Hepatic Impairment Study for Lorlatinib in Cancer Patients

A PHASE 1 STUDY TO EVALUATE THE EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB IN ADVANCED CANCER PATIENTS

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Cancers
• Intervention / Treatment: Drug: lorlatinib; Drug: lorlatinib; Drug: lorlatinib; Drug: lorlatinib; Drug: lorlatinib

Detailed Description

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
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver CTO (CTRC)
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital, Anschutz Cancer Pavilion (ACP)
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital, Anschutz Inpatient Pavilion (AIP)
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP)
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute, Emory University
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
    • Atlanta, Georgia, United States, 30322
      • Investigational Drug Service
  • Texas
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Center
    • San Antonio, Texas, United States, 78229
      • University Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative or palliative measures do not exist, or are no longer effective;
• Biliary obstruction with a biliary drain or stent;
• Neurologically stable gliomas and brain metastases;
• ECOG performance status of 0, 1, or 2;
• adequate bone marrow function;
• adequate pancreatic function;
• adequate renal function;
• female patients with negative pregnancy test

Exclusion Criteria:

• untreated esophageal varices; uncontrolled ascites;
• episodes of hepatic encephalopathy within the last 4 weeks;
• spinal cord compression; major surgery within 4 weeks prior to enrollment;
• radiation therapy within 2 weeks prior to enrollment;
• last anti-cancer treatment within 2 weeks prior to screening;
• previous high-dose chemotherapy requiring stem cell rescue;
• prior to irradiation to >25% of the bone marrow;
• gastrointestinal abnormalities;
• known prior or suspected hypersensitivity to lorlatinib or lorlatinib tablet;
• clinically significant bacterial, fungal or viral infections for non-liver cancer patients;
• clinically significant cardiovascular disease;
• uncontrolled hypertension; acute pancreatitis with predisposing characteristics;
• history of grade 3 or 4 interstitial fibrosis or interstitial lung disease;
• active hemoelysis or evidence of biliary sepsis;
• prior major gastrointestinal surgery;
• concurrent use of known strong CYP3A inhibitors, inducers and P-gp substrates with a narrow therapeutic index;
• concurrent use of CYP3A substrates with narrow therapeutic indices;
• prior treatment with lorlatinib; active bleeding disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A1 Normal hepatic function; continued daily administration of lorlatinib in patients with normal hepatic function	Drug: lorlatinib; continued daily administration of 100 mg lorlatinib; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards; Drug: lorlatinib; continued daily administration of 100 mg QD lorlatinib; Drug: lorlatinib; 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; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C
Active Comparator: Group A2 Normal hepatic function; continued daily administration of lorlatinib in patients with normal hepatic function	Drug: lorlatinib; continued daily administration of 100 mg lorlatinib; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards; Drug: lorlatinib; continued daily administration of 100 mg QD lorlatinib; Drug: lorlatinib; 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; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C
Experimental: Group C moderate hepatic impairment; continued daily administration of lorlatinib in patients with moderate hepatic impairment	Drug: lorlatinib; continued daily administration of 100 mg lorlatinib; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards; Drug: lorlatinib; continued daily administration of 100 mg QD lorlatinib; Drug: lorlatinib; 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; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C
Experimental: Group D severe hepatic impairment; continued daily administration of lorlatinib in patients with severe hepatic impairment	Drug: lorlatinib; continued daily administration of 100 mg lorlatinib; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards; Drug: lorlatinib; continued daily administration of 100 mg QD lorlatinib; Drug: lorlatinib; 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; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C
Experimental: Group B mild hepatic impairment; continued daily administration of lorlatinib in patients with mild hepatic impairment	Drug: lorlatinib; continued daily administration of 100 mg lorlatinib; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards; Drug: lorlatinib; continued daily administration of 100 mg QD lorlatinib; Drug: lorlatinib; 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; Drug: lorlatinib; continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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)	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.	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.	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.	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.	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.	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.	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).	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2020
• Primary Completion (Actual): July 8, 2021
• Study Completion (Actual): July 8, 2021

Study Registration Dates

• First Submitted: September 24, 2018
• First Submitted That Met QC Criteria: October 29, 2018
• First Posted (Actual): October 31, 2018

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: cancer; Lung cancer; pharmacokinetic; hepatic impairment; lorlatinib
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Neoplasms
• Other Study ID Numbers: B7461009; HEPATIC IMPAIRMENT (Other Identifier: Alias Study Number); lorlatinib HEPATIC IMPAIRMENT (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No