Clinical trial NCT03726333: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Cancers
Keywords: hepatic impairment
lorlatinib
cancer
pharmacokinetic
Lung cancer
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2018-10-31
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

Brief summary: 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.

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.

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

Primary outcomes:
measure: 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
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Observed Maximal Plasma Concentration (Cmax) at Steady State on Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Secondary outcomes:
measure: Number Of Patients Experienced Treatment Emergent Adverse Event Assessed by Investigator
timeFrame: 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.
measure: Objective Response Rate (ORR)
timeFrame: Baseline up to approximately 1 year
measure: Duration of Response (DR)
timeFrame: Baseline up to approximately 1 year
measure: 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
timeFrame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: The Time of The Last Quantifiable Concentration (Tlast) of Lorlatinib After Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: The Time to Cmax (Tmax) of Lorlatinib After Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Observed Minimal Plasma Concentration (Cmin) at Steady State On Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib AUClast at Steady State On Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Tlast at Steady State On Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Apparent Clearance (CL/F) at Steady State On Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite AUC24 at Steady State
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite AUClast After Single Dose
timeFrame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite AUClast at Steady State
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite Cmax After Single Dose
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite Cmax at Steady State
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite Tlast After Single Dose
timeFrame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Plasma Lorlatinib Metabolite Tlast at Steady State
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Metabolite Ratio of Lorlatinib Metabolite for AUC24 (MRAUC24) at Steady State on Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Metabolite Ratio of Lorlatinib Metabolite for Cmax (MRCmax) at Steady State on Cycle 2 Day 1
timeFrame: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
measure: Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 1 Day 1
timeFrame: Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver CTO (CTRC)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital, Anschutz Cancer Pavilion (ACP)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital, Anschutz Inpatient Pavilion (AIP)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP)
state: Colorado
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Atlanta
country: United States
facility: Investigational Drug Service
state: Georgia
city: Atlanta
country: United States
facility: The Emory Clinic
state: Georgia
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: San Antonio
country: United States
facility: Mays Cancer Center
state: Texas
city: San Antonio
country: United States
facility: University Health System
state: Texas
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: