This is a phase 1 study in advanced cancer patients with varied hepatic functions to evaluate the potential effect of hepatic impairment on pharmacokinetics and safety of lorlatinib and provide dose recommendation for patients with hepatic impairment if possible.
This will be a Phase 1, open label, multi center, multiple dose, non randomized, Phase 1 clinical trial of lorlatinib in advanced cancer patients with varying degrees of hepatic impairment and necessary age , weight , and gender matched prospect normal hepatic function patients. This study is intended to evaluate the potential effect of hepatic impairments on the PK and safety of lorlatinib after daily administration of lorlatinib and to provide dosing recommendation for patients with varied degree of hepatic impairment if possible. Patients in the study will be assigned to different groups (A1, normal liver function, control for group B; A2, normal liver function, control for group C; B, mild hepatic impairment; C, moderate hepatic impairment; D, severe hepatic impairment) according to their liver function. The enrollment of approximately 76 advanced cancer patients is anticipated in this study in order to have 8 PK-evaluable patients in each of Groups A1, A2, B and C, and 6 PK-evaluable patients in Group D for final statistical analysis. Evaluable patients are those who complete the planned PK sample collection on Cycle 2 Day 1 and have no lorlatinib dose modification until completion of Cycle 2 Day 1 PK evaluation. Patients who are not evaluable for PK will be replaced. Each patient will be treated with repeated oral once daily doses of lorlatinib in 21-day cycles until disease progression, patient refusal, or unacceptable toxicity occurs. The dose schedule may be modified as necessary for individual patients according to tolerability.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
continued daily administration of 100 mg lorlatinib
continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards
continued daily administration of 100 mg QD lorlatinib
University of Colorado Denver CTO (CTRC)
Aurora, Colorado, United States
University of Colorado Hospital, Anschutz Cancer Pavilion (ACP)
Aurora, Colorado, United States
University of Colorado Hospital, Anschutz Inpatient Pavilion (AIP)
Aurora, Colorado, United States
Area Under Plasma Lorlatinib Concentration-Time Curve From Time 0 to Dosing Interval of 24 Hours (AUC24) at Steady State On Cycle 2 Day 1
AUC24 was defined as area under the plasma concentration time profile during 1 dosing interval (24 hours).
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Observed Maximal Plasma Concentration (Cmax) at Steady State on Cycle 2 Day 1
Cmax was defined as maximum plasma concentration and was observed directly from data.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Number Of Patients Experienced Treatment Emergent Adverse Event Assessed by Investigator
An Adverse event (AE) was any untoward medical occurrence in a participant. A serious AE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect or that was considered to be an important medical event. AEs were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. The grades were defined as follows: Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. The focus of AE summaries was on treatment-emergent AE (TEAE). An AE was considered TEAE if the event occurred during the on-treatment period.
Time frame: From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after after the last lorlatinib dose. The duration is approximately 42 days.
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 relative to the response-evaluable population.
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continued daily administration of lorlatinib at 50 mg QD initially and may be adjusted based on PK and safety results from the initial several patients
continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C
University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP)
Aurora, Colorado, United States
Emory University Hospital
Atlanta, Georgia, United States
Investigational Drug Service
Atlanta, Georgia, United States
The Emory Clinic
Atlanta, Georgia, United States
Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Mays Cancer Center
San Antonio, Texas, United States
University Health System
San Antonio, Texas, United States
Time frame: Baseline up to approximately 1 year
Duration of Response (DR)
DR was measured from the date that an objective tumor response (CR or PR) was first documented (whichever occurred first) to date of objective tumor progression or death due to any cause, whichever occurred first.
Time frame: Baseline up to approximately 1 year
Lorlatinib Area Under Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) After Single Dose on Cycle 1 Day 1
AUClast was defined as area under the plasma concentration time profile from time 0 to the time of the last quantifiable concentration (Clast)
Time frame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
The Time of The Last Quantifiable Concentration (Tlast) of Lorlatinib After Single Dose on Cycle 1 Day 1
Tlast was defined as the time of the last quantifiable concentration.
Time frame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
The Time to Cmax (Tmax) of Lorlatinib After Single Dose on Cycle 1 Day 1
Tmax was defined as time for Cmax.
Time frame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Observed Minimal Plasma Concentration (Cmin) at Steady State On Cycle 2 Day 1
Cmin was defined as minimum plasma concentration and was observed directly from data.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib AUClast at Steady State On Cycle 2 Day 1
AUClast was defined as area under the plasma concentration time profile from time 0 to the time of Clast.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Tlast at Steady State On Cycle 2 Day 1
Tlast was defined as the time of the last quantifiable concentration.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Apparent Clearance (CL/F) at Steady State On Cycle 2 Day 1
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as Dose/AUC24 at steady-state.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite AUC24 at Steady State
AUC24 was defined as area under the plasma concentration time profile during one dosing interval (24 hours).
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite AUClast After Single Dose
AUClast was defined as area under the plasma concentration time profile from time 0 to the time of Clast.
Time frame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite AUClast at Steady State
AUClast was defined as area under the plasma concentration time profile from time 0 to the time of Clast.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite Cmax After Single Dose
Cmax was defined as maximum plasma concentration and was observed directly from data.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite Cmax at Steady State
Cmax was defined as maximum plasma concentration and was observed directly from data.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite Tlast After Single Dose
Tlast was defined as the time of the last quantifiable concentration.
Time frame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Plasma Lorlatinib Metabolite Tlast at Steady State
Tlast was defined as the time of the last quantifiable concentration.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Metabolite Ratio of Lorlatinib Metabolite for AUC24 (MRAUC24) at Steady State on Cycle 2 Day 1
MRAUC24 was defined as metabolite ratio of lorlatinib metabolite for AUC24.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 2 Day 1
MRAUClast was defined as metabolite ratio of lorlatinib metabolite for AUClast.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Metabolite Ratio of Lorlatinib Metabolite for Cmax (MRCmax) at Steady State on Cycle 2 Day 1
MRCmax was defined as metabolite ratio of lorlatinib metabolite for AUClast.
Time frame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 1 Day 1
MRAUClast was defined as metabolite ratio of lorlatinib metabolite for AUClast.
Time frame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.