Local Consolidative Therapy and Brigatinib in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To assess the safety, tolerability, and feasibility of brigatinib with local consolidative therapy (LCT) in tyrosine kinase inhibitor-naive ALK-rearranged advanced (non-small cell lung cancer) NSCLC.

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS) using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in advanced ALK+ NSCLC patients treated with local consolidative therapy (LCT) after achieving stable disease or partial response with first-line brigatinib treatment.

II. To determine overall survival (OS).

III. To assess time to progression (TTP) of non-LCT lesions.

EXPLORATORY OBJECTIVES:

I. To assess time to appearance of new metastatic lesion(s).

II. To determine the utility of pre-treatment, pre-LCT, and post-LCT circulating free tumor deoxyribonucleic acid (DNA) (cfDNA) as a potential prognostic and predictive biomarkers.

II. To evaluate potential impact of LCT on mechanisms of ALK resistance with molecular analysis of post-progression biopsies.

OUTLINE:

Patients receive brigatinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo LCT for up to 3 weeks in the absence of disease progression or unacceptable toxicity. Within 7 days after completion of LCT, patients receive brigatinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 3 months for up to 2 years.

Inclusion criteria

• Histologically or cytologically confirmed diagnosis of stage IV NSCLC (or recurrent NSCLC not a candidate for definitive multimodality therapy)
• Documented ALK re-arrangement as detected by: (1) FISH, (2) IHC, (3) tissue NGS, or (4) cfDNA NGS
• Subjects can be enrolled as (1) TKI naïve or (2) after ≤ 8 weeks of first-line brigatinib treatment without disease progression.
• Candidate for local consolidative therapy to at least one site of residual disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Males or females aged at least 18 years.
• Adequate organ function laboratory values, defined as:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L or at least 1500/mm3 or at least 1.5 x 109/L
• Platelet count at least 75,000/mm3 or at least 75 x 109/L
• Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline
• Serum creatinine ≤ 1.5 × ULN or ≥ 60 mL/minute for subjects with creatinine levels > 1.5 × the institutional ULN
• Serum total bilirubin less than or equal to ≤ 1.5 × ULN or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 × ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN except for subjects with liver mets for whom ALT and AST should be ≤ 5× ULN
• International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated PTT (aPTT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant
• Female patients of childbearing potential must have a negative pregnancy test documented at time of screening.
• Female patients who:

• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to use a highly effective method of contraception from the time of signing the informed consent through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
• Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
• Agree to completely abstain from heterosexual intercourse
• Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 milliseconds (msec) in males or ≤470 msec in females.
• Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

Exclusion criteria

• Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 2 years elapsed since the diagnosis of the other primary malignancy.
• Previously received any prior TKI, including ALK-targeted TKIs. Note: on-going first-line brigatinib use as specified in the Inclusion criteria is allowed.
• Previously received more than 1 regimen of chemotherapy or immunotherapy for locally advanced or metastatic disease. Note that history of consolidative immunotherapy after concurrent chemoradiotherapy (for locally advanced disease) is allowed.
• Symptomatic CNS metastasis. Asymptomatic CNS disease requiring increasing dose of corticosteroids within 7 days prior to study enrollment is also not permitted.
• Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
• The presence of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis at screening.
• Have a known or suspected hypersensitivity to brigatinib or its excipients.
• Have malabsorption syndrome or other gastrointestinal (GI) illness or condition that could affect oral absorption of the study drug.
• Be pregnant, planning a pregnancy, or breastfeeding.
• Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

• Myocardial infarction (MI) within 6 months prior to the first dose of study drug
• Unstable angina within 6 months prior to first dose of study drug
• Decompensated congestive heart failure (CHF) within 6 months prior to first dose of study drug
• History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician
• Any history of ventricular arrhythmia
• Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug
• Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure
• Have an ongoing or active infection, including, but not limited to, the requirement for intravenous (IV) antibiotics.
• Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history.
• Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the study drug.