NCT03542305

Lorlatinib Renal Impairment Study

Completed Phase 1 Results posted Last updated 21 February 2021

What this trial tests

Phase 1 trial testing Lorlatinib in Renal Impairment in 29 participants. Completed in 20 February 2020.

Timeline

23 August 2018

Primary endpoint
20 February 2020

20 February 2020

Quick facts

Lead sponsor	Pfizer
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	sequential
Masking	none
Primary purpose	other
Enrollment	29
Start date	23 August 2018
Primary completion	20 February 2020
Estimated completion	20 February 2020
Sites	2 locations across United States

Drugs / interventions tested

• Lorlatinib (lorlatinib) — full drug profile →

Conditions studied

• Renal Impairment — all drugs for Renal Impairment →

Sponsor

Pfizer — full company profile →

Who can join

Adults 18 to 75, any sex, with Renal Impairment. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib Primary · 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.

Group	Value	95% CI
Normal Function	8329	± 33
Mild Impairment	8683	± 29
Moderate Impairment	9890	± 27
Severe Impairment	11760	± 37

Maximum Observed Plasma Concentration (Cmax) of Lorlatinib Primary · 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.

Group	Value	95% CI
Normal Function	546.8	± 48
Mild Impairment	549.7	± 52
Moderate Impairment	485.9	± 24
Severe Impairment	504.8	± 50

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Secondary · 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 treatm

All-causality AEs

Group	Value	95% CI
Normal Function	5
Mild Impairment	2
Moderate Impairment	4
Severe Impairment	1

All-causality SAEs

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

Treatment-related AEs

Group	Value	95% CI
Normal Function	3
Mild Impairment	2
Moderate Impairment	1
Severe Impairment	1

Treatment-related SAEs

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities Secondary · 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

Group	Value	95% CI
Normal Function	4
Mild Impairment	2
Moderate Impairment	8
Severe Impairment	5

Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria Secondary · 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 b

Supine SBP < 90 mmHg

Group	Value	95% CI
Normal Function	0
Mild Impairment	1
Moderate Impairment	0
Severe Impairment	0

Supine SBP ≥ 30 mmHg increase

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	2
Severe Impairment	1

Supine SBP ≥ 30 mmHg decrease

Group	Value	95% CI
Normal Function	1
Mild Impairment	1
Moderate Impairment	0
Severe Impairment	0

Supine DBP < 50 mmHg

Group	Value	95% CI
Normal Function	0
Mild Impairment	1
Moderate Impairment	0
Severe Impairment	0

Supine DBP ≥ 20 mmHg increase

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	1
Severe Impairment	1

Supine DBP ≥ 20 mmHg decrease

Group	Value	95% CI
Normal Function	0
Mild Impairment	1
Moderate Impairment	0
Severe Impairment	0

Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria Secondary · 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.

PR interval ≥ 200 to <220 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	1

PR interval ≥ 200 to <240 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

PR interval ≥ 240 to <260 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

PR interval ≥ 260msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

QRS interval >120 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

QT interval ≥ 500 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

QTcF interval ≥ 450 to <480 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

QTcF interval ≥ 480 msec

Group	Value	95% CI
Normal Function	0
Mild Impairment	0
Moderate Impairment	0
Severe Impairment	0

Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib Secondary · 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.

Group	Value	95% CI
Normal Function	8015	± 32
Mild Impairment	8307	± 28
Moderate Impairment	8867	± 24
Severe Impairment	10310	± 36

Time for Cmax (Tmax) of Lorlatinib Secondary · 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.

Group	Value	95% CI
Normal Function	1.50	1.00 – 4.00
Mild Impairment	1.00	1.00 – 1.50
Moderate Impairment	1.25	1.00 – 4.00
Severe Impairment	1.00	1.00 – 1.50

Terminal Elimination Plasma Half-life (t½) of Lorlatinib Secondary · 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.

Group	Value	95% CI
Normal Function	25.64	± 4.7500
Mild Impairment	28.08	± 3.5156
Moderate Impairment	39.40	± 7.1019
Severe Impairment	41.66	± 7.6081

Apparent Clearance After Oral Dose (CL/F) of Lorlatinib Secondary · 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.

Group	Value	95% CI
Normal Function	12.02	± 33
Mild Impairment	11.51	± 29
Moderate Impairment	10.11	± 27
Severe Impairment	8.51	± 37

Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib Secondary · 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.

Group	Value	95% CI
Normal Function	436.9	± 24
Mild Impairment	462.9	± 27
Moderate Impairment	566.2	± 21
Severe Impairment	503.8	± 36

Renal Clearance (CLR) of Lorlatinib Secondary · 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.

Group	Value	95% CI
Normal Function	0.1095	± 42
Mild Impairment	0.1382	± 50
Moderate Impairment	0.08199	± 55
Severe Impairment	0.06872	± 45

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to 28 days after last dose of study treatment (approximately 29 days). Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Normal Function

Serious: 0/8 (0%)

Deaths: 0/8

Mild Impairment

Serious: 0/8 (0%)

Deaths: 0/8

Moderate Impairment

Serious: 0/8 (0%)

Deaths: 0/8

Severe Impairment

Serious: 0/5 (0%)

Deaths: 0/5

Other adverse events (13 terms — click to expand)

Reaction	System	Normal Function	Mild Impairment	Moderate Impairment	Severe Impairment
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Blood pressure increased	Investigations	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Vessel puncture site pain	General disorders	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—
Skin abrasion	Injury, poisoning and procedural complications	—	—	—	—
Skin laceration	Injury, poisoning and procedural complications	—	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Ecchymosis	Skin and subcutaneous tissue disorders	—	—	—	—

Data from ClinicalTrials.gov NCT03542305 adverse events section.

Sponsor's own 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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Safety and efficacy of anaplastic lymphoma kinase tyrosine kinase inhibitors in non‑small cell lung cancer (Review).
   Wang L, Wang W. · · 2021 · cited 42× · PMID 33200229 · DOI 10.3892/or.2020.7851
2. A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment.
   Lin S, Gong J, Canas GC, Winkle P, et al · · 2022 · cited 12× · PMID 35018553 · DOI 10.1007/s13318-021-00747-4