Hepatic Impairment Study for Lorlatinib in Cancer Patients
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT03726333 |
Recruitment Status :
Terminated
(The study stopped due to lack of enrollment)
First Posted : October 31, 2018
Last Update Posted : January 26, 2022
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Condition or disease | Intervention/treatment | Phase |
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Advanced Cancers | Drug: lorlatinib | Phase 1 |
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 (Clinical Trial) |
Actual Enrollment : | 1 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Intervention 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) |
Primary Purpose: | Treatment |
Official Title: | A PHASE 1 STUDY TO EVALUATE THE EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB IN ADVANCED CANCER PATIENTS |
Actual Study Start Date : | January 14, 2020 |
Actual Primary Completion Date : | July 8, 2021 |
Actual Study Completion Date : | July 14, 2021 |

Arm | Intervention/treatment |
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Active Comparator: Group A1 Normal hepatic function
continued daily administration of lorlatinib in patients with normal hepatic function
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Drug: lorlatinib
continued daily administration of 100 mg lorlatinib |
Active Comparator: Group A2 Normal hepatic function
continued daily administration of lorlatinib in patients with normal hepatic function
|
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 |
Experimental: Group B mild hepatic impairment
continued daily administration of lorlatinib in patients with mild hepatic imapirment
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Drug: lorlatinib
continued daily administration of 100 mg QD lorlatinib |
Experimental: Group C moderate hepatic impairment
continued daily administration of lorlatinib in patients with moderate hepatic impairment
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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 |
Experimental: Group D severe hepatic impairment
continued daily administration of lorlatinib in patients with severe hepatic impairment
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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 |
- Plasma lorlatinib AUC24 at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]observed maximal plasma concentration at steady state on cycle 2 day 1
- Plasma lorlatinib AUClast after single dose [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
- Plasma lorlatinib Tmax after single dose [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time to Cmax after single dose on cycle 1 day 1.
- Plasma lorlatinib Cmin at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]observed minimal plasma concentration at steady state on cycle 2 day 1.
- Plasma lorlatinib AUClast at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
- lorlatinib CL/F at steadys state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]lorlatinib apparent clearance at steady state on cycle 2 day 1
- plasma lorlatinib metabolite AUC24 at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]observed maximal plasma concentration at steady state on cycle 2 day 1.
- Plasma lorlatinib metabolite Cmax after single dose [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]observed maximal plasma concentration after single dose on cycle 1 day 1.
- Plasma lorlatinib metabolite Tmax after single dose [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time to Cmax after single dose on cycle 1 day 1.
- Plasma lorlatinib metabolite Tmax at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time to Cmax at steady state on cycle 2 day 1.
- Plasma lorlatinib metabolite Tlast after single dose [ Time Frame: cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
- Plasma lorlatinib metabolite Tlast at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
- MRAUC24 at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]metabolite ratio of lorlatinib metabolite for AUC24 at steady state on cycle 2 day 1
- MRAUClast at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]metabolite ratio of lorlatinib metabolite for AUClast at steady state on cycle 2 day 1
- MRCmax at steady state [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]metabolite ratio of lorlatinib metabolite for Cmax at steady state on cycle 2 day 1
- MRAUClast after single dose [ Time Frame: cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days) ]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 [ Time Frame: until at least 28 days after the last lorlatinib dose ]Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities
- ORR [ Time Frame: baseline up to approximately 1 year ]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 [ Time Frame: baseline up to approximately 1 year ]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 [ Time Frame: until at least 28 days after the last lorlatinib dose ]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 [ Time Frame: until at least 28 days after the last lorlatinib dose ]Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03726333
United States, Colorado | |
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) | |
Aurora, Colorado, United States, 80045 | |
United States, Georgia | |
Emory University Hospital | |
Atlanta, Georgia, United States, 30322 | |
Investigational Drug Service | |
Atlanta, Georgia, United States, 30322 | |
The Emory Clinic | |
Atlanta, Georgia, United States, 30322 | |
Winship Cancer Institute, Emory University | |
Atlanta, Georgia, United States, 30322 | |
United States, Texas | |
Mays Cancer Center | |
San Antonio, Texas, United States, 78229 | |
University Health System | |
San Antonio, Texas, United States, 78229 |
Study Director: | Pfizer CT.gov Call Center | Pfizer |
Responsible Party: | Pfizer |
ClinicalTrials.gov Identifier: | NCT03726333 |
Other Study ID Numbers: |
B7461009 lorlatinib HEPATIC IMPAIRMENT ( Other Identifier: Alias Study Number ) HEPATIC IMPAIRMENT ( Other Identifier: Alias Study Number ) |
First Posted: | October 31, 2018 Key Record Dates |
Last Update Posted: | January 26, 2022 |
Last Verified: | January 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
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. |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
hepatic impairment lorlatinib cancer pharmacokinetic Lung cancer |
Neoplasms Liver Diseases Digestive System Diseases |