A Study To Evaluate The Effect Of Itraconazole On Pharmacokinetics Of PF-06463922 In Healthy Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to estimate the effect of itraconazole on the single dose pharmacokinetics of PF-06463922 in healthy volunteers in the fasted state.

Detailed Description
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This will be a Phase 1, open-label, 2-period, fixed-sequence, crossover study to investigate the effect of the strong CYP3A inhibitor itraconazole on PF-06463922 PK in approximately 16 healthy volunteers. The study will consist of potentially up to 6 treatments: single dose of PF-06463922 50, 75 or 100 mg and PF-06463922 50, 75 or 100 mg in combination with multiple dose itraconazole.

Official Title
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Phase 1, Open-label, Fixed Sequence, 2-period Study To Investigate The Effect Of Multiple Doses Of Itraconazole On The Pharmacokinetics Of Single Dose Pf-06463922 In Healthy Volunteers In The Fasted Condition

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-06463922
* Drug: PF-06463922
* Drug: PF-06463922
* Drug: PF-06463922
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy female subjects of non childbearing potential and/or male subjects, who at the time of screening, are between the ages of 18 and 55 years, inclusive. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs). Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). Any condition possibly affecting drug absorption. A positive urine drug test. History of HIV, Hep B or Hep C. History of regular alcohol consumption. Screening supine 12 lead ECG demonstrating PR interval >180 msec, QTc >450 msec or a QRS interval >120 msec. Subjects 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, if deemed necessary: Use this criterion to describe any laboratory parameters that are not acceptable for the study. Examples included below: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >1.0 × upper limit of normal (ULN); Total bilirubin level >1.0 × ULN; subjects 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.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive PF-06463922 Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2. | Drug: PF-06463922<br>* Single oral dose of PF-06463922 50 mg on Day 1 of Period 1 and Day 5 of Period 2<br>* Other names: Lorlatinib;Drug: Itraconazole<br>* 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2<br>* Other names: Sporanox;|
| Experimental: Cohort 2<br>All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive PF-06463922 Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2. | Drug: PF-06463922<br>* Single oral dose of PF-06463922 75 mg on Day 1 of Period 1 and Day 5 of Period 2<br>* Other names: Lorlatinib;Drug: Itraconazole<br>* 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2<br>* Other names: Sporanox;|
| Experimental: Cohort 3<br>All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive PF-06463922 Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2. | Drug: PF-06463922<br>* Single oral dose of PF-06463922 100 mg on Day 1 of Period 1 and Day 5 of Period 2<br>* Other names: Lorlatinib;Drug: Itraconazole<br>* 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2<br>* Other names: Sporanox;|
| Experimental: Cohort 4<br>All subjects in this cohort will receive the same dose of PF-06463922 in both periods. Subjects will receive the highest safe dose (mg) of PF-06463922 as a single-dose Alone in Period 1 followed by PF-06463922 with Itraconazole in Period 2. | Drug: PF-06463922<br>* Highest safe single oral dose (mg) of PF-06463922 identified in the previous cohorts will be administered on Day 1 of Period 1 and Day 5 of Period 2<br>* Other names: Lorlatinib;Drug: Itraconazole<br>* 200 mg oral dose of itraconazole on Days 1 to 11 during Period 2<br>* Other names: Sporanox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCinf for PF-06463922 | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| Cmax for PF-06463922 | Maximum plasma concentration | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast for PF-06463922 | Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast) | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| Tmax for PF-06463922 | Time to Cmax | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and upto 168 hours post-dose. | 
| t1/2 for PF-06463922 | Terminal plasma elimination half-life | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| CL/F for PF-06463922 | Apparent clearance | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| Vz/F for PF-06463922 | Apparent volume of distribution | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| AUCinf for any potential PF-06463922 metabolite if necessary | Area under the plasma concentration-time profile from time zero extrapolated to infinite time | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| AUClast for any potential PF-06463922 metabolite if necessary | Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast) | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| Cmax for any potential PF-06463922 metabolite if appropriate | Maximum plasma concentration | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| Tmax for any potential PF-06463922 metabolite if appropriate | Time to Cmax | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| t1/2 for any potential metabolite of PF-06463922 if appropriate | Terminal plasma elimination half-life | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| MRCmax for any potential PF-06463922 metabolite if appropriate | metabolite to parent ratio for Cmax | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| MRAUClast for any potential PF-06463922 metabolite if appropriate | metabolite to parent ratio for AUClast | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| MRAUCinf for any potential PF-06463922 metabolite if appropriate | metabolite to parent ratio for AUCinf | PF-06463922 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and up to 168 hours post-dose. | 
| PR interval after PF-06463922 alone and after increased exposure of PF 06463922 (due to concomitant itraconzole administration). | Change in PR interval from baseline after administration of PF-06463922 single dose as assessed by ECG. | Within 24 hours after single dose administration of PF-06463922 alone and in combination with itraconazole. |