CompletedNCT02074553Updated Dec 11, 2023Results posted

A Cross-over Study Examining the Bioequivalence of 3 Test Formulations to a Reference Formulation of Alectinib (RO5424802) in Healthy Volunteers

A Phase 1 interventional study of Ro542-4802/F03 (Reference) and Ro542-4802/F07 (Test) in Healthy Volunteer, sponsored by Hoffmann-La Roche. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-12-11.

Sponsored by Hoffmann-La Roche · Phase 1, Interventional, and Treatment

Phase: Phase 1
Study type: Interventional
Enrollment: 97
Allocation: Randomized
Ages: 18 Years to 55 Years
Sex: All

Study summary

This 2-part, single center, open-label, randomized, single-dose, 4-sequence, 4-period cross-over study will compare the bioequivalence of three test RO5424802 capsule formulations with the reference capsule formulation in healthy adult volunteers. All participants in both fasted (Part 1) and fed (Part 2) conditions of the study will receive each of 4 treatments (Ro542-4802/F03 [RO5424802 with 50 percentage (%) sodium lauryl sulfate (SLS) (reference)], Ro542-4802/F07 [RO5424802 with 25% SLS (test)], Ro542-4802/F14 [RO5424802 with 12.5% SLS (test)] and Ro542-4802/F08 [RO5424802 with 3% SLS (test)] in a randomized sequence. Each treatment will be given as a single 600 milligrams (mg) oral administration in an upright position on Day 1 after an overnight fast, followed by a 10-day washout period. Total time on study is expected to last up to 75 days, for each enrolled participant.

Conditions studied

Healthy Volunteer

In context

Lead sponsor

Hoffmann-La Roche is the lead sponsor of 2,061 studies on the registry; 85 are open to participants now.

Of its 319 completed or terminated interventional studies of FDA-regulated products, 239 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 55 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Healthy male and surgically sterile or post-menopausal female participants 18-55 years of age
Body mass index (BMI) between 18 to 32 kilograms per meter-squared (kg/m\^2)
Non-smoking participants and former smoking participants (who have not smoked for the past six months before first dosing)
Male participants and their partners of child-bearing potential must be willing to use two effective contraceptive methods as defined by protocol
Willing to abstain from xanthine-containing beverages and food (coffee, tea, cola, chocolate, and "energy drinks") from 72 hours prior to Day -1 through the study
Willing to abstain from grapefruit, pomelo, star fruit or Seville orange containing products from day 7 prior study start until study end
Willing to avoid prolonged sun exposure while taking RO5424802 and through follow-up

Exclusion criteria

Exclusion Criteria:

Pregnant or lactating women, men with female partners who are pregnant or lactating, or women of child bearing potential
Clinically significant abnormalities on physical examination, vital signs, or laboratory test results during screening or prior to admission to the study unit
Positive test for drugs of abuse, alcohol or cotinine test at screening or prior to admission to the study unit or suspicion of regular consumption of drug(s) of abuse
History of recent alcohol consumption exceeding 2 standard drinks per day on average. Alcohol consuming is prohibited from 72 hours prior to study start until the end of the study
Participants with any risk factors or family history for QT/QTcF and electrocardiogram (ECG) abnormalities
A history of any concurrent clinically significant hematologic, renal, hepatic, pulmonary, neurological, psychiatric, allergies, gastrointestinal, metabolic or endocrine disorder, or cardiovascular disease or infections
Positive screening test for hepatitis B, C, or human immunodeficiency virus (HIV)
Use of any medications (prescriptions or over-the-counter), within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study medication with exception of acetaminophen up to 2 grams (g) per day up to 48 hours prior to dosing, not to exceed 4 g total during the week prior to dosing
Routine or chronic use of more than 2 g of acetaminophen daily
Use of any herbal supplements (for example, St. John's Wort) or any metabolic inducers within 4 weeks or 5 half-lives (whichever is longer) before the first dose of study medication, including but not limited to the following drugs: rifampin, rifabutin, glucocorticoids, carbamazepine, phenytoin, and phenobarbital
Strenuous activity, sunbathing or contact sports are not allowed from 4 days prior to study start until the end of the study
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 first dosing
Donation of blood over 450 milliliters (mL) within 45 days prior to screening

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: None (open label)
Enrollment: 97 participants (actual)

Study arms

Experimental
Ro542-4802/F03;Ro542-4802/F07;Ro542-4802/F14;Ro542-4802/F08
Participants will receive Ro542-4802/F03 (containing 50% SLS) capsules orally on Day 1 of first intervention period; then Ro542-4802/F07 (containing 25% SLS) capsules orally on Day 1 of second intervention period; then Ro542-4802/F14 (containing 12.5% SLS) capsules orally on Day 1 of third intervention period; followed by Ro542-4802/F08 (containing 3% SLS) capsules orally on Day 1 of fourth intervention period during both fasted (Part 1) and fed (Part 2) conditions. A washout period of at least 10 days will be maintained between each period.
Drug: Ro542-4802/F03 (Reference) · Drug: Ro542-4802/F07 (Test) · Drug: Ro542-4802/F08 (Test) · Drug: Ro542-4802/F14 (Test)
Experimental
Ro542-4802/F07;Ro542-4802/F08;Ro542-4802/F03;Ro542-4802/F14
Participants will receive Ro542-4802/F07 (containing 25% SLS) capsules orally on Day 1 of first intervention period; then Ro542-4802/F08 (containing 3% SLS capsules orally on Day 1 in second intervention period; then Ro542-4802/F03 (containing 50% SLS) (containing 12.5% SLS) capsules orally on Day 1 of third intervention period; followed by Ro542-4802/F14 (containing 12.5% SLS) capsules orally on Day 1 of the fourth intervention period during both fasted (Part 1) and fed (Part 2) conditions. A washout period of at least 10 days will be maintained between each period.
Drug: Ro542-4802/F03 (Reference) · Drug: Ro542-4802/F07 (Test) · Drug: Ro542-4802/F08 (Test) · Drug: Ro542-4802/F14 (Test)
Experimental
Ro542-4802/F08;Ro542-4802/F14;Ro542-4802/F07;Ro542-4802/F03
Participants will receive Ro542-4802/F08 (containing 3% SLS) capsules orally on Day 1 of first intervention period; then Ro542-4802/F14 (containing 12.5% SLS) capsules orally on Day 1 in second intervention period; then Ro542-4802/F07 (containing 25% SLS) capsules orally on Day 1 of third intervention period; followed by Ro542-4802/F03 (containing 50% SLS) capsules orally on Day 1 of the fourth intervention period during both fasted (Part 1) and fed (Part 2) conditions. A washout period of at least 10 days will be maintained between each period.
Drug: Ro542-4802/F03 (Reference) · Drug: Ro542-4802/F07 (Test) · Drug: Ro542-4802/F08 (Test) · Drug: Ro542-4802/F14 (Test)
Experimental
Ro542-4802/F14;Ro542-4802/F03;Ro542-4802/F08;Ro542-4802/F07
Participants will receive Ro542-4802/F14 (containing 12.5% SLS) capsules orally on Day 1 of first intervention period; then Ro542-4802/F03 (containing 50% SLS) capsules orally on Day 1 in second intervention period; then Ro542-4802/F08 (containing 3% SLS) capsules orally on Day 1 of third intervention period; followed by Ro542-4802/F07 (containing 25% SLS) capsules orally on Day 1 of the fourth intervention period during both fasted (Part 1) and fed (Part 2) conditions. A washout period of at least 10 days will be maintained between each period.
Drug: Ro542-4802/F03 (Reference) · Drug: Ro542-4802/F07 (Test) · Drug: Ro542-4802/F08 (Test) · Drug: Ro542-4802/F14 (Test)

Interventions

DrugRo542-4802/F03 (Reference)
Participants will receive Ro542-4802/F03 (containing 50% SLS) 600 mg capsules orally on Day 1.
DrugRo542-4802/F07 (Test)
Participants will receive Ro542-4802/F07 (containing 25% SLS) 600 mg capsules orally on Day 1.
DrugRo542-4802/F08 (Test)
Participants will receive Ro542-4802/F08 (containing 3% SLS) 600 mg capsules orally on Day 1.
DrugRo542-4802/F14 (Test)
Participants will receive Ro542-4802/F14 (containing 12.5% SLS) 600 mg capsules orally on Day 1.

What researchers measure

Primary outcomes

Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib
AUC(0-inf) is the area under the alectinib plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in nanogram times (\*) hour per milliliter (ng\*hour/mL).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib
AUC(0-last) is the area under the alectinib plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Maximum Observed Plasma Concentration (Cmax) of Alectinib
Cmax is the maximum observed plasma alectinib concentration, presented in nanogram per milliliter (ng/mL).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose

Secondary outcomes

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib
Tmax is the time from alectinib administration to reach Cmax for alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Cmax of RO5468924
Cmax is the maximum observed plasma RO5468924 concentration, presented in ng/mL. RO5468924 is the major pharmacologically active metabolite of alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Tmax of RO5468924
Tmax is the time from alectinib administration to reach Cmax for RO5468924 (the major pharmacologically active metabolite of alectinib).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
AUC(0-inf) of RO5468924
AUC(0-inf) is the area under the RO5468924 plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in ng\*hour/mL.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
AUC(0-last) of RO5468924
AUC(0-last) is the area under the RO5468924 plasma concentration versus time curve from time zero to the time of last measured concentration of RO5468924. RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924
Plasma terminal half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. RO5468924 is the major pharmacologically active metabolite of alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Elimination Rate Constant (Kel) of Alectinib and RO5468924
First-order terminal elimination rate constant (Kel) was calculated as the negative slope of the linear regression of the terminal phase in plasma alectinib and RO5468924 concentration versus time profile using appropriate time points. RO5468924 is the major pharmacologically active metabolite of alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf)
AUC(0-inf) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib + RO5468924 over time. AUC(0-inf) is presented in nanomoles times (\*) hour per liter (nmol\*hour/L).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax
Cmax is the maximum observed molar plasma concentration for alectinib + RO5468924 (major pharmacologically active metabolite of alectinib). Cmax is presented in nanomoles per liter (nmol/L).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last)
AUC(0-last) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib + RO5468924. AUC(0-last) is presented in nmol\*hour/L.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Apparent Oral Clearance (CL/F) of Alectinib
Clearance of a drug 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 fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Apparent Volume of Distribution (Vz/F) of Alectinib
Volume of distribution is defined as the theoretical volume in 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 (Vz/F) is influenced by the fraction of drug absorbed.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924
The AUC%extrap(0-inf), that is, area obtained after extrapolation (extrap) from time to last quantifiable plasma concentration (Tlast) to infinity is calculated by using the formula AUC%extrap(0-inf) = 100\*(AUC\[0-inf\] minus AUC\[0-last\])/AUC(0-inf); where AUC(0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time and AUC(0-last) is area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration. The function of this parameter is to provide information about what percentage of the theoretical curve AUC(0-inf) was possible to determine experimentally (AUC0-last).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf)
AUC(0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-inf) is presented.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Molecular Weight Adjusted M/P Ratio for AUC(0-last)
AUC(0-last) is the area under the plasma concentration versus time curve from time zero to the time of last measured concentration. AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-last) is presented.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Molecular Weight Adjusted M/P Ratio for Cmax
Cmax is the maximum observed plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib). The molecular weight adjusted M/P ratio (RO5468924/alectinib) for Cmax is presented.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924
Tlast is the time from alectinib administration to reach last quantifiable concentration of alectinib and its major pharmacologically active metabolite RO5468924.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose

Results

Posted Oct 18, 2016

Participant flow

Intervention Period 1

Participant flow — Intervention Period 1
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	12	12	12	13	12	12	12	12
Completed	12	12	12	12	12	12	12	12
Not completed	0	0	0	1	0	0	0	0
Withdrew: Family emergency	0	0	0	1	0	0	0	0

Washout Period 1

Participant flow — Washout Period 1
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	12	12	12	12	12	12	12	12
Completed	11	12	12	11	12	11	12	12
Not completed	1	0	0	1	0	1	0	0
Withdrew: Adverse event	1	0	0	0	0	0	0	0
Withdrew: Physician decision	0	0	0	1	0	0	0	0
Withdrew: Other	0	0	0	0	0	1	0	0

Intervention Period 2

Participant flow — Intervention Period 2
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	11	12	12	11	12	11	12	12
Completed	11	12	12	11	12	11	12	12
Not completed	0	0	0	0	0	0	0	0

Washout Period 2

Participant flow — Washout Period 2
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	11	12	12	11	12	11	12	12
Completed	11	12	11	11	12	10	11	12
Not completed	0	0	1	0	0	1	1	0
Withdrew: Adverse event	0	0	0	0	0	0	1	0
Withdrew: Physician decision	0	0	0	0	0	1	0	0
Withdrew: Lost to follow-up	0	0	1	0	0	0	0	0

Intervention Period 3

Participant flow — Intervention Period 3
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	11	12	11	11	12	10	11	12
Completed	11	12	11	11	12	10	11	12
Not completed	0	0	0	0	0	0	0	0

Washout Period 3

Participant flow — Washout Period 3
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	11	12	11	11	12	10	11	12
Completed	11	12	11	11	12	10	11	11
Not completed	0	0	0	0	0	0	0	1
Withdrew: Physician decision	0	0	0	0	0	0	0	1

Intervention Period 4

Participant flow — Intervention Period 4
Milestone	Part 1 (Fasted): Treatment A Then B Then C Then D	Part 1 (Fasted): Treatment B Then D Then A Then C	Part 1 (Fasted): Treatment C Then A Then D Then B	Part 1 (Fasted): Treatment D Then C Then B Then A	Part 2 (Fed): Treatment A Then B Then C Then D	Part 2 (Fed): Treatment B Then D Then A Then C	Part 2 (Fed): Treatment C Then A Then D Then B	Part 2 (Fed): Treatment D Then C Then B Then A
Started	11	12	11	11	12	10	11	11
Completed	11	12	11	11	12	10	11	11
Not completed	0	0	0	0	0	0	0	0

Outcome measures

PrimaryArea Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib

AUC(0-inf) is the area under the alectinib plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in nanogram times (\*) hour per milliliter (ng\*hour/mL).

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · ng*hour/mL

Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib
ng*hour/mL	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib	1920 ± 1000	1840 ± 754	1850 ± 841	1630 ± 792	5720 ± 1530	5050 ± 1200	4600 ± 1260	4580 ± 1240

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 100.5 · 90% CI 93.14 to 108.44The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 97.82 · 90% CI 90.71 to 105.48The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 86.66 · 90% CI 80.32 to 93.5The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 88.62 · 90% CI 85.15 to 92.24The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 80.17 · 90% CI 77.08 to 83.39The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 79.95 · 90% CI 76.84 to 83.19The reported values are percentages of geometric least square mean ratio.

PrimaryArea Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib

AUC(0-last) is the area under the alectinib plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · ng*hour/mL

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib
ng*hour/mL	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib	1790 ± 925	1680 ± 620	1620 ± 637	1380 ± 573	5540 ± 1460	4820 ± 1130	4370 ± 1170	4360 ± 1160

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 99.12 · 90% CI 91.83 to 106.99The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 93.79 · 90% CI 86.94 to 101.17The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 80.32 · 90% CI 74.41 to 86.7The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 87.42 · 90% CI 83.92 to 91.07The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 78.87 · 90% CI 75.76 to 82.11The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 78.66 · 90% CI 75.53 to 81.92The reported values are percentages of geometric least square mean ratio.

PrimaryMaximum Observed Plasma Concentration (Cmax) of Alectinib

Cmax is the maximum observed plasma alectinib concentration, presented in nanogram per milliliter (ng/mL).

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · ng/mL

Maximum Observed Plasma Concentration (Cmax) of Alectinib
ng/mL	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Maximum Observed Plasma Concentration (Cmax) of Alectinib	106 ± 53.3	91.7 ± 34.5	67.0 ± 23.6	42.2 ± 19.2	271 ± 81.8	232 ± 59.3	206 ± 50.4	204 ± 57.1

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 90.34 · 90% CI 82.33 to 99.12The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 66.28 · 90% CI 60.45 to 72.68The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 41.04 · 90% CI 37.40 to 45.03The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 86.30 · 90% CI 81.77 to 91.09The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment C · Geometric least square mean ratio: 77.00 · 90% CI 73.01 to 81.20The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 75.65 · 90% CI 71.71 to 79.82The reported values are percentages of geometric least square mean ratio.

SecondaryTime to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib

Tmax is the time from alectinib administration to reach Cmax for alectinib.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Median · hours

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib
hours	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib	3.25 (1.50 to 12.0)	3.00 (1.00 to 5.00)	3.00 (2.00 to 6.00)	4.00 (2.50 to 10.0)	8.00 (4.05 to 18.0)	8.00 (5.00 to 18.0)	6.00 (4.00 to 12.0)	6.00 (4.00 to 10.0)

SecondaryCmax of RO5468924

Cmax is the maximum observed plasma RO5468924 concentration, presented in ng/mL. RO5468924 is the major pharmacologically active metabolite of alectinib.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · ng/mL

Cmax of RO5468924
ng/mL	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Cmax of RO5468924	33.0 ± 15.4	30.7 ± 14.9	21.9 ± 8.94	11.3 ± 5.71	98.8 ± 28.6	92.2 ± 28.7	71.4 ± 20.6	65.2 ± 16.8

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 91.67 · 90% CI 82.34 to 102.05The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 67.24 · 90% CI 60.44 to 74.79The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 34.32 · 90% CI 30.83 to 38.21The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 95.15 · 90% CI 89.10 to 101.62The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 73.26 · 90% CI 68.67 to 78.16The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 67.76 · 90% CI 63.48 to 72.33The reported values are percentages of geometric least square mean ratio.

SecondaryTmax of RO5468924

Tmax is the time from alectinib administration to reach Cmax for RO5468924 (the major pharmacologically active metabolite of alectinib).

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Median · hours

Tmax of RO5468924
hours	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Tmax of RO5468924	8.00 (8.00 to 12.0)	8.02 (6.00 to 12.1)	8.00 (6.00 to 12.0)	8.07 (4.00 to 12.1)	12.0 (6.00 to 24.0)	10.0 (5.03 to 24.0)	8.02 (6.00 to 12.1)	9.00 (5.00 to 24.0)

SecondaryAUC(0-inf) of RO5468924

AUC(0-inf) is the area under the RO5468924 plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in ng\*hour/mL.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · ng*hour/mL

AUC(0-inf) of RO5468924
ng*hour/mL	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
AUC(0-inf) of RO5468924	968 ± 397	936 ± 419	754 ± 298	534 ± 279	3010 ± 819	2660 ± 687	2200 ± 578	2100 ± 543

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 95.77 · 90% CI 87.54 to 104.79The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 78.69 · 90% CI 71.97 to 86.04The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 53.91 · 90% CI 49.27 to 58.98The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 90.16 · 90% CI 86.14 to 94.37The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 73.76 · 90% CI 70.52 to 77.15The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 70.94 · 90% CI 67.80 to 74.22The reported values are percentages of geometric least square mean ratio.

SecondaryAUC(0-last) of RO5468924

AUC(0-last) is the area under the RO5468924 plasma concentration versus time curve from time zero to the time of last measured concentration of RO5468924. RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · ng*hour/mL

AUC(0-last) of RO5468924
ng*hour/mL	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
AUC(0-last) of RO5468924	876 ± 375	826 ± 376	641 ± 248	392 ± 199	2780 ± 773	2460 ± 669	2000 ± 531	1890 ± 477

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 93.05 · 90% CI 84.24 to 102.78The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 74.35 · 90% CI 67.37 to 82.06The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 43.94 · 90% CI 39.78 to 48.53The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 90.21 · 90% CI 86.12 to 94.49The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 72.72 · 90% CI 69.48 to 76.12The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 69.34 · 90% CI 66.23 to 72.61The reported values are percentages of geometric least square mean ratio.

SecondaryPlasma Terminal Half-Life (t1/2) of Alectinib and RO5468924

Plasma terminal half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. RO5468924 is the major pharmacologically active metabolite of alectinib.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · hours

Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924
hours	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Alectinib	23.6 ± 11.1	24.3 ± 11.1	25.6 ± 11.2	28.8 ± 17.4	19.8 ± 6.56	21.3 ± 10.6	21.4 ± 10.3	21.9 ± 12.0
RO5468924	28.1 ± 8.29	30.7 ± 9.63	31.8 ± 12.7	41.7 ± 19.8	28.3 ± 6.79	27.4 ± 5.27	29.1 ± 7.13	31.0 ± 7.74

SecondaryElimination Rate Constant (Kel) of Alectinib and RO5468924

First-order terminal elimination rate constant (Kel) was calculated as the negative slope of the linear regression of the terminal phase in plasma alectinib and RO5468924 concentration versus time profile using appropriate time points. RO5468924 is the major pharmacologically active metabolite of alectinib.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · 1/hour

Elimination Rate Constant (Kel) of Alectinib and RO5468924
1/hour	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Alectinib	0.0340 ± 0.0113	0.0333 ± 0.0119	0.0312 ± 0.0108	0.0303 ± 0.0123	0.0371 ± 0.00732	0.0369 ± 0.0117	0.0371 ± 0.0117	0.0367 ± 0.0110
RO5468924	0.0267 ± 0.00750	0.0248 ± 0.00767	0.0240 ± 0.00654	0.0199 ± 0.00753	0.0256 ± 0.00493	0.0263 ± 0.00540	0.0252 ± 0.00618	0.0236 ± 0.00538

SecondaryTotal Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf)

AUC(0-inf) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib + RO5468924 over time. AUC(0-inf) is presented in nanomoles times (\*) hour per liter (nmol\*hour/L).

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · nmol*hour/L

Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf)
nmol*hour/L	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf)	6040 ± 2870	5780 ± 2290	5450 ± 2310	4470 ± 2370	18400 ± 4600	16200 ± 3650	14300 ± 3570	14100 ± 3490

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 98.79 · 90% CI 91.25 to 106.95The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 91.58 · 90% CI 84.65 to 99.08The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 73.41 · 90% CI 67.81 to 79.47The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 88.81 · 90% CI 85.62 to 92.13The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 77.74 · 90% CI 74.99 to 80.60The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 76.65 · 90% CI 73.92 to 79.49The reported values are percentages of geometric least square mean ratio.

SecondaryTotal Molar Concentration of Alectinib and RO5468924 as Derived by Cmax

Cmax is the maximum observed molar plasma concentration for alectinib + RO5468924 (major pharmacologically active metabolite of alectinib). Cmax is presented in nanomoles per liter (nmol/L).

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · nmol/L

Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax
nmol/L	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax	257 ± 123	221 ± 79.6	164 ± 52.6	106 ± 48.6	754 ± 209	662 ± 162	566 ± 138	548 ± 141

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 89.41 · 90% CI 81.7 to 97.84The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 66.84 · 90% CI 61.12 to 73.1The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 42.32 · 90% CI 38.68 to 46.32The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 88.76 · 90% CI 84.21 to 93.56The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 75.82 · 90% CI 71.99 to 79.86The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 73.26 · 90% CI 69.53 to 77.19The reported values are percentages of geometric least square mean ratio.

SecondaryTotal Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last)

AUC(0-last) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib + RO5468924. AUC(0-last) is presented in nmol\*hour/L.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · nmol*hour/L

Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last)
nmol*hour/L	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last)	5660 ± 2620	5310 ± 1980	4780 ± 1710	3740 ± 1560	17600 ± 4370	15400 ± 3500	13400 ± 3260	13200 ± 3200

Statistical analysis

Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment B · Geometric least square mean ratio: 97.23 · 90% CI 89.85 to 105.21The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment C · Geometric least square mean ratio: 87.16 · 90% CI 80.59 to 94.26The reported values are percentages of geometric least square mean ratio.
Part 1 (Fasted): Treatment A vs Part 1 (Fasted): Treatment D · Geometric least square mean ratio: 67.86 · 90% CI 62.71 to 73.43The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment B · Geometric least square mean ratio: 88.28 · 90% CI 85.06 to 91.63The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment C · Geometric least square mean ratio: 76.79 · 90% CI 74.03 to 79.65The reported values are percentages of geometric least square mean ratio.
Part 2 (Fed): Treatment A vs Part 2 (Fed): Treatment D · Geometric least square mean ratio: 75.43 · 90% CI 72.70 to 78.27The reported values are percentages of geometric least square mean ratio.

SecondaryApparent Oral Clearance (CL/F) of Alectinib

Clearance of a drug 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 fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · liters/hour

Apparent Oral Clearance (CL/F) of Alectinib
liters/hour	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Apparent Oral Clearance (CL/F) of Alectinib	377 ± 149	380 ± 152	383 ± 151	449 ± 199	113 ± 30.9	126 ± 31.5	141 ± 39.3	141 ± 40.2

SecondaryApparent Volume of Distribution (Vz/F) of Alectinib

Volume of distribution is defined as the theoretical volume in 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 (Vz/F) is influenced by the fraction of drug absorbed.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · liters

Apparent Volume of Distribution (Vz/F) of Alectinib
liters	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Apparent Volume of Distribution (Vz/F) of Alectinib	12200 ± 6240	12200 ± 5120	12900 ± 4430	16500 ± 7300	3180 ± 1260	3730 ± 1530	4180 ± 1920	4290 ± 2240

SecondaryPercent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924

The AUC%extrap(0-inf), that is, area obtained after extrapolation (extrap) from time to last quantifiable plasma concentration (Tlast) to infinity is calculated by using the formula AUC%extrap(0-inf) = 100\*(AUC\[0-inf\] minus AUC\[0-last\])/AUC(0-inf); where AUC(0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time and AUC(0-last) is area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration. The function of this parameter is to provide information about what percentage of the theoretical curve AUC(0-inf) was possible to determine experimentally (AUC0-last).

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · percent AUC

Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924
percent AUC	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Alectinib	6.43 ± 4.06	7.45 ± 6.25	9.91 ± 8.08	12.5 ± 10.9	3.04 ± 2.57	4.24 ± 5.01	4.49 ± 4.86	4.52 ± 5.54
RO5468924	10.2 ± 3.67	12.6 ± 6.14	14.9 ± 6.89	26.0 ± 11.2	7.84 ± 2.57	7.84 ± 2.52	9.12 ± 3.39	9.94 ± 3.93

SecondaryAdjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Mean · no units

Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924
no units	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Alectinib	0.987 ± 0.0252	0.983 ± 0.0277	0.973 ± 0.0622	0.976 ± 0.0337	0.994 ± 0.00812	0.991 ± 0.0189	0.990 ± 0.0206	0.991 ± 0.0153
RO5468924	0.977 ± 0.0233	0.970 ± 0.0293	0.963 ± 0.0591	0.958 ± 0.0687	0.986 ± 0.0124	0.980 ± 0.0186	0.977 ± 0.0178	0.982 ± 0.0195

SecondaryMolecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf)

AUC(0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-inf) is presented.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Geometric mean · ratio

Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf)
ratio	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf)	0.54 ± 0.0705	0.52 ± 0.0720	0.43 ± 0.0512	0.34 ± 0.0233	0.55 ± 0.0468	0.56 ± 0.0393	0.51 ± 0.0290	0.49 ± 0.0300

SecondaryMolecular Weight Adjusted M/P Ratio for AUC(0-last)

AUC(0-last) is the area under the plasma concentration versus time curve from time zero to the time of last measured concentration. AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-last) is presented.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Geometric mean · ratio

Molecular Weight Adjusted M/P Ratio for AUC(0-last)
ratio	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Molecular Weight Adjusted M/P Ratio for AUC(0-last)	0.52 ± 0.0708	0.49 ± 0.0838	0.41 ± 0.0458	0.29 ± 0.0347	0.52 ± 0.0474	0.54 ± 0.0384	0.48 ± 0.0264	0.46 ± 0.0237

SecondaryMolecular Weight Adjusted M/P Ratio for Cmax

Cmax is the maximum observed plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib). The molecular weight adjusted M/P ratio (RO5468924/alectinib) for Cmax is presented.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Geometric mean · ratio

Molecular Weight Adjusted M/P Ratio for Cmax
ratio	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Molecular Weight Adjusted M/P Ratio for Cmax	0.33 ± 0.0376	0.34 ± 0.0446	0.33 ± 0.0438	0.28 ± 0.0206	0.38 ± 0.0445	0.42 ± 0.0304	0.36 ± 0.0223	0.34 ± 0.0207

SecondaryTime to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924

Tlast is the time from alectinib administration to reach last quantifiable concentration of alectinib and its major pharmacologically active metabolite RO5468924.

Time frame:: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Reported as:: Median · hours

Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924
hours	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
Alectinib	96.0 (60.0 to 96.1)	96.0 (60.0 to 96.1)	96.0 (60.0 to 96.2)	96.0 (60.0 to 96.1)	96.0 (72.1 to 96.1)	96.0 (72.0 to 96.1)	96.0 (72.0 to 96.1)	96.0 (72.0 to 96.2)
RO5468924	96.0 (48.0 to 96.1)	96.0 (48.0 to 96.0)	96.0 (60.0 to 96.2)	72.0 (36.0 to 96.2)	96.0 (96.0 to 96.1)	96.0 (96.0 to 96.1)	96.0 (96.0 to 96.1)	96.0 (96.0 to 96.2)

Adverse events

Collected over Day 1 through follow-up (up to 47 days). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Part 1 (Fasted): Treatment A	—	0/47 (0%)	3/47 (6.4%)
Part 1 (Fasted): Treatment B	—	0/45 (0%)	3/45 (6.7%)
Part 1 (Fasted): Treatment C	—	0/46 (0%)	3/46 (6.5%)
Part 1 (Fasted): Treatment D	—	0/47 (0%)	3/47 (6.4%)
Part 2 (Fed): Treatment A	—	0/45 (0%)	6/45 (13.3%)
Part 2 (Fed): Treatment B	—	0/47 (0%)	6/47 (12.8%)
Part 2 (Fed): Treatment C	—	0/46 (0%)	4/46 (8.7%)
Part 2 (Fed): Treatment D	—	0/46 (0%)	7/46 (15.2%)

Most frequent other events

Showing 10 of 29

Most frequent other events
Event	Part 1 (Fasted): Treatment A	Part 1 (Fasted): Treatment B	Part 1 (Fasted): Treatment C	Part 1 (Fasted): Treatment D	Part 2 (Fed): Treatment A	Part 2 (Fed): Treatment B	Part 2 (Fed): Treatment C	Part 2 (Fed): Treatment D
HeadacheNervous system disorders	0/47	1/45	0/46	1/47	2/45	0/47	1/46	2/46
DiarrhoeaGastrointestinal disorders	1/47	0/45	0/46	0/47	0/45	2/47	0/46	0/46
Infrequent bowel movementsGastrointestinal disorders	1/47	0/45	0/46	0/47	1/45	2/47	1/46	0/46
Skin irritationSkin and subcutaneous tissue disorders	0/47	0/45	0/46	0/47	0/45	2/47	0/46	0/46
Ear painEar and labyrinth disorders	0/47	1/45	0/46	0/47	0/45	0/47	0/46	0/46
Dry eyeEye disorders	0/47	1/45	0/46	0/47	0/45	0/47	0/46	0/46
Back painMusculoskeletal and connective tissue disorders	0/47	1/45	0/46	0/47	1/45	0/47	0/46	0/46
CoughRespiratory, thoracic and mediastinal disorders	0/47	1/45	0/46	0/47	0/45	0/47	0/46	0/46
MyalgiaMusculoskeletal and connective tissue disorders	0/47	0/45	0/46	0/47	1/45	0/47	0/46	0/46
Electrocardiogram abnormalInvestigations	0/47	0/45	0/46	0/47	1/45	0/47	0/46	0/46

Baseline characteristics

The Safety Analysis Set included all participants who received at least 1 dose of the study drug and had at least 1 safety assessment after dosing.

Age, Continuous
Age, Continuous(years)	Part 1 (Fasted): Study Population	Part 2 (Fed): Study Population	Total
Mean	37.6 ± 10.01	36.1 ± 10.49	36.9 ± 10.2

Sex: Female, Male
Sex: Female, Male(Participants)	Part 1 (Fasted): Study Population	Part 2 (Fed): Study Population	Total
Female	8	6	14
Male	41	42	83

Study locations

1 site

Austin, Texas 78744, United States

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 11, 2023, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02074553
Lead sponsor: Hoffmann-La Roche
Responsible party: Sponsor
First posted: Feb 28, 2014
Start date: Feb 2014
Primary completion: Sep 2014
Completion: Sep 2014
Results posted: Oct 18, 2016
Last update: Dec 11, 2023

Study contacts

Clinical Trials

study director · Hoffmann-La Roche

View the source record on ClinicalTrials.gov ↗

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A Cross-over Study Examining the Bioequivalence of 3 Test Formulations to a Reference Formulation of Alectinib (RO5424802) in Healthy Volunteers

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