Single-dose Study of [14C]Lorlatinib (PF-06463922) Metabolism In Healthy Male Volunteers

NCT03184168 | Completed Phase 1 FDA Drug

• 2 other identifiers: B746101714C ADME
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This open-label, radiolabeled, single 100-mg dose study in 6 healthy male volunteers has been designed to further the understanding of human metabolism of lorlatinib. A prior radiolabel study using \[14C\]lorlatinib (study B7461004) identified an unexpected major metabolite in plasma; a benzoic acid metabolite (M8) resulting from cleavage of the amide and aromatic ether bonds of lorlatinib, accounting for 21.0% of the circulating radioactivity. However, due to the position of the 14C radiolabel on the carbonyl carbon, the metabolic fate of the larger fragment of lorlatinib resulting from this cleavage, the pyrido-pyrazole substructure, could not be determined. In this current study, the radiolabel will be on the pyrazole ring allowing for monitoring the metabolic fate of the pyrido-pyrazole part of the lorlatinib molecule cleaved during the formation of the M8 metabolite. Since M8 will not be radiolabeled, its concentrations in plasma will be determined using a validated assay. The sample size of 6 was selected to ensure at least 4 fully evaluable subjects with completed collections of plasma, urine, and fecal samples. This is a standard sample size used for mass-balance/ADME studies which include assessment of metabolic profiling, and is not based on empirical data or hypothesis testing criteria. Metabolic profiling of radiolabeled components will be performed on pooled plasma samples as well as on cumulative urine and feces excreted until Day 14 postdose or until one of the following early release criteria is met: 1) recovery in excreta of at least 90% of administered radioactivity, or 2) less than 1% of administered radioactivity being recovered in excreta from two consecutive days (ie, total for urine + feces should be \<1% on 2 consecutive days). Plasma concentrations of both lorlatinib and its unlabeled M8 metabolite will be analyzed using validated assays. Information from this study will complement the metabolic profiling results from study B7461004, will help guide in the assessment of potential drug-drug interactions (DDIs) and the need for other DDI studies with lorlatinib. Banked biospecimens will be collected for the purpose of conducting research. Collecting biospecimens for exploratory analyses makes it possible to better understand the investigational product's mechanism of action and to seek explanations for differences in, for example, exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study.

Conditions

Healthy Volunteers

Keywords

healthy volunteers, lorlatinib, PF-06463922, ADME, NSCLC, radiolabel, metabolism

Outcome Measures

Primary Outcomes (1)

• Metabolic profiling for lorlatinib will be determined in plasma, urine and fecal samples.

  Percent (%) of each radiolabeled drug-related material (parent and each metabolite) will be determined in plasma, urine and feces.

  Assessments will be made up to 14 days post dose

Secondary Outcomes (5)

• Maximum exposure in plasma will be determined for lorlatinib, M8 metabolite and total radioactivity

  Assessments will be made up to 14 days postdose

• Time of maximum exposure in plasma will be determined for lorlatinib, M8 metabolite and total radioactivity

  Assessments will be made up to 14 days post dose

• Exposure up to the last quantifiable concentration will be determined for lorlatinib, M8 metabolite and total radioactivity

  Assessments will be made up to 14 days post dose

• The overall exposure in plasma will be determined for lorlatinib, M8 metabolite and total radioactivity

  Assessments will be made up to 14 days post dose

• The terminal elimination half life in plasma will be estimated from plasma profiles over time for lorlatinib, M8 metabolite and total radioactivity

  Assessments will be made up to 14 days post dose

Other Outcomes (1)

• Relative routes of excretion of total radioactivity

  Assessments will be made up to 14 days post dose

Study Arms (1)

treatment

EXPERIMENTAL

\[14C\]lorlatinib

Drug: [14C]lorlatinib

Interventions

[14C]lorlatinib DRUG

Extemporaneously compounded oral solution of \[14C\]lorlatinib (approximately 100 mg/100 µCi)

Also known as: [14C]PF-06463922

treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy (no clinically relevant abnormalities) males, 18 to 55 years at the time of screening.
• BMI of 17.5-30.5 kg/m2; and a total body weight \>50 kg (110 lb).
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.

You may not qualify if:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, CV, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding seasonal allergies).
• Any condition possibly affecting drug absorption (eg, gastrectomy).
• A positive urine drug test.
• History of regular alcohol consumption exceeding 14 drinks/week within 6 months before screening.
• Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the dose of investigational product (whichever is longer).
• Screening BP ≥ 140 mm Hg (systolic) or 90 mm Hg (diastolic) following at least 5 minutes of rest. If systolic or diastolic BP is higher at screening, repeat 2 times and use average of 3 BP values.
• Screening supine 12 lead ECG QTc interval \>450 msec or QRS interval \>120 msec, or PR interval \> 180 msec. If QTc or QRS exceed, ECG should be repeated 2 more times and the average of the 3 QTc or QRS should be used.
• Subjects with ANY of the following abnormalities in clinical laboratory tests at screening (and confirmed with single repeat): AST or ALT level \> 1.0 × ULN; Total bilirubin level \> 1.5 × ULN. If history of Gilbert's syndrome, subject would be eligible provided the direct bilirubin level is ≤ ULN.
• Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to study drug dose. Acetaminophen may be used at dosed up to 1 g/day. Limited use of nonRx medications may be permitted following approval by the sponsor. Herbal supplements and hormone replacement therapy must have been discontinued at least 28 days prior to study drug dose.
• Blood donation (excluding plasma) of \~ 1 pint (500 mL) or more within 60 days prior to dosing.
• History of HIV, hepatitis B, or hepatitis C; positive testing for HIV, HepBsAg, HepBcAb, or HCVAb.
• Unwilling or unable to comply with the criteria in the Lifestyle Requirements section.
• Investigator site staff members directly involved in the conduct of the study and their family members, site staff members supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results.
• History of irregular bowel movements eg, regular episodes of diarrhea or constipation, irritable bowel syndrome or lactose intolerance.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (1)

Covance Clinical Research Unit Inc.

Madison, Wisconsin, 53704, United States

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Model Details: Open-label, radiolabeled, single-dose study of an oral solution of \[14C\]lorlatinib (100 mg/100 µCi) in 6 healthy male volunteers. Confinement from Day -1 through Day 14 (or until 1 of 2 early release criteria is met). No returns; one follow-up phone call (at 28 to 35 days post dose).

Study Record Dates

• First Submitted: May 17, 2017
• First Posted: June 12, 2017
• Study Start: July 5, 2017
• Primary Completion: August 7, 2017
• Study Completion: August 25, 2017
• Last Updated: September 12, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)