Hepatic Impairment Study for Lorlatinib in Cancer Patients
- Registration Number
- NCT03726333
- Lead Sponsor
- Pfizer
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group B mild hepatic impairment lorlatinib continued daily administration of lorlatinib in patients with mild hepatic impairment Group A1 Normal hepatic function lorlatinib continued daily administration of lorlatinib in patients with normal hepatic function Group A2 Normal hepatic function lorlatinib continued daily administration of lorlatinib in patients with normal hepatic function Group D severe hepatic impairment lorlatinib continued daily administration of lorlatinib in patients with severe hepatic impairment Group C moderate hepatic impairment lorlatinib continued daily administration of lorlatinib in patients with moderate hepatic impairment
- Primary Outcome Measures
Name Time Method 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 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. AUC24 was defined as area under the plasma concentration time profile during 1 dosing interval (24 hours).
Observed Maximal Plasma Concentration (Cmax) at Steady State on Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Cmax was defined as maximum plasma concentration and was observed directly from data.
- Secondary Outcome Measures
Name Time Method Duration of Response (DR) Baseline up to approximately 1 year DR was measured from the date that an objective tumor response (CR or PR) was first documented (whichever occurred first) to date of objective tumor progression or death due to any cause, whichever occurred first.
The Time to Cmax (Tmax) of Lorlatinib After Single Dose on Cycle 1 Day 1 Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Tmax was defined as time for Cmax.
Observed Minimal Plasma Concentration (Cmin) at Steady State On Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Cmin was defined as minimum plasma concentration and was observed directly from data.
Number Of Patients Experienced Treatment Emergent Adverse Event Assessed by Investigator 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. An Adverse event (AE) was any untoward medical occurrence in a participant. A serious AE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect or that was considered to be an important medical event. AEs were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. The grades were defined as follows: Grade 0: no change from normal or reference range; Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. The focus of AE summaries was on treatment-emergent AE (TEAE). An AE was considered TEAE if the event occurred during the on-treatment period.
Objective Response Rate (ORR) Baseline up to approximately 1 year ORR was defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 relative to the response-evaluable population.
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 Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. AUClast was defined as area under the plasma concentration time profile from time 0 to the time of the last quantifiable concentration (Clast)
Plasma Lorlatinib Tlast at Steady State On Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Tlast was defined as the time of the last quantifiable concentration.
Apparent Clearance (CL/F) at Steady State On Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as Dose/AUC24 at steady-state.
The Time of The Last Quantifiable Concentration (Tlast) of Lorlatinib After Single Dose on Cycle 1 Day 1 Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Tlast was defined as the time of the last quantifiable concentration.
Plasma Lorlatinib AUClast at Steady State On Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. AUClast was defined as area under the plasma concentration time profile from time 0 to the time of Clast.
Plasma Lorlatinib Metabolite AUC24 at Steady State Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. AUC24 was defined as area under the plasma concentration time profile during one dosing interval (24 hours).
Plasma Lorlatinib Metabolite Cmax After Single Dose Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Cmax was defined as maximum plasma concentration and was observed directly from data.
Metabolite Ratio of Lorlatinib Metabolite for Cmax (MRCmax) at Steady State on Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. MRCmax was defined as metabolite ratio of lorlatinib metabolite for AUClast.
Plasma Lorlatinib Metabolite AUClast After Single Dose Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. AUClast was defined as area under the plasma concentration time profile from time 0 to the time of Clast.
Plasma Lorlatinib Metabolite AUClast at Steady State Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. AUClast was defined as area under the plasma concentration time profile from time 0 to the time of Clast.
Plasma Lorlatinib Metabolite Cmax at Steady State Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Cmax was defined as maximum plasma concentration and was observed directly from data.
Plasma Lorlatinib Metabolite Tlast After Single Dose Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Tlast was defined as the time of the last quantifiable concentration.
Plasma Lorlatinib Metabolite Tlast at Steady State Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. Tlast was defined as the time of the last quantifiable concentration.
Metabolite Ratio of Lorlatinib Metabolite for AUC24 (MRAUC24) at Steady State on Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. MRAUC24 was defined as metabolite ratio of lorlatinib metabolite for AUC24.
Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 1 Day 1 Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. MRAUClast was defined as metabolite ratio of lorlatinib metabolite for AUClast.
Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 2 Day 1 Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose. MRAUClast was defined as metabolite ratio of lorlatinib metabolite for AUClast.
Trial Locations
- Locations (10)
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
Investigational Drug Service
🇺🇸Atlanta, Georgia, United States
The Emory Clinic
🇺🇸Atlanta, Georgia, United States
Winship Cancer Institute, Emory University
🇺🇸Atlanta, Georgia, United States
Mays Cancer Center
🇺🇸San Antonio, Texas, United States
University Health System
🇺🇸San Antonio, Texas, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States