Back to resultsHepatic Impairment Study for Lorlatinib in Cancer Patients
Primary Purpose
Advanced Cancers
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
lorlatinib
lorlatinib
lorlatinib
lorlatinib
lorlatinib
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Cancers focused on measuring hepatic impairment, lorlatinib, cancer, pharmacokinetic, Lung cancer
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
Sites / Locations
- University of Colorado Denver CTO (CTRC)
- University of Colorado Hospital, Anschutz Cancer Pavilion (ACP)
- University of Colorado Hospital, Anschutz Inpatient Pavilion (AIP)
- University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP)
- Emory University Hospital
- Investigational Drug Service
- The Emory Clinic
- Winship Cancer Institute, Emory University
- Mays Cancer Center
- University Health System
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Active Comparator
Active Comparator
Experimental
Experimental
Experimental
Arm Label
Group A1 Normal hepatic function
Group A2 Normal hepatic function
Group B mild hepatic impairment
Group C moderate hepatic impairment
Group D severe hepatic impairment
Arm Description
continued daily administration of lorlatinib in patients with normal hepatic function
continued daily administration of lorlatinib in patients with normal hepatic function
continued daily administration of lorlatinib in patients with mild hepatic imapirment
continued daily administration of lorlatinib in patients with moderate hepatic impairment
continued daily administration of lorlatinib in patients with severe hepatic impairment
Outcomes
Primary Outcome Measures
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
Plasma lorlatinib Cmax at steady state
observed maximal plasma concentration at steady state on cycle 2 day 1
Secondary Outcome Measures
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.
Plasma lorlatinib Tlast after single dose
the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
Plasma lorlatinib Tmax after single dose
the time to Cmax after single dose on cycle 1 day 1.
Plasma lorlatinib Cmin at steady state
observed minimal plasma concentration at steady state on cycle 2 day 1.
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.
Plasma lorlatinib Tlast at steady state
the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
lorlatinib CL/F at steadys state
lorlatinib apparent clearance at steady state on cycle 2 day 1
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
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.
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.
Plasma lorlatinib metabolite Cmax at steady state
observed maximal plasma concentration at steady state on cycle 2 day 1.
Plasma lorlatinib metabolite Cmax after single dose
observed maximal plasma concentration after single dose on cycle 1 day 1.
Plasma lorlatinib metabolite Tmax after single dose
the time to Cmax after single dose on cycle 1 day 1.
Plasma lorlatinib metabolite Tmax at steady state
the time to Cmax at steady state on cycle 2 day 1.
Plasma lorlatinib metabolite Tlast after single dose
the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
Plasma lorlatinib metabolite Tlast at steady state
the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
MRAUC24 at steady state
metabolite ratio of lorlatinib metabolite for AUC24 at steady state on cycle 2 day 1
MRAUClast at steady state
metabolite ratio of lorlatinib metabolite for AUClast at steady state on cycle 2 day 1
MRCmax at steady state
metabolite ratio of lorlatinib metabolite for Cmax at steady state on cycle 2 day 1
MRAUClast after single dose
metabolite ratio of lorlatinib metabolite for AUClast after single dose on cycle 1 day 1
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
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
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
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
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03726333
Brief Title
Hepatic Impairment Study for Lorlatinib in Cancer Patients
Official Title
A PHASE 1 STUDY TO EVALUATE THE EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB IN ADVANCED CANCER PATIENTS
Study Type
Interventional
2. Study Status
Record Verification Date
January 2022
Overall Recruitment Status
Terminated
Why Stopped
The study stopped due to lack of enrollment
Study Start Date
January 14, 2020 (Actual)
Primary Completion Date
July 8, 2021 (Actual)
Study Completion Date
July 14, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pfizer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Cancers
Keywords
hepatic impairment, lorlatinib, cancer, pharmacokinetic, Lung cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
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)
Allocation
Non-Randomized
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group A1 Normal hepatic function
Arm Type
Active Comparator
Arm Description
continued daily administration of lorlatinib in patients with normal hepatic function
Arm Title
Group A2 Normal hepatic function
Arm Type
Active Comparator
Arm Description
continued daily administration of lorlatinib in patients with normal hepatic function
Arm Title
Group B mild hepatic impairment
Arm Type
Experimental
Arm Description
continued daily administration of lorlatinib in patients with mild hepatic imapirment
Arm Title
Group C moderate hepatic impairment
Arm Type
Experimental
Arm Description
continued daily administration of lorlatinib in patients with moderate hepatic impairment
Arm Title
Group D severe hepatic impairment
Arm Type
Experimental
Arm Description
continued daily administration of lorlatinib in patients with severe hepatic impairment
Intervention Type
Drug
Intervention Name(s)
lorlatinib
Intervention Description
continued daily administration of 100 mg lorlatinib
Intervention Type
Drug
Intervention Name(s)
lorlatinib
Intervention Description
continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards
Intervention Type
Drug
Intervention Name(s)
lorlatinib
Intervention Description
continued daily administration of 100 mg QD lorlatinib
Intervention Type
Drug
Intervention Name(s)
lorlatinib
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
lorlatinib
Intervention Description
continued daily administration of lorlatinib at the dose level determined based on preliminary PK and safety results from first several patients in Group C
Primary Outcome Measure Information:
Title
Plasma lorlatinib AUC24 at steady state
Description
area under plasma concentration-time curve from time 0 to dosing interval of 24 hours (AUC24) at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib Cmax at steady state
Description
observed maximal plasma concentration at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Secondary Outcome Measure Information:
Title
Plasma lorlatinib AUClast after single dose
Description
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.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib Tlast after single dose
Description
the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib Tmax after single dose
Description
the time to Cmax after single dose on cycle 1 day 1.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib Cmin at steady state
Description
observed minimal plasma concentration at steady state on cycle 2 day 1.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib AUClast at steady state
Description
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.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib Tlast at steady state
Description
the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
lorlatinib CL/F at steadys state
Description
lorlatinib apparent clearance at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
plasma lorlatinib metabolite AUC24 at steady state
Description
area under plasma concentration-time curve from time 0 to dosing interval of 24 hours (AUC24) at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite AUClast after single dose
Description
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.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite AUClast at steady state
Description
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.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite Cmax at steady state
Description
observed maximal plasma concentration at steady state on cycle 2 day 1.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite Cmax after single dose
Description
observed maximal plasma concentration after single dose on cycle 1 day 1.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite Tmax after single dose
Description
the time to Cmax after single dose on cycle 1 day 1.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite Tmax at steady state
Description
the time to Cmax at steady state on cycle 2 day 1.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite Tlast after single dose
Description
the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
Time Frame
cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
Plasma lorlatinib metabolite Tlast at steady state
Description
the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
MRAUC24 at steady state
Description
metabolite ratio of lorlatinib metabolite for AUC24 at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
MRAUClast at steady state
Description
metabolite ratio of lorlatinib metabolite for AUClast at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
MRCmax at steady state
Description
metabolite ratio of lorlatinib metabolite for Cmax at steady state on cycle 2 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
MRAUClast after single dose
Description
metabolite ratio of lorlatinib metabolite for AUClast after single dose on cycle 1 day 1
Time Frame
cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Title
number of patients experienced treatment emergent adverse event assessed by investigator
Description
Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities
Time Frame
until at least 28 days after the last lorlatinib dose
Title
ORR
Description
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
Time Frame
baseline up to approximately 1 year
Title
DR
Description
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
Time Frame
baseline up to approximately 1 year
Title
number of patients experienced treatment related adverse event assessed by investigator
Description
Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities
Time Frame
until at least 28 days after the last lorlatinib dose
Title
number of patients experienced treatment emergent serious adverse event assessed by investigator
Description
Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities
Time Frame
until at least 28 days after the last lorlatinib dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
University of Colorado Denver CTO (CTRC)
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Colorado Hospital, Anschutz Cancer Pavilion (ACP)
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Colorado Hospital, Anschutz Inpatient Pavilion (AIP)
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP)
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Investigational Drug Service
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
The Emory Clinic
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Winship Cancer Institute, Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Mays Cancer Center
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University Health System
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing 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.
Links:
URL
https://pmiform.com/clinical-trial-info-request?StudyID=B7461009
Description
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Hepatic Impairment Study for Lorlatinib in Cancer Patients
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