Evaluate Taste and Relative Bioavailability of Two Microsphere Formulations of Crizotinib in Healthy Participants

Study Overview
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Brief Summary
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The primary purpose of the study is to estimate the relative bioavailability and palatability of 2 new crizotinib formulations to the commercially available crizotinib formulated capsule at a 250 mg dose administered under fasted conditions in adult healthy participants. Additionally, this study aims to assess the safety and tolerability of crizotinib 250 mg single dose in 4 formulations when given fasted, with high fat meal, or with a proton pump inhibitor in healthy participants. Finally, this study will explore the effect of food or proton pump inhibitor on the pharmacokinetics of the 2 new crizotinib formulations. We hypothesize 1 of the 2 new crizotinib formulations will have improved relative bioavailability and palatability than the formulated capsule under fasted or fed conditions with or without a proton pump inhibitor.

Official Title
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A PHASE 1, OPEN LABEL, CROSSOVER STUDY TO EVALUATE PALATABILITY AND RELATIVE BIOAVAILABILITY OF TWO PEDIATRIC MICROSPHERE FORMULATIONS OF CRIZOTINIB IN HEALTHY PARTICIPANTS

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Treatment A
* Drug: Treatment B
* Drug: Treatment C
* Drug: Treatment D
* Drug: Treatment E
* Drug: Treatment F
* Drug: Treatment G
* Drug: Treatment H


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, and laboratory tests. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). Any condition possibly affecting drug absorption (eg, gastrectomy, gastric or intestinal bypass surgery, cholecystectomy). Any condition possibly affecting the ability to taste (eg, dysgeusia, respiratory infection). History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (HCVAb). Hepatitis B vaccination is allowed. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of crizotinib. Participants with history of known sensitivity to esomeprazole or substituted benzimidazoles. Previous administration with an investigational product within 30 days or 5 half-lives preceding the first dose of crizotinib (whichever is longer). A positive urine drug test or cotinine test. Screening supine blood pressure (BP) ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility. Baseline 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QT interval corrected using the Fridericia's method [QTcF] >450 msec, complete left bundle branch block [LBBB], signs of an acute or indeterminate-age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second- or third-degree atrioventricular [AV] block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 msec, or the QRS complex exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS complex values should be used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat test, if deemed necessary: Aspartate aminotransferase (AST) or ALT level ≥1.5 × upper limit of normal (ULN); Total bilirubin (TBili) level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN; Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (See Appendix 10.2 for calculation method). Male participants who are unwilling or unable to comply with the contraception requirement listed in Section 10.4.1. History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine). Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing. History of sensitivity to heparin or heparin-induced thrombocytopenia. Participants who currently smoke. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sequence 1<br>Receive treatments in the following order from Periods 1-6: A, B, C, D, E, G | Drug: Treatment A<br>* Single 250 mg crizotinib dose as coated microsphere 1 (cMS1) formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment B<br>* A single 250 mg crizotinib dose as coated microsphere 2 (cMS2) formulation will be administered on the morning of Day 1 after overnight fast of at least 10 hours.<br>Drug: Treatment C<br>* A single 250 mg crizotinib dose as FC formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment D<br>* A single 250 mg crizotinib dose as OS will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment E<br>* 250 mg crizotinib as cMS1 formulation will be administered with high-fat, high-calorie meal after an overnight fast of at least 10 hours.<br>Drug: Treatment G<br>* 40 mg esomeprazole will be administered 1 hour prior to dinner on Day -5 through Day -1. A single 250 mg crizotinib dose as cMS1 formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>|
| Other: Sequence 2<br>Receive treatments in the following order from Periods 1-6: A, C, B, D, E, G | Drug: Treatment A<br>* Single 250 mg crizotinib dose as coated microsphere 1 (cMS1) formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment B<br>* A single 250 mg crizotinib dose as coated microsphere 2 (cMS2) formulation will be administered on the morning of Day 1 after overnight fast of at least 10 hours.<br>Drug: Treatment C<br>* A single 250 mg crizotinib dose as FC formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment D<br>* A single 250 mg crizotinib dose as OS will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment E<br>* 250 mg crizotinib as cMS1 formulation will be administered with high-fat, high-calorie meal after an overnight fast of at least 10 hours.<br>Drug: Treatment G<br>* 40 mg esomeprazole will be administered 1 hour prior to dinner on Day -5 through Day -1. A single 250 mg crizotinib dose as cMS1 formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>|
| Other: Sequence 3<br>Receive treatments in the following order from Periods 1-6: B, A, C, D, E, G | Drug: Treatment A<br>* Single 250 mg crizotinib dose as coated microsphere 1 (cMS1) formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment B<br>* A single 250 mg crizotinib dose as coated microsphere 2 (cMS2) formulation will be administered on the morning of Day 1 after overnight fast of at least 10 hours.<br>Drug: Treatment C<br>* A single 250 mg crizotinib dose as FC formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment D<br>* A single 250 mg crizotinib dose as OS will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment E<br>* 250 mg crizotinib as cMS1 formulation will be administered with high-fat, high-calorie meal after an overnight fast of at least 10 hours.<br>Drug: Treatment G<br>* 40 mg esomeprazole will be administered 1 hour prior to dinner on Day -5 through Day -1. A single 250 mg crizotinib dose as cMS1 formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>|
| Other: Sequence 4<br>Receive treatments in the following order from Periods 1-6: B, C, A, D, F, H | Drug: Treatment A<br>* Single 250 mg crizotinib dose as coated microsphere 1 (cMS1) formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment B<br>* A single 250 mg crizotinib dose as coated microsphere 2 (cMS2) formulation will be administered on the morning of Day 1 after overnight fast of at least 10 hours.<br>Drug: Treatment C<br>* A single 250 mg crizotinib dose as FC formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment D<br>* A single 250 mg crizotinib dose as OS will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment F<br>* 250 mg crizotinib as cMS2 will be administered with a high-fat, high-calorie meal after an overnight fast of at least 10 hours.<br>Drug: Treatment H<br>* 40 mg esomeprazole will be administered 1 hour prior to dinner on Day -5 through Day -1. A single 250 mg crizotinib dose as cMS2 formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>|
| Other: Sequence 5<br>Receive treatments in the following order from Periods 1-6: C, A, B, D, F, H | Drug: Treatment A<br>* Single 250 mg crizotinib dose as coated microsphere 1 (cMS1) formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment B<br>* A single 250 mg crizotinib dose as coated microsphere 2 (cMS2) formulation will be administered on the morning of Day 1 after overnight fast of at least 10 hours.<br>Drug: Treatment C<br>* A single 250 mg crizotinib dose as FC formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment D<br>* A single 250 mg crizotinib dose as OS will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment F<br>* 250 mg crizotinib as cMS2 will be administered with a high-fat, high-calorie meal after an overnight fast of at least 10 hours.<br>Drug: Treatment H<br>* 40 mg esomeprazole will be administered 1 hour prior to dinner on Day -5 through Day -1. A single 250 mg crizotinib dose as cMS2 formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>|
| Other: Sequence 6<br>Receive treatments in the following order from Periods 1-6: C, B, A, D, F, H | Drug: Treatment A<br>* Single 250 mg crizotinib dose as coated microsphere 1 (cMS1) formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment B<br>* A single 250 mg crizotinib dose as coated microsphere 2 (cMS2) formulation will be administered on the morning of Day 1 after overnight fast of at least 10 hours.<br>Drug: Treatment C<br>* A single 250 mg crizotinib dose as FC formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment D<br>* A single 250 mg crizotinib dose as OS will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>Drug: Treatment F<br>* 250 mg crizotinib as cMS2 will be administered with a high-fat, high-calorie meal after an overnight fast of at least 10 hours.<br>Drug: Treatment H<br>* 40 mg esomeprazole will be administered 1 hour prior to dinner on Day -5 through Day -1. A single 250 mg crizotinib dose as cMS2 formulation will be administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | 0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours post-dose in Periods 1, 2, 3, 5, and 6. | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | 0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours post-dose in Periods 1, 2, 3, 5, and 6. | 
| Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration. | 0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours post-dose in Periods 1, 2, 3, 5, and 6. | 
| Number of subjects reporting overall liking of drug formulation | Overall liking assesses the degree that a participant likes a drug formulation based on sensory attributes experienced by the participant after tasting a product. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Number of subjects reporting bitterness of drug formulation | Bitterness assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Number of subjects reporting mouth feel from drug formulation | Mouth feel assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Number of subjects reporting tongue/mouth burn from drug formulation | Tongue/mouth burn assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Number of subjects reporting throat burn from drug formulation | Throat burn assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Percentage of subjects reporting overall liking of drug formulation | Overall liking assesses the degree that a participant likes a drug formulation based on sensory attributes experienced by the participant after tasting a product. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Percentage of subjects reporting bitterness of drug formulation | Bitterness assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Percentage of subjects reporting mouth feel from drug formulation | Mouth feel assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Percentage of subjects reporting tongue/mouth burn from drug formulation | Tongue/mouth burn assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 
| Percentage of subjects reporting throat burn from drug formulation | Throat burn assesses the degree that a participant experienced this sensory attribute after tasting a drug formulation. It is scored based on a measurement of taste questionnaire. | 1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult, Bioavailability, Crizotinib, Drug Interactions, Esomeprazole, Humans, Microsphere, Pharmacokinetics, Safety, Taste