Hepatic Impairment Study for Lorlatinib in Cancer Patients

Advanced Cancers Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03726333
• Other study ID #: B7461009
• Secondary ID: lorlatinib HEPAT
• Status: Terminated
• Phase: Phase 1
• Start date: January 14, 2020
• Est. completion date: July 14, 2021

Study information

• Verified date: January 2022
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: July 14, 2021
• Est. primary completion date: July 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Cancers
• Liver Diseases
• Neoplasms

Intervention

Drug:
• lorlatinib
continued daily administration of 100 mg lorlatinib
• lorlatinib
continued daily administration of lorlatinib at the dose level same as Group C for the first 22 days and 100 mg QD afterwards
• lorlatinib
continued daily administration of 100 mg QD lorlatinib
• 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
• 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

Locations

Country	Name	City	State
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	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	University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP)	Aurora	Colorado
United States	Mays Cancer Center	San Antonio	Texas
United States	University Health System	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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