Lorlatinib Renal Impairment Study

• ClinicalTrials.gov Identifier: NCT03542305
• Recruitment Status: Completed
• First Posted: May 31, 2018
• Results First Posted: February 21, 2021
• Last Update Posted: February 21, 2021
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: May 18, 2018
• First Posted Date: May 31, 2018
• Results First Submitted Date: February 2, 2021
• Results First Posted Date: February 21, 2021
• Last Update Posted Date: February 21, 2021
• Actual Study Start Date: August 23, 2018
• Actual Primary Completion Date: February 20, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2021)

• Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  AUCinf was calculated by AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration; Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
• Maximum Observed Plasma Concentration (Cmax) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  Cmax was observed directly from data.

Original Primary Outcome Measures (submitted: May 18, 2018)

• AUC [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).
• Cmax [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  Maximum Observed Plasma Concentration (Cmax)

Current Secondary Outcome Measures (submitted: February 2, 2021)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 29 days) ]
  An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event did not need to have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Number of participants with both all-causality and treatment-related TEAEs are presented below.
• Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities [ Time Frame: Screening, Day -1, Day 2 and Day 6 ]
  The hematology, chemistry and urinalysis tests were included in the laboratory examination. Hematology evaluation included hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin concentration and erythrocyte mean corpuscular hemoglobin. Chemistry evaluation included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid albumin, total protein, lipase and amylase. Urinalysis evaluation included decimal logarithm of reciprocal of hydrogen ion activity [pH], glucose, protein, blood, ketones, microscopy, ketones, nitrite, leukocyte esterase, urobilinogen, urine bilirubin and bacteria. The lab abnormalities were reported in accordance with the sponsor reporting standards.
• Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria [ Time Frame: Baseline up to 28 days after last dose of study treatment (approximately 29 days) ]
  Vital signs evaluations included supine diastolic blood pressure (DBP), and supine systolic blood pressure (SBP) were measured with the participant's arm supported at the level of the heart and recorded to the nearest mmHg after approximately 5 minutes of rest. Number of participants with vital signs data meeting the categorical summarization criteria is presented. The pre-specified criteria of vital signs data were categorized as follows: SBP (minimum) <90 mmHg, maximum of decrease and increase from baseline for SBP >=30 mmHg; DBP (minimum) <50 mmHg, maximum of decrease and increase from baseline for DBP>=20 mmHg.
• Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria [ Time Frame: Screening, Day -1, 0 hours (pre-dose), 1 hour, 2 hours, 4 hours, 24 hours and 120 hours postdose. ]
  ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), and QT interval corrected for heart rate using Fridericia's formula (QTcF interval). The pre-specified criteria of ESG data were categorized as below.

Original Secondary Outcome Measures (submitted: May 18, 2018)

AE [ Time Frame: Baseline up to 28 days after last dose of study treatment ]

Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to [study drug] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.

Current Other Pre-specified Outcome Measures (submitted: February 2, 2021)

• Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  AUClast was calculated by linear/Log trapezoidal method.
• Time for Cmax (Tmax) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  Tmax was observed directly from data as time of first occurrence.
• Terminal Elimination Plasma Half-life (t½) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  t1/2 was calculated by ln(2)/kel.
• Apparent Clearance After Oral Dose (CL/F) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  CL/F was calculated by Dose/AUCinf.
• Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  Vz/F was calculated by Dose/(AUCinf*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
• Renal Clearance (CLR) of Lorlatinib [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose ]
  CLR was calculated by Ae/AUClast. Ae was cumulative amount of drug recovered unchanged in urine, which was calculated by sum of (urine concentration × sample volume) for each collection interval from 0 to time 120 hours postdose. Sample volume = (urine weight in g/1.020), where 1.020 g/mL is the approximate specific gravity of urine.

Original Other Pre-specified Outcome Measures (submitted: May 18, 2018)

• AUClast [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
• Tmax [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  Time to Reach Maximum Observed Plasma Concentration (Tmax)
• t1/2 [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
• CL/F [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  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. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
• Vz/F [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  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 absorbed.
• Renal clearance [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours post-dose ]
  Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to infinity (AUCinf)

Descriptive Information

• Brief Title: Lorlatinib Renal Impairment Study
• Official Title: A PHASE 1, SINGLE DOSE OPEN-LABEL STUDY TO EVALUATE THE PHARMACOKINETICS OF LORLATINIB IN SUBJECTS WITH IMPAIRED RENAL FUNCTION
• Brief Summary: This is a Phase 1, open-label, multi-center, single treatment study in subjects with normal renal function and varying degrees of renal impairment.
• Detailed Description: This is a Phase 1, open-label, multi-center, single treatment study in subjects with normal renal function and varying degrees of renal impairment. Each subject will receive a single oral dose of lorlatinib administered in the fasted state. Subjects with mild, moderate, and severe renal impairment will be enrolled and normal healthy subjects will be enrolled as matched controls.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Renal Impairment

Intervention

Drug: Lorlatinib

Lorlatinib single oral dose

Study Arms

• Experimental: Mild
  Mild renal impairment
  Intervention: Drug: Lorlatinib
• Experimental: Moderate
  Moderate renal impairment
  Intervention: Drug: Lorlatinib
• Experimental: Severe
  Severe renal impairment
  Intervention: Drug: Lorlatinib
• Normal
  Normal renal function
  Intervention: Drug: Lorlatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 19, 2020): 29
• Original Estimated Enrollment (submitted: May 18, 2018): 32
• Actual Study Completion Date: February 20, 2020
• Actual Primary Completion Date: February 20, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Female subjects of non-childbearing potential
• Body mass index (BMI) of 17.5 to 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
• Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Demonstrate stable renal function

Exclusion Criteria:

• Renal allograft recipients
• Any condition possibly affecting drug absorption (eg, gastrectomy)
• A positive urine drug test
• History of regular alcohol consumption exceeding 7 drinks/week for female subjects or 14 drinks/week for male subjects (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) 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 first dose of investigational product (whichever is longer).
• Screening supine triplicate 12 lead ECG demonstrating a corrected QT (QTc) interval >450 msec or a QRS interval >120 msec
• Second-degree or third-degree AV block (unless paced) or baseline PR interval >180 msec at any time prior to dosing of study treatment.
• Abnormalities in clinical laboratory tests at screening
• Pregnant or breastfeeding female subjects
• History of HIV, Hepatitis B, Hepatitis C, HIT, sensitivity to heparin
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03542305
• Other Study ID Numbers: B7461010; RENAL IMPAIRMENT ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: February 2021