Clinical Trials /

Hepatic Impairment Study for Lorlatinib in Cancer Patients

NCT03726333

Description:

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.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: B7461009
  • SECONDARY ID: lorlatinib HEPATIC IMPAIRMENT
  • SECONDARY ID: HEPATIC IMPAIRMENT
  • NCT ID: NCT03726333

Conditions

  • Advanced Cancers

Interventions

DrugSynonymsArms
lorlatinibGroup A1 Normal hepatic function
lorlatinibGroup A2 Normal hepatic function
lorlatinibGroup B mild hepatic impairment
lorlatinibGroup C moderate hepatic impairment
lorlatinibGroup D severe hepatic impairment

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Group A1 Normal hepatic functionActive Comparatorcontinued daily administration of lorlatinib in patients with normal hepatic function
  • lorlatinib
Group A2 Normal hepatic functionActive Comparatorcontinued daily administration of lorlatinib in patients with normal hepatic function
  • lorlatinib
Group B mild hepatic impairmentExperimentalcontinued daily administration of lorlatinib in patients with mild hepatic imapirment
  • lorlatinib
Group C moderate hepatic impairmentExperimentalcontinued daily administration of lorlatinib in patients with moderate hepatic impairment
  • lorlatinib
Group D severe hepatic impairmentExperimentalcontinued daily administration of lorlatinib in patients with severe hepatic impairment
  • lorlatinib

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Plasma lorlatinib AUC24 at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:area under plasma concentration-time curve from time 0 to dosing interval of 24 hours (AUC24) at steady state on cycle 2 day 1

Secondary Outcome Measures

Measure:Plasma lorlatinib AUClast after single dose
Time Frame:cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description: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.
Measure:Plasma lorlatinib Tlast after single dose
Time Frame:cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
Measure:Plasma lorlatinib Tmax after single dose
Time Frame:cycle 1 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:the time to Cmax after single dose on cycle 1 day 1.
Measure:Plasma lorlatinib Cmin at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:observed minimal plasma concentration at steady state on cycle 2 day 1.
Measure:Plasma lorlatinib AUClast at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description: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.
Measure:Plasma lorlatinib Tlast at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
Measure:lorlatinib CL/F at steadys state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:lorlatinib apparent clearance at steady state on cycle 2 day 1
Measure: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)
Safety Issue:
Description:area under plasma concentration-time curve from time 0 to dosing interval of 24 hours (AUC24) at steady state on cycle 2 day 1
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:observed maximal plasma concentration at steady state on cycle 2 day 1.
Measure: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)
Safety Issue:
Description:observed maximal plasma concentration after single dose on cycle 1 day 1.
Measure: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)
Safety Issue:
Description:the time to Cmax after single dose on cycle 1 day 1.
Measure: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)
Safety Issue:
Description:the time to Cmax at steady state on cycle 2 day 1.
Measure: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)
Safety Issue:
Description:the time of the last quantifiable concentration (Tlast) after single dose on cycle 1 day 1.
Measure: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)
Safety Issue:
Description:the time of the last quantifiable concentration (Tlast) at steady state on cycle 2 day 1.
Measure:MRAUC24 at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:metabolite ratio of lorlatinib metabolite for AUC24 at steady state on cycle 2 day 1
Measure:MRAUClast at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:metabolite ratio of lorlatinib metabolite for AUClast at steady state on cycle 2 day 1
Measure:MRCmax at steady state
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:metabolite ratio of lorlatinib metabolite for Cmax at steady state on cycle 2 day 1
Measure:MRAUClast after single dose
Time Frame:cycle 2 day 1 up to 24 hours post lorlatinib dose (each cycle is 21 days)
Safety Issue:
Description:metabolite ratio of lorlatinib metabolite for AUClast after single dose on cycle 1 day 1
Measure:number of patients experienced treatment emergent adverse event assessed by investigator
Time Frame:until at least 28 days after the last lorlatinib dose
Safety Issue:
Description:Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities
Measure:ORR
Time Frame:baseline up to approximately 1 year
Safety Issue:
Description: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
Measure:DR
Time Frame:baseline up to approximately 1 year
Safety Issue:
Description: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
Measure:number of patients experienced treatment related adverse event assessed by investigator
Time Frame:until at least 28 days after the last lorlatinib dose
Safety Issue:
Description:Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities
Measure:number of patients experienced treatment emergent serious adverse event assessed by investigator
Time Frame:until at least 28 days after the last lorlatinib dose
Safety Issue:
Description:Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • hepatic impairment
  • lorlatinib
  • cancer
  • pharmacokinetic

Last Updated

December 16, 2019