Bioequivalence Study for Crizotinib Encapsulated Microsphere Formulation (eMS)

Study Overview
=================
Brief Summary
-----------------
Bioequivalence study to evaluate the pharmacokinetics of a new crizotinib encapsulated microsphere (eMS) formulation

Detailed Description
-----------------
In order to overcome the poor taste/palatability associated with the original oral solution formulation of crizotinib for pediatric patients, an encapsulated microsphere (eMS) formulation with improved palatability compared with the oral solution and acceptable PK characteristics was developed. The primary objective of this study is to establish the bioequivalence of the eMS formulation to the current commercial formulation, ie, formulated capsule (FC), in adult healthy participants to support the commercialization of this new formulation.

Official Title
-----------------
A PHASE 1, OPEN-LABEL, CROSSOVER STUDY TO ESTABLISH BIOEQUIVALENCE OF AN ENCAPSULATED MICROSPHERE FORMULATION (eMS) TO THE FORMULATED CAPSULE (FC) OF CRIZOTINIB IN HEALTHY ADULT PARTICIPANTS

Conditions
-----------------
Healthy Participants

Intervention / Treatment
-----------------
* Drug: Crizotinib
* Drug: Crizotinib
* Drug: Crizotinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must be 18 to 55 years of age, inclusive, at the time of signing the informed consent document (ICD). Male and female of non-childbearing potential 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, which includes compliance with the requirements and restrictions listed in theICD and in this protocol. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease. Any condition possibly affecting crizotinib absorption (eg, gastrectomy, cholecystectomy, appendectomy). History of HIV infection, chronic hepatitis B, or hepatitis C; positive testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C antibody (HCVAb). Positive COVID-19 test. History of sensitivity to heparin or heparin induced thrombocytopenia. Known history of hypersensitivity to crizotinib or any components of the formulations. Other medical or psychiatric condition: recent or active suicidal ideation/behavior, laboratory abnormality or conditions related to the COVID-19 pandemic that make the participant inappropriate. Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of crizotinib. Previous administration with an investigational drug within 30 days or 5 half-lives preceding the first dose of crizotinib (whichever is longer). Positive urine drug test or cotinine test. Supine BP >=140 mm Hg (systolic) or >=90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP >=140 mm Hg (systolic) or >=90 mm Hg (diastolic), BP should be repeated 2 more times. Any clinically significant abnormality in 12-lead ECG, including QTcF >450 msec, Computer-interpreted ECGs may be overread by a physician experienced in reading ECGs before excluding participants. AST or ALT level > (ULN); TBili level >ULN; participants with a history of Gilbert's syndrome may have direct bilirubin <= ULN; eGFR <90 ml/min/1.73 m2 per CKD-EPI equation. Male participants who are unwilling or unable to comply with the contraception requirement. History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing. Participants who currently smoke. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol. Investigator site staff members or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Three Period Treatment Sequence<br>Participants will receive a single 250 mg crizotinib dose of the formulated capsule(FC) formulation, a single 250 mg crizotinib dose of the encapsulated microsphere (eMS) formulation administered by sprinkling the contents into a dry glass vial, and a single 250 mg crizotinib dose of the encapsulated microsphere (eMS) formulation (administered as intact capsules) | Drug: Crizotinib<br>* A single 250 mg crizotinib dose of the FC formulation<br>* Other names: Treatment A;Drug: Crizotinib<br>* A single 250 mg crizotinib dose of the encapsulated microsphere (eMS) formulation administered by sprinkling the contents into a dry glass vial<br>* Other names: Treatment B;Drug: Crizotinib<br>* A single 250 mg crizotinib dose of the single 250 mg crizotinib dose of the encapsulated microsphere (eMS) formulation (administered as intact capsules) . The intact capsules will be swallowed whole.<br>* Other names: Treatment C;|
| Experimental: Two Period Treatment Sequence<br>Participants will receive a single 250 mg crizotinib dose of the formulated capsule(FC) formulation, a single 250 mg crizotinib dose of the encapsulated microsphere (eMS) formulation administered by sprinkling the contents into a dry glass vial | Drug: Crizotinib<br>* A single 250 mg crizotinib dose of the FC formulation<br>* Other names: Treatment A;Drug: Crizotinib<br>* A single 250 mg crizotinib dose of the encapsulated microsphere (eMS) formulation administered by sprinkling the contents into a dry glass vial<br>* Other names: Treatment B;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma AUCinf after administration of the FC formulation | Area under the plasma concentration-time profile from time zero extrapolated to infinite time Method of Determination: Linear-log trapezoidal method | Day 1, Pre-dose, hour 1, 2,4,6,8,12,24,48,72,96,144 (Periods 1-3) | 
| Plasma Cmax after administration of the FC formulation | Maximum plasma concentration Method of Determination: Observed directly from the data | Day 1, Pre-dose, hour 1, 2,4,6,8,12,24,48,72,96,144 (Periods 1-3) | 
| Plasma AUClast after administration of the FC formulation | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) Method of Determination: AUClast + (Clast/kel) Where Clast is the predicted plasma concentration at the last quantifiable time point and kel is the elimination rate constant estimated from the loglinear regression analysis. | Day 1, Pre-dose, hour 1, 2,4,6,8,12,24,48,72,96,144 (Periods 1-3) | 
| Plasma AUCinf after administration of the unencapsulated eMS formulation | Area under the plasma concentration-time profile from time zero extrapolated to infinite time Method of Determination: Linear-log trapezoidal method | Day 1, Pre-dose, hour 1, 2,4,6,8,12,24,48,72,96,144 (Periods 1-3) | 
| Plasma Cmax after administration of the unencapsulated eMS formulation | Maximum plasma concentration Method of Determination: Observed directly from the data | Day 1, Pre-dose, hour 1, 2,4,6,8,12,24,48,72,96,144 (Periods 1-3) | 
| Plasma AUClast after administration of the unencapsulated eMS formulation | Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration (Clast) Method of Determination: AUClast + (Clast/kel) Where Clast is the predicted plasma concentration at the last quantifiable time point and kel is the elimination rate constant estimated from the loglinear regression analysis. | Day 1, Pre-dose, hour 1,2,4,6,8,12,24,48,72,96,144 (Periods 1-3) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Crizotinib, Encapsulated Microsphere Formulation, Healthy adult participants