Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

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

Summary: The goal of this clinical research study is to learn if brigatinib combined with local consolidative therapy (LCT-- surgery and/or radiation) can help to control non-small cell lung cancer (NSCLC) in patients who are ALK-positive.
  Researchers also want to learn about the safety, tolerability, and feasibility of this combination.
  This is an investigational study. LCT is FDA approved and commercially available for the treatment of NSCLC. Brigatinib is FDA approved and commercially available for metastatic (has spread) NSCLC that is ALK -positive. It is considered investigational to combine brigatinib with LCT to treat NSCLC patients with a specific genetic mutation and are ALK-positive. The study doctor can explain how the study drug and LCT are designed to work.
  Up to 24 participants will take part in this study. All will take part at MD Anderson.

Detailed description: STUDY DETAILS:
  Screening Tests
  Signing this consent form does not mean that you will be able to take part in this study. The following screening tests will be performed within 4 weeks before your first dose of study drug/LCT to help the doctor decide if you are eligible:
  -  You will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine tests and biomarker testing (including genetic biomarkers). Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug.
  -  You will have an EKG to check your heart function.
  -  You will have a CT, PET/CT, and/or MRI to check the status of the disease.
  -  If available, leftover tumor tissue from a previous procedure will be collected for biomarker testing (including genetic biomarkers) and for immune system testing. Researchers will also look for certain genes and try to learn if these genes are related to cancer risk and response to treatments. If no tumor tissue available you will have an image-guided tumor biopsy. To perform an image-guided biopsy, a needle is inserted into the affected area using imaging such as CT, ultrasound, or MRI to collect cells or tissue from an organ, lymph node, or suspected tumor mass. The doctor will use the imaging to guide the needle into the area. Two (2) types of samples may be collected. It will either be a fine needle aspirate (FNA) that collects cells and/or a core biopsy that collects a small piece of tissue.
  -  If your ALK status is not known, the tumor tissue collected above will also be used for this testing.
  -  If you can become pregnant, blood (up to 1 teaspoon) or urine will be collected for a pregnancy test. To take part in this study, you must not be pregnant.
  The study doctor will discuss the screening test results with you. If the screening tests show that you are not eligible to take part in the study, you will not be enrolled. Other treatment options will be discussed with you.
  Study Groups:
  Each cycle is 28 days. If you are found to be eligible to take part in this study, you will take brigatinib by mouth with a glass of water (about 8 ounces) 1 time every day while on study. For the first 7 days, you will take a lower dose of brigatinib. After that, you will receive the full dose for the rest of the study. You may take your dose with or without food.
  After taking brigatinib for 2 cycles, you will receive LCT as long as the disease has not spread or worsened. You will not take brigatinib while you are receiving LCT, but you will begin it again after LCT is complete.
  Your study doctor will discuss which LCT option (radiation and/or surgery) is best for you. The LCT part of the study should take no more than 3 weeks. You will sign a separate consent for surgery and/or radiation therapy which describes the treatment in more detail, including its risks.
  Depending on how well you tolerate the study drug or LCT you receive, you may be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.
  Study Visits
  On Days 1, 8, and 15 of Cycle 1:
  -  You will have a physical exam.
  -  Blood (about 1½ tablespoons) will be drawn for routine tests If you can become pregnant, every 12 weeks (about every 3 cycles) starting on Day 1 of Cycle 1, blood (up to 1 teaspoon) or urine will be collected for a pregnancy test.
  Every 4 weeks (for as long as you take brigatinib):
  -  You will have a physical exam.
  -  Blood (about 1½ tablespoons) will be drawn for routine tests.
  -  You will have an EKG. At the end of Cycle 2 (about 8 weeks after your first dose of brigatinib), you will have a CT or PET/CT scan and an MRI to check the status of the disease.
  Before you begin your LCT:
  -  You will have a physical exam.
  -  Blood (about 5½ tablespoons) will be drawn for routine tests and biomarkers, including genetic biomarkers.
  -  You may have a CT or PET/CT scan and an MRI to check the status of the disease.
  -  If you can become pregnant, blood (up to 1 teaspoon) or urine will be collected for a pregnancy test.
  If you have surgery as part of LCT, any leftover tissue removed during surgery (normal tissue [non-cancerous tissue], tumor tissue, and lymph tissue) will be collected and stored at MD Anderson for use in future biomarker testing related to this study. No extra tissue will be removed, as it is tissue that would be removed anyway for surgery and to check the status of the disease.
  Within 7 days after finishing LCT:
  -  You will have a physical exam.
  -  You will have an EKG to check your heart function.
  -  Blood (about 5½ tablespoons) will be drawn for routine tests and biomarker testing, including genetic testing.
  End-of-Treatment Visit
  Within 14 days of taking your last dose of study drug:
  -  You will have a physical exam.
  -  You may have an EKG.
  -  Blood (about 5½ tablespoons) will be drawn for routine tests and biomarker testing, including genetic biomarkers.
  -  You may have a CT or PET/CT scan and an MRI to check the status of the disease.
  -  If you can become pregnant, blood (up to 1 teaspoon) or urine will be collected for a pregnancy test.
  Safety Follow-up Visit
  About 30 days after your last dose of study drug:
  -  You will have a physical exam.
  -  Blood (about 1½ tablespoons) will be drawn for routine tests. Long-Term Follow-up During Long-Term Follow-up, you will be called every 3 months for up to 2 years after your last dose of study drug and asked how you are doing and if you have taken any other anti-cancer drugs. Your medical records may also be checked for this information. If you had routine tests (such as blood draws and/or imaging scans) as part of your standard care during this time, the results of these tests will be collected. Each call should last about 15-20 minutes.
  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. Courses 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.

Eligibility: Inclusion Criteria:
  -  Histologically or cytologically confirmed diagnosis of stage IV non-small cell lung cancer (NSCLC) (or recurrent NSCLC not a candidate for definitive multimodality therapy)
  -  Documented ALK re-arrangement as detected by: (1) Fluorescence in situ hybridization (FISH), (2) immunohistochemistry (IHC), (3) tissue next generation sequencing (NGS), or (4) cfDNA NGS
  -  Subjects can be enrolled as (1) tyrosine kinase inhibitor (TKI) naive or (2) after =< 8 weeks of first-line brigatinib treatment without disease progression
  -  Measurable disease according to RECIST 1.1. At least one lesion of at least 1.0 cm in the long-axis diameter for a non-lymph node or at least 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1. If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of at least 1.5 cm
  -  Candidate for local consolidative therapy to at least one site of residual disease
  -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L or at least 1500/cubic millimeters or at least 1.5 x 10^9/L
  -  Platelet count at least 75,000/cubic millimeters or at least 75 x 10^9/L
  -  Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline
  -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or >= 60 mL/minute for subjects with creatinine levels > 1.5 x the institutional ULN
  -  Serum total bilirubin less than or equal to =<1.5 x ULN or direct bilirubin =< ULN or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN except for subjects with liver metastases (mets) for whom ALT and AST should be =< 5 x ULN
  -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x 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 x 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: a.) Are postmenopausal for at least 1 year before the screening visit, OR b.) Are surgically sterile, OR c.) If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, 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: a.) Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or b.) Agree to completely abstain from heterosexual intercourse
  -  Have normal QT interval on screening electrocardiography (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 central nervous system (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: a.) Myocardial infarction (MI) within 6 months prior to the first dose of study drug b.) Unstable angina within 6 months prior to first dose of study drug c.) Decompensated congestive heart failure (CHF) within 6 months prior to first dose of study drug d.) History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician e.) Any history of ventricular arrhythmia f.) 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

Relevance to patient case: not relevant