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

Study Overview
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Brief Summary
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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.

Official Title
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Single-Arm Study of Lorlatinib in Participants With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) Whose Disease Progressed After One Prior Second-Generation ALK Tyrosine Kinase Inhibitor (TKI)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Lorlatinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lorlatinib<br>Participants will take 100 mg (four, 25 mg tablets) once daily. | Drug: Lorlatinib<br>* 25 milligram (mg) tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Overall Objective Response (OR) based on independent central review (ICR) | OR (Objective Response) based on ICR assessment is defined as complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. | every 6 weeks up to approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Overall OR based on Investigator (INV) | OR based on INV assessment is defined as CR or PR according to RECIST v1.1. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. | every 6 weeks up to approximately 4 years | 
| Percentage of Patients With Intra-Cranial Objective Response (IC-OR) based on ICR/derived INV | IC-OR is defined as Intra-Cranial complete response (IC-CR) or partial response (IC-PR) according to RECIST v1.1. 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. | every 6 weeks up to approximately 4 years | 
| Time to Response (TTR) based on ICR/derived INV | TTR is defined, for participants with a confirmed OR, as the time from the date of first dose to the first documentation of objective response (CR or PR) which is subsequently confirmed. | every 6 weeks up to approximately 4 years | 
| Time to Intra-Cranial Response (IC-TTR) based on ICR/derived investigator | IC-TTR is defined, for participants with a confirmed intra-cranial objective response, 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. | every 6 weeks up to approximately 4 years | 
| Duration of Response (DoR) based on ICR/ derived investigator | DoR is defined, for participants with a confirmed objective response, as the time from first documentation of objective response (CR or PR whichever is earlier) to the date of first documentation of PD or death due to any cause, whichever occurs first | every 6 weeks up to approximately 4 years | 
| Duration of Intra-Cranial Response (IC-DoR) based on ICR/ derived INV | IC-DoR is defined, for participants with a confirmed objective intra-cranial response, as the time from first documentation of objective intra-cranial response (CR or PR whichever is earlier) to the date of first documentation of PD in brain or death due to any cause, whichever occurs first. | every 6 weeks up to approximately 4 years | 
| Progression Free Survival (PFS) based on ICR/derived INV | PFS is defined as the time from date of first dose to the date of the first documentation of PD (per RECIST v1.1) or death due to any cause, whichever occurs first. | every 6 weeks up to approximately 4 years | 
| Time To Progression (TTP) based on ICR/derived INV | TTP is defined as the time from date of first dose to the date of the first documentation of PD (per RECIST v1.1). | every 6 weeks up to approximately 4 years | 
| Adverse Event (AE) as graded by NCI CTCAE (v 4.03) | Frequency of patients experiencing treatment-emergent AEs (TEAEs) | From study start up to approximately 4 years |