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6.3.5 d1 cycle 2 and

The safety profile of the Study Drug is well-known at this point of this research study and many patients may be demonstrating stable tolerance of the Study Drug. For these patients, at the treating physician's discretion, even numbered cycle visits that do not include imaging procedures (i.e., CT scan, Brain MRI) may be conducted as telemedicine visits. When standard clinic assessments (i.e.,
symptoms/adverse event, blood pressure and heart rate) are not conducted, to maintain data integrity, these missed assessments are to be noted in the EDC as deviations (planned) and indicate that visit was conducted remotely.  
6.4 **EOT Visit**
This visit should occur 30 days (+/- 3 days) after brigatinib treatment stops for whatever reason (adverse event, progression, or at discretion of the investigator). Patients who have an ongoing grade 4 AE or SAE at the time of discontinuation from treatment will be contacted every 2 weeks until the event is resolved, determined to be irreversible by the investigator, or until the patient begins an alternate form of treatment. NOTE: The first EOT follow up visit is to be performed 30 days (+/- 3 days) after the date a participant receives the last dose of study drug. The date of the EOT visit will not match the date the last dose of study drug was administered and should be entered accordingly on the eCRF/EDC system. Clinical evaluation: focused medical history on symptoms/adverse events, comprehensive physical examination (to include weight), vital signs, ECOG performance status.  
Laboratory studies:
- **Hematology**: CBC with differential - **Serum Chemistries**: blood urea nitrogen (BUN), creatinine, bilirubin, ALT (SGPT), AST (SGOT), alkaline phosphatase, amylase, creatinine phosphokinase (CPK)
AE: Adverse events will be assessed according to the NCI CTCAE v. 4.0. All SAEs (see section 7.0) ongoing 30 days or more after last dose of study drug is administered should be followed at least every 4 weeks until they resolve to baseline (or CTCAE grade ≤1), stabilize, or are considered to be chronic/irreversible regardless of causality. See also section 7 for documentation of AEs/SARs, when applicable, for patients remaining in the study after transition from cohort A or B to cohort C. Concomitant medications: Review for any changes since previous visit. Tissue acquisition: At time of progression on study therapy, biopsy will be repeated in patients who consent to this optional biopsy; see section 6.6 and laboratory manual for additional details. Blood sample: A blood sample for ctDNA will be requested at time of progression on current therapy. Time of progression for cohort C means patient's further progression (as indicated by CT scan) from their entry into cohort C); see section 6.6 and the laboratory study for additional details.  
Cohort C: For patients enrolling in cohort C from cohorts A or B end of treatment is not required; however:  
- The EOT section of the eCRF form must still be completed; - To avoid repeating assessments, EOT (cohort A or B) and screening
(cohort C) assessments (including CT scans, brain MRIs, etc.), reasonable efforts should be taken to perform these assessments as standard of care at EOT to be used for cohort C screening assessments;
- Data relevant to each cohort's participation in the study will be independent according to their cohort assignment and recorded on each applicable eCRF for (i.e., EOT for cohort A or B, screening for cohort C).  
- In the event of active AE's which continue past the subjects transition to cohort C, and continuing past the transition date, they are to be recorded under the new Subject number within the Medical History Log, to be updated upon change in AE. severity or status.
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6.5 post-treatment/follow-up assessments

Long-term follow up will occur every 3 months from the last administration of protocol-directed therapy for up to 2 years or until death, whichever occurs first. Subsequent therapy and survival status will be documented. Each cohort A, cohort B and cohort C participant's follow-up data will be captured from their time of enrollment in the cohort (for up to 2 years, or until death, whichever occurs first).
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note

- The first post-treatment follow-up is to be performed 30 days (+/- 3 days)
after the date a participant receives the last dose of study drug.  
- The date of the EOT visit will not match the date the last dose of study drug was administered and should be entered accordingly on the eCRF/EDC system.  
- Follow-up may occur via review of medical records, and on-site visits are not required. To maintain the every 3 month follow-up schedule, these methods should be used for long-term follow up of cohort A or B participants, when their participation and treatment in the study continues as a cohort C participant.
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6.6 correlative studies procedures 6.6.1

Tumor biopsy (core biopsy) after progression on previous ALK inhibitor and within 60 days prior to D1 of study treatment is mandatory i.e., if tissue available from pre-study biopsy, this tissue will be accessed for correlative studies, otherwise, patients must consent to tumor biopsy to meet eligibility criteria. All subjects must consent to provide tumor blocks or slides. If archival tissue is not available and biopsies to obtain fresh tumor tissue cannot be performed with minimal risk to the subject, subjects may be permitted to enroll on the study with prior approval of the Study PI.  
Patients who undergo biopsies and subsequently found to have insufficient will be permitted to enroll on the study with prior approval of the study PI. Patients who have standard of care next-generation sequencing performed are able to enroll on the study, but must have sufficient tumor tissue to participate in the study (i.e. next generation sequencing cannot be substituted for providing tumor sample). Core biopsies may be performed by clinical personnel trained in this procedure for standard of care collections. The number of passes made through the tumor per biopsy will be determined by the treating physician and the physician performing the biopsy procedure with primary consideration being safety. The tissue collected will be divided into aliquots (depending on size of collection, up to 4 aliquots per collection) to enable enough tissue for planned correlative studies. Additional details regarding processing, storing and handling tissue will be provided in a separate laboratory manual. Biological samples collected for the study will be shipped to and stored in the research laboratories at the University of Colorado until the completion of the study. With patient consent, any remaining tumor tissue after protocol specific studies are complete will be stored for future research concerning lung cancer.
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6.6.2 blood sample for ctdna

Blood samples from enrolled patients will be evaluated via next generation sequencing for circulating tumor DNA (no germline studies will be performed). If possible, blood sample at progression should be performed while patient is still taking brigatinib; if drug is discontinued, the blood sample should be performed within 2 days of discontinuation.
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6.6.3 risks of correlative study

Likely: local discomfort and minor bleeding Less likely: moderate or major bleeding, need for blood transfusion, hospitalization due to bleeding or other complications, infection, bowel perforation or damage to adjacent organs
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lung (core needle biopsy in

Less likely: pneumothorax, hemothorax, intraparenchymal hemorrhage, hemoptysis, bronchopleural fistula, air embolism, and vascular injury In order to minimize the risk of a biopsy, only qualified personnel will perform these procedures. Prior to the procedure, the physician performing the procedure will discuss the risks with each study participant, answer any questions, and obtain separate procedure consent. For biopsies of lesions that are not superficial and clearly palpable, imaging studies such as CT scan will be used to guide the biopsy in order to minimize the risk of damage to adjacent structures. After liver biopsies, patients will be observed for approximately 4 hours (range 4-6 hours) after the procedure, or per institutional standard guidelines. Less than the goal quantity of tissue is acceptable for each type of biopsy, and will be left to the clinical judgment of the physician performing the procedure.
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6.6.4 risks of correlative study

All biopsy procedures require local anesthesia using lidocaine, xylocaine, or related compounds. There is a small risk of an allergic reaction associated with these drugs. In order to minimize the risk of local anesthesia, only qualified personnel will perform the biopsy procedure. Patients will be queried if they have had previous allergic reactions to local anesthetics.
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intravenous conscious sedation

Certain biopsy procedures may require IVCS. IVCS is a minimally depressed level of consciousness that retains the patient's ability to maintain a patent airway independently and continuously and respond appropriately to physical stimulation and verbal commands. The medications used to induce conscious sedation include the benzodiazepine midazolam and the opioid agonist fentanyl, as per standard of care. IVCS is performed once over a 30-60 minute period, and may require administration of multiple doses of each agent over this time-frame. Rarely, IVCS will last longer than 60 minutes.
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midazolam

See http://www.drugs.com/pro/midazolam-injection.html for complete prescribing information on midazolam, including complete information on risks associated with its use. The risks of midazolam include respiratory depression and respiratory arrest, especially when used for sedation in non-critical settings. Respiratory arrest could require intubation. In very rare cases, when this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Other serious cardiorespiratory adverse events have occurred after administration of midazolam, including airway obstruction, oxygen desaturation, apnea, and cardiac arrest, rarely resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment, particularly in patients with hemodynamic instability. Agitation, involuntary movements, hyperactivity and combativeness have been reported in adults patients treated with midazolam. Concomitant use of midazolam with other respiratory depressants like fentanyl may increase the risk of hypoventilation, airway obstruction, desaturation or apnea, and may contribute to profound and/or prolonged drug effect. Prolonged sedation may also be seen midazolam is administered concomitantly with drugs known to inhibit the P450 3A4 enzyme system such as cimetidine, erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. Adverse effects reported after intravenous administration of a single dose when used as a sedative include the following (percentage is percentage of adult patients with adverse events): hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), "oversedation" (1.6%), headache (1.5%), and drowsiness (1.2%). In addition, the following local effects at the site of the injection have been reported: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), induration (1.7%), and phlebitis (0.4%).  
Additional rare (<1.0%) adverse events occurring when midazolam is used as a sedative include:
- Respiratory (laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea);
- Cardiovascular (bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm);
- Gastrointestinal (acid taste, excessive salivation, retching);
- CNS/Neuromuscular (retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia);
- Special Senses (blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness);
- Integumentary (hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site);
- Hypersensitivity (allergic reactions including anaphylactoid reactions, hives, rash, pruritus);
- Miscellaneous (yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma).
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fentanyl

See http://www.drugs.com/pro/fentanyl-injection.html for complete prescribing information on fentanyl (Duragesic®), including complete information on risks associated with its use. Fentanyl may cause muscle rigidity, particularly involving the muscles of respiration. Skeletal muscle movements in the extremities, neck and external eye have also been reported with fentanyl; rarely, these have been strong enough to pose patient management problems. Fentanyl may also produce euphoria, miosis, bradycardia and bronchoconstriction, as seen with other narcotic analgesics. The most common serious adverse reactions reported with fentanyl include respiratory depression, apnea, rigidity, and bradycardia. If these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm and diaphoresis. The risks of IVCS also include inhibition of the gag reflex and concomitant risk of aspiration and allergic reactions to the sedative or analgesic medications. The chances of serious risks from IVCS are small but real; for example, in a prospective study of 14,149 patients undergoing IVCS during upper gastrointestinal endoscopies, the rate of immediate cardiopulmonary events was 2 in 1000. The 30-day mortality was 1 per 2,000 cases. In this study, there was a strong association between lack of monitoring and use of high-dose benzodiazepines with adverse outcomes. There was also an association between the use of local anesthetic sprays to the oropharynx and the development of
62 of 82 pneumonia (Waring JP, B.T., Hirota WK, et al Gastrointestinal Endoscopy).  
In order to minimize the risk of IVCS, only qualified personnel (M.D. and R.N) will be responsible for conscious sedation. A minimum of two individuals will be involved in the care of patients undergoing conscious sedation—the physician performing the biopsy procedure, and the individual (R.N.) who monitors the patients and his/her response to both the sedation and the procedure, and who is capable of assisting with any supportive or resuscitative measures. The room where the procedure utilizing IVCS takes place in the interventional radiology suite will have adequate equipment to provide supplemental oxygen, monitor vital signs, and maintain an airway should this be necessary. An emergency cart will also be immediately accessible to the room where the procedure is to take place, and emergency support services will be available on page. Patients will be screened and evaluated for their fitness to undergo conscious sedation by a trained physician. Patients with active cardiac disease are excluded from this study. No local anesthetic spray to the oropharynx will be necessary, given that endoscopy is not a planned procedure. Following the procedure, patients will be observed closely in the recovery room according to standard institutional guidelines.
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6.6.5 risks of correlative study

Blood draws may be associated with slight discomfort from the needle-stick, localized erythema, bleeding/bruising, or soreness around the area where the needle is inserted. Insertion of an intravenous catheter (I.V.) has similar risks, in addition to a small risk of infection at the site where the needle is inserted. In order to minimize the risk of blood draws and I.V. insertion, only trained personnel will perform these procedures, according to standard institutional guidelines.
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6.6.6 risks of study procedures-imaging

CT scans will expose study participants to controlled amounts of radiation. The total dose of radiation from these tests is not anticipated to cause any adverse effects. There is also a risk of an allergic reaction to the intravenous contrast dye used during CT imaging, as well as a risk of experiencing feelings of anxiety or claustrophobia while undergoing a CT scan. There are no anticipated risks with the use of ultrasound. In order to minimize these risks, patients will be queried, as per standard institutional practice, regarding their history of reactions to intravenous contrast dye. If a patient has had such a reaction, she/he will be premedicated, or dye will not be used, as per standard institutional practice. If a patient has previously experienced anxiety or claustrophobia while undergoing a CT scan, she/he will be encouraged to discuss this with her primary oncologist. Anxiolytics may be considered by the patient's primary oncologist as indicated.  
6.7 **Assessment of Safety**
Any patient who receives treatment on this protocol should be evaluable for toxicity. The criteria used to assess safety (typically the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Please refer back to the Time and Events table for the schedule of AE assessment.  
6.8 **Assessment of Efficacy**
Patients will be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1for objective response and disease progression.27 See section 8.3.
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6.8.1 assessment of disease-tumor measurement

See the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247)
for additional details on RECIST1.1.  
Measurable disease will be defined as the presence of at least one measurable lesion that can be accurately measured in at least one dimension with the longest diameter a minimum size of:
- >10 mm by CT scan (CT scan slice thickness no greater than 5mm)
- 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non- measurable).  
- 20 mm by chest x-ray.  
- >10 mm by MRI scan (MRI scan slice thickness no greater than 5 mm)
For malignant lymph nodes to be considered pathologically enlarged and measurable, a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5mm). At baseline and in follow-up, only the short axis will be measured and followed. All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non- measurable lesions, will be considered non-measurable. Lesions considered truly non-measurable include: leptomeningeal disease; ascites; pleural/pericardial effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques. All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions will only be considered measurable when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesions is recommended.
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6.8.2 baseline documentation of target

All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longer diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease. All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as "present" or "absent", or in rare cases "unequivocal progression".
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6.8.3 evaluation of target lesions

NOTE: In addition to the information below, also see section 4.3.2 in the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST)
Committee, version 1.1 for special notes on the assessment of target lesions.25 Complete response (CR) −Disappearance of all target lesions. Any pathological lymph node (LN) (whether target or non-target) must have decreased in short axis to <10mm. Partial response (PR) −At least a 30% decrease in the sum of the LD of the target lesions taking as reference the baseline sum LD. Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the target lesions taking as reference the smallest sum LD recorded since the treatment started including baseline if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. The appearance of one or more new lesions also constitutes PD.  
Stable disease (SD) −Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD since the treatment started.
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6.8.4 evaluation of non-target lesions

Complete response (CR)−Disappearance of all non-target lesions and normalization of tumor marker levels. All LN must be non-pathological in size (<10mm short axis).  
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.  
Progressive disease (PD) −Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
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6.8.5 evaluation of best overall

The best overall response is the best response recorded from the start of the study treatment until the end of treatment provided the confirmation criteria are met. To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat studies that should be performed ≥ 4 weeks after the criteria for response are first met. If a CR/PR cannot be confirmed the original "response" should be considered stable disease. The best overall response will be defined according to the following table:  
| Overall                    |                                         |                                                                   |
|----------------------------|-----------------------------------------|-------------------------------------------------------------------|
| Response First  Time Point | Overall Response Subsequent Time  Point | BEST Overall Response                                             |
| CR                         | CR                                      | CR                                                                |
| CR                         | PR                                      | SD, PD, or PR1                                                    |
| CR                         | SD                                      | SD provided minimum criteria for SD duration met, otherwise, PD   |
| CR                         | PD                                      | SD provided minimum criteria for SD duration met, otherwise, PD   |
| CR                         | NE2                                     | SD provided minimum criteria for SD duration met, otherwise,  NE2 |
| PR                         | CR                                      | PR                                                                |
| PR                         | PR                                      | PR                                                                |
| PR                         | SD                                      | SD                                                                |
| PR                         | PD                                      | SD provided minimum criteria for SD duration met, otherwise, PD   |
| PR                         | NE2                                     | SD provided minimum criteria for SD duration met, otherwise,  NE2 |
| NE                         | NE2                                     | NE2                                                               |  
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration for SD was met. However, sometimes 'CR' may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 2 NE=inevaluable
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7.0 adverse events 7.1 intentionally

7.2.1 **Adverse Event (AE)**
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal laboratory finding, symptom, or disease temporally associated with the use of a drug) in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE (e.g., surgical insertion of central line) need not be considered AEs and should not be recorded as an AE. Disease progression should not be recorded as an AE, unless it is attributable by the investigator to the study therapy.
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7.2.2 suspected adverse reaction (sar)

A suspected adverse reaction (SAR) is any AE for which there is a *reasonable* possibility that the drug is the cause. *Reasonable possibility* means that there is evidence to suggest a causal relationship between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. Causality assessment to a study drug is a medical judgment made in consideration of the following factors: temporal relationship of the AE to study drug exposure, known mechanism of action or side effect profile of study treatment, other recent or concomitant drug exposures, normal clinical course of the disease under investigation, and any other underlying or concurrent medical conditions. Other factors to consider in considering drug as the cause of the AE:
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7.2.3 unexpected ae or sar

An AE or SAR is considered unexpected if the specificity or severity of it is not consistent with the applicable product information (e.g., Investigator's Brochure (IB) for an unapproved investigational product or package insert/summary of product characteristics for an approved product). Unexpected also refers to AEs or SARs that are mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
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7.2.4 serious ae or sar

An AE or SAR is considered serious if, in the view of either the investigator or sponsor, it results in any of the following outcomes:
- Single occurrence of an uncommon event known to be strongly associated - with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
- One or more occurrences of an event not commonly associated with drug exposure, but otherwise uncommon in the population (e.g., tendon
- rupture); often more than once occurrence from one or multiple studies would be needed before the sponsor could determine that there is
- *reasonable possibility* that the drug caused the event. - An aggregate analysis of specific events observed in a clinical trial that indicates the events occur more frequently in the drug treatment group
- than in the concurrent or historical control group.  
- Death;
- Is life-threatening (places the subject at immediate risk of death from
- the event as it occurred); - Requires inpatient hospitalization (>24 hours) or prolongation of
- existing hospitalization;*
- Results in congenital anomaly/birth defect;
- Results in a persistent or significant incapacity orsubstantial - disruption of the ability to conduct normal life functions;
- Important medical events that may not result in death, be life-
- threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical
- judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definition. For reporting purposes, also consider the occurrences of pregnancy as an event which must be reported as an important medical event.
* Hospitalization for anticipated or protocol specified procedures such as administration of chemotherapy, central line insertion, metastasis interventional therapy, resection of primary tumor, or elective surgery, will not be considered serious adverse events.  
Pregnancy that occurs during the study must also be reported as an SAE.
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7.3 documentation of non-serious aes

For non-serious AEs or SARs, documentation must begin from day 1 of study treatment and continue through the 30-day follow-up period after treatment is discontinued. Collected information should be recorded in the Case Report Forms (CRF) for that patient. Please include a description of the event, its severity or adverse event grade, onset and resolved dates (if applicable), and the relationship to the study drug.  
Documentation should occur at least monthly. For patients with two Subject Identification Numbers (SI\#), resulting as participants in Cohort A or Cohort B, and then Cohort C (upon disease progression), each AE should be recorded as applicable to their cohort participation including the following:
- An original AE under their SI\#1 should be completed (followed and recorded to resolution) under that cohort.  
- AEs for Cohort C should be applicable to their participation under Cohort C:  
a. AEs from SI\#1 should be recorded once resolved under SI\# 1. b. AE history from the patient's SI\#1 to be included as medical history for the patient under their SI\# 2.  
c. Original AEs under SI\#1 that increase in severity to be recorded as a new AE under the patient's SI\#2 (as cohort C).
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7.4 saes or serious sars

After informed consent but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be collected (e.g. SAEs related to invasive procedures such as biopsies, medication washout). For any other experience or condition that meets the definition of an SAE or a serious SAR, recording of the event must begin from day 1 of study treatment and continue through the 30-day follow-up period after treatment is discontinued.
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7.4.2 documentation and notification

All SAEs or Serious SARs must be recorded as an SAE within the study electronic data capture system and the printed SAE eCRF must be submitted to Criterium Project Manager & Duke Principal Investigator via email at ARIAT002SAE@criteriuminc.com within 24 hours of learning of its occurrence.
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7.4.3 reporting institutional review board

Sites using a local IRB/REB of record, are required to submit adverse events per their local IRB/REB policy.
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reporting of pregnancy pregnancy

It is not known what effects *brigatinib* has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age group and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below.  
Female patients must meet 1 of the following:
- Postmenopausal for at least 1 year before the screening visit, or
- Surgically sterile, or
- If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing of the informed consent form 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) must agree to 1 of the following:
- Practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
- completely abstain from heterosexual intercourse.  
If a subject becomes pregnant during the study, or within 30 days of the subject's last dose of study drug, the investigator is to stop dosing with study drug immediately. A pregnancy is not considered to be an AE or SAE; however, it must be reported to Takeda at Toll-Free Fax \#: 1-800-963-6290, E-mail: takedaoncocases@cognizant.com using the Pregnancy Report Form within the same timelines as an SAE. This applies to female subjects as well as female partners of male subjects. A pregnancy should be followed through to outcome, whenever possible. Once the outcome of the pregnancy is known, the Pregnancy Outcome Report Form should be completed and reported to the IND Office and Takeda. It is not known whether brigatinib passes into the breast milk. Mothers should not breastfeed while receiving study drug. In cases of pregnancy or suspected pregnancy, the patient is to be discontinued immediately (within 24 hours) from the study and the female subject should be referred to an obstetrician- gynecologist, preferably one experienced in reproductive toxicity for further evaluation and counseling. In addition to reporting to Takeda, pregnancy, suspected pregnancy, positive pregnancy test and pregnancy outcome must be reported to the Criterium Project Manager & Duke Principal Investigator immediately via email:
ARIAT002SAE@criteriuminc.com If the pregnancy results in spontaneous abortion or stillbirth, the event should be reported as an SAE. If there are any abnormal outcomes that meet the serious criteria, it must be reported as an SAE. Please follow the SAE reporting instructions in Section 7.3.2. Pregnancy outcomes must be collected for the female partners of any males who took study drug in this study. Consent to report information regarding these pregnancy outcomes should be obtained from the female partner.
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overdose

An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study treatment that exceeds the dose described in the protocol. Overdoses are not considered AEs; however, all overdoses should be recorded on an Overdose Report Form and submitted to Criterium Project Manager and Duke Principal Investigator within 24 hours. An overdose should be reported even if it does not result in an AE. Overdoses do not need to be recorded on the eCRF; dosing information is recorded on the dose administration eCRF. Email for submitting an Overdose Report Form to Criterium Project Manager and Duke PI: ARIAT002SAE@criteriuminc.com.
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takeda reporting requirements

The sponsor or designee is responsible for emailing pregnancy and overdose reports to Takeda at takedaoncocases@cognizant.com as soon as they are aware.
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fda expedited reporting requirements for

If an investigator deems that an event is a Suspected Unexpected Serious Adverse Reaction (SUSAR), de-identified supporting documentation defining the event and causality within 24 hrs. of knowledge of the event should be emailed to the Criterium Project Manager and Duke Principal Investigator at: ARIAT002SAE@criteriuminc.com. Once the Duke Principal Investigator determines an event is a SUSAR, the MedWatch 3500A form will be created by Criterium Project Manager or designee and submitted to the FDA.
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the medwatch 3500a form can

http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.  
(Please be sure and access **form 3500a**, and not form 3500). ATOMIC, as the Sponsor of the study, will make the final determination regarding FDA submission). Criterium Project Manager or designee is responsible for emailing expedited reports to Takeda Pharmaceuticals, Inc. at takedaoncocases@cognizant.com immediately but no later than 24 hours after the FDA submission. Criterium Project Manager or designee will also be responsible for informing each site of all serious and unexpected SARs reported to the FDA via email as soon as possible.
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product complaints or medication errors

A product complaint is a verbal, written, or electronic expression that implies dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who identify a potential product complaint situation should immediately contact Takeda Pharmacovigilance or designee (see below) and report the event. Whenever possible, the associated product should be maintained in accordance with the label instructions pending further guidance from a Takeda Quality representative. A medication error is a preventable event that involves an identifiable patient and that leadsto inappropriate medication use, which may result in patient harm. While overdoses and underdoses constitute medication errors, doses missed inadvertently by a patient do not. Investigators must record all medication errors (including overdose) on the appropriate CRF form. Individuals who identify a potential medication error situation should immediately contact Takeda (see below) and report the event.  
  
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an SAE form should be completed and sent to Takeda Pharmacovigilance
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7.5 data and safety monitoring

The Principal Investigator will provide continuous monitoring of patient safety in this trial with annual reporting to the ATOMIC Data and Safety Monitoring Committee (DSMC).  
Additional safety meetings/teleconferences will be held at a frequency dependent on study accrual, and in consultation with the study biostatistician. These meetings will include the investigators as well as protocol nurses, clinical research associates, regulatory associates, data managers, biostatisticians, and any other relevant personnel the principal investigators may deem appropriate. At these meetings, the research team will discuss all issues relevant to study progress, including enrollment, safety, regulatory, data collection, etc. The team will produce summaries or minutes of these meetings. These summaries will be available for inspection when requested by any of the regulatory bodies charged with the safety of human subjects and the integrity of data. The Data and Safety Monitoring Committee (DSMC) will be constituted by ATOMIC and will review the study on an annual basis. The Duke PI, with Criterium Project Manager's support, will be responsible for submitting the following information for review: 1) safety and accrual data including the number of patients treated; 2) significant developments reported in the literature that may affect the safety of participants or the ethics of the study; 3) preliminary response data; and 4) summaries of team meetings that have occurred since the last report. Findings of the DSMC review will be disseminated by memo to the participating sites.
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8.0 statistical considerations 8.1 study

The statistical design for this protocol involves a single arm phase II trial to investigate the clinical activity of brigatinib in three patient populations (Cohorts A, B, and C). Each cohort will be assessed separately. A Simon two-stage design is used to determine the primary endpoint of objective response rate (ORR). (Eisenhauer et al. 2009) Secondary endpoints include duration of response, PFS, intracranial PFS, extracranial PFS, OS and safety. We will also explore for any association between presence and/or type of mutation at baseline and efficacy outcomes (ORR and PFS). Resistance mutations will also be identified using a tumor sample from progression as well as ctDNA from peripheral blood samples.
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8.2 sample size and accrual

With the number of sites being increased, the study is expected to complete accrual (40 patients in each of the 3 cohorts) in about 2 years from amendment approval. The primary endpoint is objective tumor response of brigatinib via RECIST1.1. A true response rate of 20% would be considered active and worthy of further investigation, and a response rate of 5% will be considered inactive and not worthy of further investigation. A two-stage design will be used for this study. (Simon 1989) Twenty patients will be initially entered in Stage I of the study for each cohort, assuming all twenty are eligible. If there are at least 2 responses among the 20 eligible patients, an additional 20 patients will be entered into that cohort. If there are fewer than 2 responses among the first twenty patients in a cohort, then the cohort will be stopped early for futility. If at least 5 responses are observed among the 40 eligible patients in a cohort, then the treatment will be considered promising for that cohort population. Table below gives the characteristics of this design as a function of the true response rate. If the true response rate of a cohort is 20%, for example, then the probability of stopping that cohort early for futility is 7% and the overall probability of rejecting the treatment for that cohort after the second stage is 11%. This is comparable to a power of 89%. If the true response rate of a cohort is 10%, the probability of stopping that cohort early is 39% and the overall probability of rejecting the treatment for that cohort after the second stage is 67%.  
| PROBABILTY OF RESPONSE                                                                        |      |      |      |      |      |       |
|-----------------------------------------------------------------------------------------------|------|------|------|------|------|-------|
| 0.05                                                                                          | 0.10 | 0.15 | 0.20 | 0.25 | 0.30 |       |
| Probability of stopping                                                                       | 0.74 | 0.39 | 0.18 | 0.07 | 0.02 | 0.008 |
| early (<2 responses) Probability >1  responses during stage  1 (and rejecting the  treatment) | 0.22 | 0.28 | 0.14 | 0.04 | 0.01 | 0.002 |
| Overall probability of                                                                        | 0.96 | 0.67 | 0.32 | 0.11 | 0.03 | 0.009 |
| rejecting the treatment                                                                       |      |      |      |      |      |       |  
8.3 **Data Analysis Plans**
All analyses for the three cohorts will be separated. A modified intent-to-treat approach will be followed in all data summaries using all available data in the analyses. Consequently, no special adjustments to the data are intended for dealing with missing values or patients who withdraw prior to completing study. Patients who sign informed consent for the study but who voluntarily withdraw prior to treatment or never initiate treatment due to the development of inter-current illness or death will not be included in the analysis. Patients who sign inform consent and subsequently have a change in their functional status, laboratory values, or other eligibility criteria prior to initiating treatment, which makes them ineligible will not be included in the analysis. All patients who enroll and start study therapy will be included in the analysis. Patients who are not able to get radiographic assessment due to decline in performance status, symptomatic progression, and any other reason will be considered non-responders and will be considered as having disease progression at the time they discontinue protocol therapy. The primary endpoint is objective response rate (ORR); the secondary endpoints are duration of response, PFS, intracranial PFS, extra-cranial PFS, OS and the evaluation of the AE using NCI CTCAE version 4.0. For the primary analysis on ORR, the ORR and its 95% CI will be estimated using the statistical methodtaking into account the 2-stage design.28 Mean and median of duration of response and their 95% CIs will be estimated. Time to event endpoints, including PFS and OS, will be summarized using the method of Kaplan and Meier. PFS is the time from Day 1 treatment to disease progression or death, whichever comes first. OS is the time from Day 1 treatment to death of all causes. Patients without relevant events at last follow up will be treated as censored. Median PFS and median OS will be provided as well as their 95%CI. The association of survival endpoints with baseline covariates will be evaluated using Cox regression models. Treatmentrelated adverse events will be summarized by type, grade, and attribution.  
The association between presence and/or type of mutation or mechanism of resistance at baseline and efficacy outcomes will be explored using logistic regression (ORR) and Cox regression model (PFS). The frequency/rate of resistance mutations after brigatinib will be estimated using tumor samples collected at time of progression. The association between cfDNA from peripheral blood samples and resistance mutations will be evaluated using Wilcoxon rank sum test. All demographic and analytic data will be summarized by descriptive statistics. Categorical data will be summarized using frequency tables while summary statistics such as means, medians, standard deviation, range, etc. will be provided for continuous data.
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9.0 study management 9.1 institutional

It is expected that the IRB/REB will have the proper representation and function in accordance with federally mandated regulations. The IRB/REB should approve the consent form and protocol. In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles that have their origin in the Declaration of Helsinki. Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study and will be given the opportunity to review the consent form. Each consent form must include all the relevant elements currently required by applicable regulations (i.e., FDA, Health Canada, and local or state regulations). Once this essential information has been provided to the patient and the investigator is assured that the patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing an IRB/REB-approved consent form. Prior to a patient's participation in the trial, the written informed consent form should be signed and personally dated by the patient and by the person who conducted the informed consent discussion. Patients in cohort C will have progressed on brigatinib and will be receiving a higher than the standard dose brigatinib. Depending on the institutional practice and policies this may require patients on cohort C to sign a "post- progression" treatment informed consent document.  
9.2 **Required Documentation**
Before a site can be open to enrollment, the following documentation must be on file with Criterium, Inc.  
- A copy of the official IRB/REB approval letter for the protocol and informed consent
- IRB/REB membership list - IRB FWA documentation and GCP compliance statement, or REB
equivalent, as applicable
- CVs and medical licensure for the principal investigator and any subinvestigators who are listed on the 1572.  
- Current GCP certificates for site PI and all sub-investigators on the 1572 - Form FDA 1572 appropriately filled out and signed with appropriate Financial Disclosures for PI and all sub-investigators on the1572
- Laboratory certificates (e.g., CLIA (and CAP if applicable)) and associated lab normal values
- Executed clinical research contract - Protocol signature page of IRB/REB approved protocol
- Investigator Brochure acknowledgement of receipt
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9.3 enrollment procedures

All patients must be approved by the Duke Principal Investigator or designee before enrollment to study. Site is to email completed eligibility checklist, signed informed consents with all but first initial of first and last name of patient censored and all deidentified source documents used to confirm eligibility to:
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ariat002pm@criteriuminc.com

Enrollment confirmations will be sent via email. Date of enrollment will be defined as the date of the confirmation e-mail in the EDC.
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9.4 data management and monitoring/auditing

Data for each cohort (A, B and C) participant data will be captured from their time of enrollment in the cohort for up to 2 years, or until death, whichever occurs first. Data will be collected through a web-based electronic data capture system. All study institutions will be given a password to directly enter their own data into the study electronic case report forms (eCRFs). Criterium, Inc. will coordinate and manage data for quality control assurance and integrity. All data will be collected and entered by site research coordinators or other designees from participating institutions. The investigators at each site will be required to submit de-identified source documentation to Criterium, Inc for routine data monitoring upon request. On site monitoring visits will be performed by ATOMIC representative according to the Monitoring Plan. During these visits, information recorded in the eCRFs will be verified against source documents. Data will be reviewed for safety information, legibility, completeness, and accuracy.
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9.5 adherence to the protocol

Except for an emergency situation in which proper care for the protection, safety, and well-being of the study patient requires alternative treatment, the study shall be conducted exactly as described in the approved protocol.
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9.5.1 emergency modifications

Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior Duke Principal Investigator or their respective institution's IRB/IEC/REB approval/favorable opinion.  
For investigators relying on their own institution's IRB/REB, as soon as possible after the modification has been made, the implemented deviation or change and the reasons for it should be submitted to:
- To Duke Principal Investigator for agreement - The institution's IRB/REB for review and approval. (Once IRB/REB's response is received, this should be forwarded to the Criterium Project Manager).
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9.5.2 other protocol deviations/violations

A protocol deviation is any unplanned variance from an IRB/REB approved protocol that:
- Is generally noted or recognized after it occurs - Has no substantive effect on the risks to research participants
- Has no substantive effect on the scientific integrity of the research plan or the value of the data collected
- Did not result from willful or knowing misconduct on the part of the investigator(s).  
An unplanned protocol variance is considered a violation if the variance meets any of the following criteria:
- Has harmed or increased the risk of harm to one or more research participants.  
- Has damaged the scientific integrity of the data collected for the study. - Results from willful or knowing misconduct on the part of the investigator(s).  
- Demonstrates serious or continuing noncompliance with federal regulations, State laws, or University policies.
If a deviation or violation occurs, please follow the guidelines below:
For Institutions Relying on Their Own IRB/REB: In addition to adhering to the policies regarding protocol compliance set forth by your institution's IRB/REB, the following is also required:
Protocol Deviations: In the event a deviation from protocol procedures is identified, record the deviation in the electronic data capture system. The protocol was amended in 2020 adding the ability, in limited situations and at treating physician's discretion, for some Day 1 even cycles to be conducted as telemedicine visits. Some standard in clinic assessments (i.e., symptoms/adverse event, blood pressure and heart rate) will not be conducted with these remote visits. To maintain data integrity, these missed assessments are to be noted in the EDC as protocol deviations (planned) and indicate the visit was conducted remotely. For purposes of regulatory reporting, these are not considered Protocol Deviations and will not require reporting to your IRB/REB, or the Duke Principal Investigator or designee to determine safety.  
Protocol Violations: Any protocol violation that occurs must be reported to your IRB/REB per institutional policies and reported to the Criterium Project Manager within 5 days.  
Duke Principal Investigator or designee will determine if the violation affects the safety of the patient and integrity of the data. Once your institution's IRB/REB response is received, please forward to the Criterium Project Manager within 5 business days of receipt via email.
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9.5.3 termination rules

The Duke principal investigator and the study sponsor have the right to terminate this clinical study at any time. The Duke principal investigator and study sponsor, as appropriate, will be involved in any decisions regarding terminating the study, temporarily suspending enrollment, or stopping ongoing treatment with study treatment. Reasons for terminating the clinical study or a study site's participation include, but are not limited to, the following:  
- The incidence or severity of an adverse reaction related to treatment in this study or other studies indicates a potential health hazard to patients
- Patient enrollment is unsatisfactory - Data recording is significantly inaccurate or incomplete
- Study site personnel are noncompliant with study procedures
- Pattern of noncompliance is observed
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9.6 amendments to the protocol

Should amendments to the protocol be required, the amendments will be originated and documented by the Principal Investigator at Duke. It should also be noted that when an amendment to the protocol substantially alters the study design or the potential risk to the patient, a revised consent form might be required. The written amendment, and if required the amended consent form, must be sent to your site IRB/REB for approval prior to implementation. All sites must submit their informed consent revisions to the Criterium Project Manager or designee for review and approval prior to submission to their IRB/REB.
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9.7 record retention

Study documentation includes all eCRFs, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB/REB correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study. Government agency regulations and directives require that all study documentation pertaining to the conduct of a clinical trial must be retained by the study investigator. In the case of a study with a drug seeking regulatory approval and marketing, these documents shall be retained for at least two years after the last approval of marketing application in an International Conference on Harmonization (ICH) region. In Canada the Principal Investigator will retain the study records in a secure and confidential location for 25 years as required by Canadian law. In all other cases, study documents should be kept on file until three years after the completion and final study report of this investigational study.
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9.8 obligations of investigators

The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of all study patients. The Principal Investigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study completion.  
The Principal Investigator at each institution or site will be responsible for assuring that all the required data will be collected and entered into the eCRFs. Periodically, data monitoring will be conducted and the Principal Investigator or designee must provide de-identified source upon request to permit remote verification of proper entry of data. At the completion of the study, all eCRFs will be reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of the data.
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10.0 appendices appendix a ecog

Grade **Description**  
| 0   | Fully active, able to carry on all pre-disease performance without  restriction.                                                                           |
|-----|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1   | Restricted in physically strenuous activity but ambulatory and able to carry  out work of a light or sedentary nature (e.g. light housework, office work). |
| 2   | Ambulatory and capable of all self-care but unable to carry out any work  activities. Up and about more than 50% of waking hours.                          |
| 3   | Capable of only limited self-care, confined to bed or chair more than 50%  of waking hours.                                                                |
| 4   | Completely disabled. Cannot carry on any self-care. Totally confined to  bed or chair.                                                                     |  
Appendix B: Model Patient Diary for Brigatinib (see as auxiliary patient document) Appendix C: **Prohibited Drugs, Juices and Herbal Supplements, and Medications to be used**
with Caution (see as auxiliary patient document)
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