Hepatic Impairment Study for Lorlatinib in Cancer Patients

Study Overview
=================
Brief Summary
-----------------
This is a phase 1 study in advanced cancer patients with varied hepatic fucntions 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.

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.

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

Conditions
-----------------
Advanced Cancers

Intervention / Treatment
-----------------
* Drug: lorlatinib
* Drug: lorlatinib
* Drug: lorlatinib
* Drug: lorlatinib
* Drug: lorlatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients in the study will be assigned to different groups according to their liver function. Patients in each group will receive specific lorlatinib dose. Plasma samples for pharmacokinetic analysis will be collected in all patients. Safety and efficacy will also be followed in all patients until at least 28 days after the last study treatment.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma lorlatinib AUC24 at steady state | area under plasma concentration-time curve from time 0 to dosing interval of 24 hours (AUC24) at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib Cmax at steady state | observed maximal plasma concentration at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma lorlatinib AUClast after single dose | 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. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib Tlast after single dose | the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib Tmax after single dose | the time to Cmax after single dose on cycle 1 day 1. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib Cmin at steady state | observed minimal plasma concentration at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib AUClast at steady state | area under plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib Tlast at steady state | the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| lorlatinib CL/F at steadys state | lorlatinib apparent clearance at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| plasma lorlatinib metabolite AUC24 at steady state | area under plasma concentration-time curve from time 0 to dosing interval of 24 hours (AUC24) at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite AUClast after single dose | 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. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite AUClast at steady state | area under plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite Cmax at steady state | observed maximal plasma concentration at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite Cmax after single dose | observed maximal plasma concentration after single dose on cycle 1 day 1. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite Tmax after single dose | the time to Cmax after single dose on cycle 1 day 1. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite Tmax at steady state | the time to Cmax at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite Tlast after single dose | the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1. | cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| Plasma lorlatinib metabolite Tlast at steady state | the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1. | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| MRAUC24 at steady state | metabolite ratio of lorlatinib metabolite for AUC24 at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| MRAUClast at steady state | metabolite ratio of lorlatinib metabolite for AUClast at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| MRCmax at steady state | metabolite ratio of lorlatinib metabolite for Cmax at steady state on cycle 2 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| MRAUClast after single dose | metabolite ratio of lorlatinib metabolite for AUClast after single dose on cycle 1 day 1 | cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) | 
| number of patients experienced treatment emergent adverse event assessed by investigator | Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities | until at least 28 days after the last lorlatinib dose | 
| ORR | objective response rate (ORR) is defined as the percent of patients with complete response (CR) or partial response (PR) based on investigator evaluation, according to RECIST v1.1 relative to the response-evaluable population | baseline up to approximately 1 year | 
| DR | Duration of response (DR) will be measured from the date that an objective tumor response (CR or PR) is first documented (whichever occurs first) to date of objective tumor progression or death due to any cause, whichever occurs first | baseline up to approximately 1 year | 
| number of patients experienced treatment related adverse event assessed by investigator | Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities | until at least 28 days after the last lorlatinib dose | 
| number of patients experienced treatment emergent serious adverse event assessed by investigator | Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities | until at least 28 days after the last lorlatinib dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hepatic impairment, lorlatinib, cancer, pharmacokinetic, Lung cancer