are pregnant or lactating, or women of child bearing potential
• Positive test for drugs of abuse or alcohol
• Participation in an investigational drug or device study within 45 days or 5 half-lives (whichever time period is longer) or 6 months for biologic therapies prior to study drug administration
• History of hypersensitivity to any of the additives in the alectinib formulation
• Participants under judicial supervision, guardianship, or curatorship
• History of severe drug-related allergic reactions or drug-induced hepatotoxicity

Healthy Participants

• Use of any medications (prescription or over-the-counter), within 2 weeks or 5 half-lives (whichever longer) prior to study drug administration
• Use of any herbal supplements or any metabolic inducers within 4 weeks, or 5 half-lives (whichever is longer) prior to study drug administration

Participants with Hepatic Impairment

• Positive screening test for human immunodeficiency virus (HIV)
• History of liver transplantation
• Hepatocellular carcinoma or acute liver disease
• Severe ascites at screening or admission to the clinic
• Recent history (past 2 years) or current severe hepatic encephalopathy (Grade 3 or higher)
• Any evidence of progressive liver disease within the last 4 weeks
• Presence of surgically created or transjugular intrahepatic portal systemic shunts

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Slovakia
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02621047
• Other Study ID Numbers: NP29783; 2015-002976-25 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: November 2017