Hepatic Impairment Study for Lorlatinib in Cancer Patients

• ClinicalTrials.gov Identifier: NCT03726333
• Recruitment Status: Recruiting
• First Posted: October 31, 2018
• Last Update Posted: November 11, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

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.

Condition or disease	Intervention/treatment	Phase
Advanced Cancers	Drug: lorlatinib	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 76 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
• Estimated Study Start Date: December 31, 2019
• Estimated Primary Completion Date: August 16, 2022
• Estimated Study Completion Date: January 25, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Group A1 Normal hepatic function; continued daily administration of lorlatinib in patients with normal hepatic function	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	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	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	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

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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

Secondary Outcome Measures :

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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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
8. 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
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

Locations

United States, California

Keck Hospital of USC - Norris Healthcare Center (HC3); Not yet recruiting

Los Angeles, California, United States, 90033

Keck Hospital of USC; Not yet recruiting

Los Angeles, California, United States, 90033

LAC+USC Medical Center; Not yet recruiting

Los Angeles, California, United States, 90033

USC/Norris Comprehensive Cancer Center; Not yet recruiting

Los Angeles, California, United States, 90033

Hoag Memorial Hospital Presbyterian; Not yet recruiting

Newport Beach, California, United States, 92663

United States, Colorado

University of Colorado Denver CTO (CTRC); Recruiting

Aurora, Colorado, United States, 80045

University of Colorado Hospital, Anschutz Cancer Pavilion (ACP); Recruiting

Aurora, Colorado, United States, 80045

University of Colorado Hospital, Anschutz Inpatient Pavilion (AIP); Recruiting

Aurora, Colorado, United States, 80045

University of Colorado Hospital, Anschutz Outpatient Pavilion (AOP); Recruiting

Aurora, Colorado, United States, 80045

United States, Georgia

Emory University Hospital; Recruiting

Atlanta, Georgia, United States, 30322

The Emory Clinic; Recruiting

Atlanta, Georgia, United States, 30322

Winship Cancer Institute, Emory University; Recruiting

Atlanta, Georgia, United States, 30322

United States, New York

SUNY Upstate Medical University; Not yet recruiting

Syracuse, New York, United States, 13210

United States, Texas

Mays Cancer Center; Not yet recruiting

San Antonio, Texas, United States, 78229

University Health System; Not yet recruiting

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03726333 History of Changes
• 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
• Last Update Posted: November 11, 2019
• Last Verified: November 2019

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

Keywords provided by Pfizer:

hepatic impairment; lorlatinib; cancer; pharmacokinetic

Additional relevant MeSH terms:

Liver Diseases; Neoplasms; Digestive System Diseases