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A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China

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ClinicalTrials.gov Identifier: NCT03909971
Recruitment Status : Recruiting
First Posted : April 10, 2019
Last Update Posted : February 18, 2021
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE February 5, 2019
First Posted Date  ICMJE April 10, 2019
Last Update Posted Date February 18, 2021
Actual Study Start Date  ICMJE April 28, 2019
Actual Primary Completion Date August 10, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
Objective Response (OR) in Cohort 1 on independent central radiology (ICR) [ Time Frame: From time of Study Start up to 33 months ]
Cohort 1: Disease progression after crizotinib as the only ALK inhibitor. OR is defined as a complete response (CR) or partial response (PR) recorded from enrollment until disease progression or start of new anti cancer therapy.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
  • Objective Response (OR) in Cohort 2 on independent central radiology (ICR) [ Time Frame: From time of Study Start up to 33 months ]
    Cohort 2: Disease progression after one ALK inhibitor other than crizotinib. OR is defined as a complete response (CR) or partial response (PR) recorded from enrollment until disease progression or start of new anti cancer therapy
  • Progression free survival (PFS) as assessed by RECIST v1.1 per ICR assessment and investigator assessment in both Cohorts. [ Time Frame: From time of Study Start up to 33 months ]
    PFS is defined as the time from randomization to the date of the first documentation of objective progression of disease or death due to any cause, whichever occurs first.
  • Overall survival (OS) as assessed by RECIST v1.1 per ICR assessment and investigator assessment and in both Cohorts. [ Time Frame: From time of Study Start up to 125 months ]
    OS is defined as time from date of randomization to date of death due to any cause
  • Intracranial objective response (IC OR) as assessed by RECIST v1.1 per ICR assessment and investigator assessment in both Cohorts. [ Time Frame: From time of Study Start up to 33 months ]
    IC-OR defined as complete response (CR) or partial response (PR) based on intracranial disease in the subset of patients with at least 1 intracranial lesion per RECIST version 1.1 (modified) recorded from randomization until disease progression or start of new anti-cancer therapy
  • Duration of response (DoR) as assessed by RECIST v1.1 per ICR assessment and investigator assessment in both Cohorts. [ Time Frame: From time of Study Start up to 33 months ]
    DoR is defined as the time from the first documentation of CR or PR to the first documentation of disease progression or death due to any cause, whichever occurs first.
  • Duration of intracranial response (IC DoR) as assessed by RECIST v1.1 per ICR assessment and investigator assessment in both Cohorts. [ Time Frame: From time of Study Start up to 33 months ]
    DoR is defined as the time from the first documentation of CR or PR to the first documentation of disease progression or death due to any cause, whichever occurs first. IC-DoR is limited to Intra Cranial lesions only on subjects with CNS metastases.
  • • Time to tumor response (TTR) as assessed by RECIST v1.1 per ICR assessment and investigator assessment in both Cohorts. [ Time Frame: From time of Study Start up to 33 months ]
    TTR is defined as the time from first dose to first documentation of objective tumor response (CR or PR). TTR will only be summarized for the subgroup of subjects with an objective response.
  • Adverse Event (AE) as graded by NCI CTCAE v 4.03) [ Time Frame: From time of Study Start up to 33 months ]
    Frequency of patients experiencing treatment-emergent AEs (TEAEs)
  • Laboratory abnormalities as graded by NCI CTCAE v 4.03) [ Time Frame: From time of Study Start up to 33 months ]
    Frequency of patients with laboratory test abnormalities
  • Vital signs (blood pressure) [ Time Frame: From time of Study Start up to 33 months ]
    Summary of actual values and changes from baseline
  • 12-Lead Electrocardiograms (ECG) (P Wave, QRS Complex, QTc Interval, etc)) [ Time Frame: From time of Study Start up to 33 months ]
    Summary of actual values and changes from baseline
  • Echocardiograms or multigated acquisition scan (MUGA) [ Time Frame: From time of Study Start up to 33 months ]
    Summary of actual values and changes from baseline
  • Pharmacokinetics (Cmax) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Vital signs (pulse rate) [ Time Frame: From time of Study Start up to 33 months ]
    Summary of actual values and changes from baseline
  • Body weight [ Time Frame: From time of Study Start up to 33 months ]
    Summary of actual values and changes from baseline
  • Pharmacokinetics (Tmax) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (AUCt) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (AUCtau) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (AUCinf) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (CL/F) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (Vz/F) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (t1/2) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
  • Pharmacokinetics (Rac) [ Time Frame: From time of Study Start up to 33 months ]
    To evaluate the pharmacokinetics (PK) of lorlatinib and potential pharmacokinetic/pharmacodynamics (PK/PD) relationship for lorlatinib
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China
Official Title  ICMJE A PHASE 2, MULTI-CENTER, OPEN-LABEL, DUAL-COHORT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LORLATINIB (PF-06463922) MONOTHERAPY IN ALK INHIBITOR-TREATED LOCALLY ADVANCED OR METASTATIC ALK-POSITIVE NON-SMALL CELL LUNG CANCER PATIENTS IN CHINA
Brief Summary A Phase 2, multi center, open label, dual cohort study to evaluate the efficacy and safety of lorlatinib (PF 06463922) monotherapy in ALK inhibitor treated locally advanced or metastatic ALK positive non small cell lung cancer patients in China
Detailed Description

This is a Phase 2, China only, multi center, open label, dual cohort study, in ALK positive locally advanced or metastatic NSCLC patients will be enrolled to receive lorlatinib monotherapy.

  • (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor.
  • (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Non-Small-Cell Lung
Intervention  ICMJE Drug: Lorlatinib
ALK inhibitor-treated ALK-positive NSCL treatment
Other Name: PF-06463922
Study Arms  ICMJE Experimental: Lorlatinib
Lorlatinib single agent, 100 mg (4 x 25 mg) oral tables, QD, continuously
Intervention: Drug: Lorlatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 10, 2022
Actual Primary Completion Date August 10, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK positive NSCLC where ALK status has been previously established by the Ventana ALK (D5F3) CDx Assay (Roche Diagnostics), the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), or the EML4 ALK Fusion Gene Detection Kit (AmoyDx).
  2. Subject should have:

    1. (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor;
    2. (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib, with or without prior crizotinib.
  3. Prior treatment with an ALK inhibitor must have completed 5 half lives prior to study entry.
  4. All Subjects must have at least 1 measurable extracranial target lesion according to RECIST v1.1 that has not been previously irradiated. CNS metastases are allowed if:

    1. Asymptomatic: either not currently requiring corticosteroid treatment, or on a stable or decreasing dose of 10 mg QD prednisone or equivalent; or
    2. Previously diagnosed and treatment has been completed with full recovery from the acute effects of radiation therapy or surgery prior to enrollment, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability.
  5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2.
  6. Age 18 years (or 20 years as required by local regulation).
  7. Adequate bone marrow functions:

    1. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
    2. Platelets 100,000/mm3 or 100 x 109/L;
    3. Hemoglobin 9 g/dL.
  8. Adequate pancreatic function:

    1. Serum total amylase 1.5 x upper limit of normal (ULN);*
    2. Serum lipase 1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then subject may be enrolled.
  9. Adequate renal function:

    a. Serum creatinine 1.5 x ULN or estimated creatinine clearance 60 mL/min as calculated using the method standard for the institution.

  10. Adequate liver function:

    1. Total serum bilirubin 1.5 x ULN;
    2. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 2.5 x ULN (5.0 x ULN in case of liver metastases).
  11. Acute effects of prior radiotherapy and chemotherapy resolved to baseline severity or to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 except for AEs that in the investigator's judgment do not constitute a safety risk for the subject.
  12. Serum or urine pregnancy test (for females of childbearing potential) negative at screening. Female subjects of non childbearing potential must meet at least 1 of the following criteria:

    1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (which may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state if appropriate;
    2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    3. Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
  13. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
  14. Willing and able to comply with the study scheduled visits, treatment plans, laboratory tests, and other procedures.

Exclusion Criteria:

Subjects with any of the following characteristics/conditions will not be included in the study:

  1. More than 1 prior chemotherapy regimen prior to enrollment in advanced/metastatic setting.

    If disease recurred/relapsed within the adjuvant chemotherapy treatment or <=6 months after the completion of the adjuvant chemotherapy, then the adjuvant chemotherapy is considered as the first line systemic chemotherapy to the disease.

  2. Systemic anti cancer therapy completed within a minimum of 5 half lives of study enrollment.
  3. Prior therapy with an antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways, including, but not limited to, anti programmed cell death protein 1 (anti PD 1), anti programmed cell death protein ligand 1 (anti PD L1), anti PD L2, anti cluster of differentiation 137 (anti CD137), or anti cytotoxic T lymphocyte associated antigen 4 (anti CTLA 4) antibody.
  4. Known epidermal growth factor receptor (EGFR) activating mutations; known prior therapy with EGFR TKI(s) (the prior treatment with brigatinib is allowed as an ALK TKI).
  5. Major surgery within 4 weeks prior to enrollment. Minor surgical procedures (eg, port insertion) are not excluded, but sufficient time should have passed for adequate wound healing.
  6. Radiation therapy within 2 weeks prior to enrollment. Palliative radiation must have been completed at least 48 hours prior to enrollment. Stereotactic or partial brain irradiation must have completed at least 2 weeks prior to enrollment. Whole brain irradiation must have completed at least 4 weeks prior to enrollment.
  7. Spinal cord compression unless the subject has good pain control attained through therapy, and there is complete recovery of neurological function for the 4 weeks prior to enrollment.
  8. Gastrointestinal abnormalities, including inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection or lap band; active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease; treatment for active peptic ulcer disease in the past 6 months; malabsorption syndromes.
  9. Known prior or suspected severe hypersensitivity to lorlatinib or any component in the formulation; known prior therapy with lorlatinib.
  10. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
  11. Clinically significant cardiovascular disease (both arterial and venous) and non vascular cardiac conditions, (active or within 3 months prior to enrollment, which may include, but not are limited to:

    • Arterial disease such as cerebral vascular accident/stroke (including transient ischemic attack -TIA), myocardial infarction, unstable angina;
    • Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary embolism;
    • Nonvascular cardiac disease such as congestive heart failure (New York Heart Association Classification Class ≥ II), second degree or third degree atrioventricular block (unless paced) or any AV block with PR interval >220 msec; or
    • Ongoing cardiac dysrhythmias of CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless subject is otherwise healthy such as long distance runners, etc.), machine read electrocardiogram (ECG) with QTc >470 msec, or congenital long QT syndrome.
  12. Subject with predisposing characteristics for acute pancreatitis according to investigator judgment, including but not limited to uncontrolled hyperglycemia, current gallstone disease, in the last month prior to enrollment.
  13. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis.
  14. Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, or localized and presumed cured prostate cancer or any in situ cancer which does not currently require treatment) within the last 3 years prior to enrollment.
  15. Concurrent use of any of the following food or drugs (consult the sponsor if in doubt whether a food or a drug falls into any of the above categories) within 12 days prior to the first dose of administration of lorlatinib:

    1. Known strong CYP3A inhibitors (eg, strong CYP3A inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, ritonavir alone and with danoprevir or elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, telaprevir, troleandomycin, and voriconazole). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed;
    2. Known CYP3A substrates with narrow therapeutic index, such as astemizole*, terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine) (*withdrawn from US market);
    3. Known strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's Wort);
    4. Known P glycoprotein (P gp) substrates with a narrow therapeutic index (eg, digoxin).
  16. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator and/or the sponsor, would make the subject inappropriate for entry into this study.
  17. Subject who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
  18. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.
  19. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 97 days if male or 21 days if female, after the last dose of investigational product
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03909971
Other Study ID Numbers  ICMJE B7461024
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP