Study of Lorlatinib In People With ALK-positive Non-small Cell Lung Cancer

Phase 4CompletedNCT04362072

Pfizer71 enrolled

Overview

The purpose of this clinical trial is to learn whether the study medicine (called lorlatinib) is safe and effective for the treatment of non-small cell lung cancer that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene. This study is seeking participants whose lung cancer has progressed after receiving either alectinib or ceritinib as their first treatment. Participants will take part in this study for up to approximately 4 years, depending on when the study is completed and how their cancer responds to the study treatment. They will take lorlatinib orally (by mouth) once daily. Participants will visit the study site about every six weeks to meet with the study team. During these visits, the study team will monitor the safety and effects of lorlatinib.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Carcinoma Non-Small-Cell Lung

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants must have evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, American Joint Committee on Cancer \[AJCC\] v7.0) that carries an ALK rearrangement. * Disease Status Requirements: disease progression after alectinib or ceritinib as first line therapy (the study will limit enrollment of participants with best response of progression or indeterminate on prior alectinib to 8 participants). Participants may have had prior chemotherapy, but only if before starting treatment with alectinib or ceritinib. * Tumor Requirements: All Participants must have at least one measurable target extracranial lesion according to RECIST v1.1. Participants with asymptomatic CNS metastases (including participants controlled with stable or decreasing steroid use within the last 2 weeks prior to study entry) will be eligible. Participants who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) will be eligible if the LM/CM is visualized on magnetic resonance imaging (MRI) or if documented baseline cerebral spinal fluid (CSF) positive cytology is available. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. * Adequate bone marrow functioning, pancreatic function, renal function and liver function * Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade ≤1 except for adverse events (AEs) that in the investigator' judgment do not constitute a safety risk for the participant. * Systemic anti-cancer therapy with alectinib or ceritinib discontinued within a minimum of 5 half-lives prior to first dose of lorlatinib on the study (unless clinically meaningful tumor flare per discretion of the investigator, in which discussion with the sponsor is warranted). * Male participants are eligible to participate if they agree to use proper contraception during the intervention period and for at least 98 days after the last dose of study intervention * Female participants are eligible to participate if they are not pregnant or breastfeeding, and agree to use proper contraception during the intervention period and for at least 35 days after the last dose of study intervention. * Capable of giving signed informed consent and willingness and ability to comply with the study scheduled visits and other procedures. Exclusion criteria: * Prior ALK TKI treatment or anti-cancer treatment other than first line alectinib or ceritinib. * Spinal cord compression unless the participant has good pain control attained through therapy, and there is stabilization or recovery of neurological function for the 4 weeks prior to randomization. * 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. * Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness. * Clinically significant vascular (both arterial and venous) and non-vascular cardiac conditions, (active or within 3 months prior to enrollment) * Participants presenting with abnormal Left Ventricular Ejection Fraction (LVEF) by echocardiogram or Multi-Gated Acquisition Scan according to institutional lower limits. * Participants with predisposing characteristics for acute pancreatitis according to investigator judgment * History or known presence of interstitial fibrosis, interstitial lung disease, pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. * 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, would make the participant inappropriate for entry into this study. * Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ (DCIS) of the breast or localized and presumed cured prostate cancer) within the last 3 years prior to randomization. * Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry. * Prior irradiation to \>25% of the bone marrow. * Concurrent use of any of the following food or drugs within 12 days prior to the first dose of lorlatinib: known strong CYP3A inducers, known strong CYP3A inhibitors, known CYP3A substrates with narrow therapeutic index, known permeability glycoprotein (P-gp) substrates with a narrow therapeutic index * Major surgery within 4 weeks prior to enrollment. * Known prior or suspected severe hypersensitivity to study interventions or any component in their formulations. * Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study.

Locations (31)

UCI Medical Center/Chao Family Comprehensive Cancer Center

Orange, California, United States

Rajiv Gandhi Cancer Institute And Research Centre

New Delhi, DEL, India

Healthcare Global Enterprises

Bengaluru, Karnataka, India

Bhakti Vedanta Hospital and Research Institute

Thane, Maharashtra, India

Rajiv Gandhi Cancer Institute And Research Centre

New Delhi, National Capital Territory of Delhi, India

Outcomes

Primary Outcomes

Percentage of Participants With Confirmed Overall Objective Response (OR) as Per Independent Central Review (ICR) as Assessed by RECIST v1.1

Confirmed OR based on ICR assessment was defined as complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumor (RECIST) version(v)1.1 from date of first dose until documented progressive disease (PD) or start of new anti-cancer therapy without regard to discontinuation from treatment. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after criteria for response are first met. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions.

Time frame: From date of first dose until documented PD or start of new anti-cancer therapy, whichever occurred earlier (maximum treatment exposure up to 42.78 months)

Secondary Outcomes

Percentage of Participants With Confirmed OR as Per Investigator (INV) as Assessed by RECIST v 1.1

Confirmed OR based on derived investigator assessment was defined as CR or PR according to RECIST v1.1 from date of first dose until PD or start of new anti-cancer therapy without regard to discontinuation from treatment. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after criteria for response are first met. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions.

Time frame: From date of first dose until documented PD or start of new anti-cancer therapy, whichever occurred earlier (maximum treatment exposure up to 42.78 months)

Percentage of Participants With Confirmed Intracranial (IC) Objective Response (IC-OR) as Per ICR as Assessed by RECIST v 1.1

IC-OR based on ICR assessment was defined as IC-CR or PR according to RECIST v1.1 from date of first dose until documented IC-PD or start of new anti-cancer therapy without regard to discontinuation from treatment. Both IC-CR and IC-PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions.

Time frame: From date of first dose until documented PD or start of new anti-cancer therapy, whichever occurred earlier (maximum treatment exposure up to 42.78 months)

Percentage of Participants With Confirmed IC-OR as Per INV as Assessed by RECIST v 1.1

IC-OR based on derived investigator assessment was defined as IC-CR or PR according to RECIST v1.1 from date of first dose until documented IC-PD or start of new anti-cancer therapy without regard to discontinuation from treatment. Both IC-CR and IC-PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions.

Time frame: From date of first dose until documented PD or start of new anti-cancer therapy, whichever occurred earlier (maximum treatment exposure up to 42.78 months)

Time to Response (TTR) as Per ICR as Assessed by RECIST v 1.1

TTR based on ICR assessments was defined, for participants with a confirmed OR, as the time from the date of first dose to the first documentation of OR (CR or PR) which was subsequently confirmed. For participants whose OR proceeded from PR to CR, the onset of PR was taken as the onset of response. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters.

Time frame: From date of first dose until first documented objective response, CR or PR (maximum treatment exposure up to 42.78 months)

TTR as Per INV as Assessed by RECIST v 1.1

TTR based on derived investigator assessments was defined, for participants with a confirmed objective response, as the time from the date of first dose to the first documentation of objective response (CR or PR) which is subsequently confirmed. For participants whose OR proceeds from PR to CR, the onset of PR is taken as the onset of response. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters.

Time frame: From date of first dose until first documented objective response, CR or PR (maximum treatment exposure up to 42.78 months)

Duration of Response (DOR) as Per ICR as Assessed by RECIST v 1.1

DOR: for participants with confirmed OR per ICR, as time from first documentation of OR (CR/PR whichever was earlier) to date of first documentation of PD/death due to any cause, whichever occurred first. CR:disappearance of all target and non-target lesions. PR:at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD:at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study. Addition to relative increase of 20%, sum must also demonstrate absolute increase of at least 5mm. Appearance of one/ more new lesions: sign of progression. For non-target PD:unequivocal progression of existing non-target lesions. Participants who completed/discontinued study without PD/death, as well as who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date/last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis:Kaplan-Meier method.

Time frame: From first documented OR (CR or PR) to date of first documented PD or death due to any cause or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

DOR as Per INV as Assessed by RECIST v 1.1

DOR: for participants with confirmed OR per investigator,as time from first documentation of OR(CR/PR whichever was earlier) to date of first documentation of PD/death due to any cause, whichever occurred first. CR:disappearance of all target and non-target lesions. PR:at least 30% decrease in sum of diameters of target,taking as reference baseline sum diameters. PD:at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study. Addition to relative increase of 20%,sum must also demonstrate absolute increase of at least 5mm. Appearance of one/more new lesions:sign of progression. For non-target PD:unequivocal progression of existing non-target lesions. Participants who completed/discontinued study without PD/death,as well as who received alternate anti-cancer therapy prior to PD,were censored at their last adequate response assessment date/last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis:Kaplan-Meier method.

Time frame: From first documented OR (CR or PR) to date of first documented PD or death due to any cause or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

Duration of Intracranial Response (IC-DoR) as Per ICR as Assessed by RECIST v 1.1

IC-DoR: for participants with confirmed objective intra-cranial response per ICR, as time from first documentation of objective intra-cranial response (CR/PR whichever is earlier) to date of first documentation of PD in brain or death due to any cause, whichever occurs first. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. Appearance of one/more new lesions:sign of progression. For non-target PD: unequivocal progression of existing non-target lesions. Participants who completed or discontinued study without PD or death, as well as participants who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date or last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis: Kaplan-Meier method.

Time frame: From first documented IC-OR (CR or PR) to date of first documented PD or death due to any cause or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

IC-DoR as Per INV as Assessed by RECIST v 1.1

IC-DoR: for participants with confirmed objective intra-cranial response, per investigator as time from first documentation of objective intra-cranial response (CR or PR whichever is earlier) to date of first documentation of PD in brain or death due to any cause, whichever occurs first. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. Appearance of one/more new lesions: sign of progression. For non-target PD: unequivocal progression of existing non-target lesions. Participants who completed or discontinued study without PD or death, as well as who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date or last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis: Kaplan-Meier method.

Time frame: From first documented IC-OR (CR or PR) to date of first documented PD or death due to any cause or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

Time to Tumor Progression (TTP) as Per ICR as Assessed by RECIST v 1.1

TTP according to RECIST v1.1 as time from date of first dose to the date of the first documentation of PD per IRC. PD was defined as at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions. Participants who completed or discontinued study without PD or death, as well as participants who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date or last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis was performed using Kaplan-Meier method.

Time frame: From date of first dose until first documented PD or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

TTP as Per INV as Assessed by RECIST v 1.1

TTP according to RECIST v1.1 as time from date of first dose to the date of the first documentation of PD per investigator. PD was defined as at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions. Participants who completed or discontinued study without PD or death, as well as participants who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date or last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis was performed using Kaplan-Meier method.

Time frame: From date of first dose until first documented PD or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

Progression-Free Survival (PFS) as Per ICR as Assessed by RECIST v 1.1

PFS according to RECIST v1.1 was defined as the time from date of first dose to the date of the first documentation of PD per ICR or death due to any cause, whichever occurred first. PD was defined as at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions. Participants who completed or discontinued study without PD or death, as well as participants who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date or last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis was performed using Kaplan-Meier method.

Time frame: From date of first dose until first documented PD or death or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

PFS as Per INV as Assessed by RECIST v 1.1

PFS according to RECIST v1.1 was defined as the time from date of first dose to the date of the first documentation of PD per investigator or death due to any cause, whichever occurred first. PD was defined as at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered sign of progression. For non-target PD: unequivocal progression of existing non-target lesions. Participants who completed or discontinued study without PD or death, as well as participants who received alternate anti-cancer therapy prior to PD, were censored at their last adequate response assessment date or last adequate assessment prior to start date of alternate anti-cancer therapy. Analysis was performed using Kaplan-Meier method.

Time frame: From date of first dose until first documented PD or death or censoring date, whichever occurred first (maximum treatment exposure up to 42.78 months)

Time to Intra-Cranial Response (IC-TTR) as Per ICR as Assessed by RECIST v 1.1

IC-TTR: for participants with a confirmed IC-OR per ICR, was defined as the time from the date of first dose to the first documentation of objective intra-cranial response (CR or PR) which is subsequently confirmed. For participants whose IC-OR proceeds from PR to CR, the onset of PR was taken as the onset of response. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters.

Time frame: From date of first dose to the first documented objective intra-cranial response (CR or PR) (maximum treatment exposure up to 42.78 months)

IC-TTR as Per INV as Assessed by RECIST v 1.1

IC-TTR: for participants with a confirmed IC-OR per investigator, was defined as the time from the date of first dose to the first documentation of objective intra-cranial response (CR or PR) which is subsequently confirmed. For participants whose IC-OR proceeds from PR to CR, the onset of PR was taken as the onset of response. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of diameters of target, taking as reference baseline sum diameters.

Time frame: From date of first dose to the first documented objective intra-cranial response (CR or PR) (maximum treatment exposure up to 42.78 months)

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in participant or clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. A TEAE was defined as any event that occurs for first time during on-treatment period or AEs that were observed prior to start of study treatment but increased in severity during on-treatment period (defined as time from first dose of study treatment through end of safety follow-up period, ie at least 28 days, and no more than 35 days after discontinuation of treatment, or start of new anti-cancer therapies \[follow up systemic therapy, follow up radiation therapy or follow-up surgery\], whichever occurs first). Adverse events occurring on same day as first dose of study treatment were also considered to have occurred during the on-treatment period.

Time frame: From first dose of the study treatment (Day 1) maximum up to 28-35 days after last dose of study drug or the new anti-cancer therapy date, whichever is earlier (maximum treatment exposure up to 43.78 months)

Number of Participants With Treatment-Related TEAEs

An AE was any untoward medical occurrence in participant or clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. A TEAE was defined as any event that occurs for first time during on-treatment period or AEs that were observed prior to start of study treatment but increased in severity during on-treatment period (defined as time from first dose of study treatment through end of safety follow-up period, ie at least 28 days, and no more than 35 days after discontinuation of treatment, or start of new anti-cancer therapies \[follow up systemic therapy, follow up radiation therapy or follow-up surgery\], whichever occurs first). Adverse events occurring on same day as first dose of study treatment were also considered to have occurred during the on-treatment period. An AE was considered treatment related if investigator considered event related to study drugs or the information was unknown.

Number of Participants With Maximum Grade 3 or 4 TEAEs by National Cancer Institute Common Terminology Criteria for AEs [NCI CTCAE] v.4.03

An AE was any untoward medical occurrence in participant or clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. A TEAE was defined as any event that occurs for first time during on-treatment period or AEs that were observed prior to start of study treatment but increased in severity during on-treatment period (defined as time from first dose of study treatment through end of safety follow-up period, ie at least 28 days, and no more than 35 days after discontinuation of treatment, or start of new anti-cancer therapies, whichever occurs first). Adverse events occurring on same day as first dose of study treatment were also considered to have occurred during the on-treatment period. TEAEs were graded according to NCI CTCAE v4.03 as grade 3= severe AE and grade 4= life threatening consequences; urgent intervention indicated.

Number of Participants With Maximum Grade 3 or 4 Treatment-Related AEs

An AE was any untoward medical occurrence in participant or clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. An AE was considered treatment related if investigator considered event related to study drugs or the information was unknown. TEAEs were graded according to CTCAE v4.03 as grade 3= severe AE and grade 4= life threatening consequences.

Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs)

A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions) or resulted in congenital anomaly/birth defect or was considered an important medical event. TESAEs were defined as any event that occurs for first time during on-treatment period or SAEs that were observed prior to start of study treatment but increased in severity during on-treatment period (defined as time from first dose of study treatment through end of safety follow-up period, ie at least 28 days, and no more than 35 days after discontinuation of treatment, or start of new anti-cancer therapies, whichever occurs first).

Number of Participants With Treatment-Related TESAEs

SAE was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions) or resulted in congenital anomaly/birth defect or was considered an important medical event. TESAEs were defined as any event that occurs for first time during on-treatment period or SAEs that were observed prior to start of study treatment but increased in severity during on-treatment period (defined as time from first dose of study treatment through end of safety follow-up period, ie at least 28 days, and no more than 35 days after discontinuation of treatment/ start of new anti-cancer therapies, whichever occurs first). SAE was considered treatment related if investigator considered event related to study drugs or information was unknown.