Trial of Brigatinib After Treatment With Next-Generation ALK Inhibitors

Phase 2 Trial of Brigatinib After Treatment With Next-Generation ALK Inhibitors in Refractory ALK Rearranged Non-Small Cell Lung Cancer (NSCLC)

The purpose of this study is to evaluate the safety and effectiveness of this investigational drug, brigatinib (AP261136) in patients with advanced non-small cell lung cancer Non-small cell lung cancer (NSCLC) who have had first-line treatment for their cancer and it still got worse, even after, or while taking drugs called ALK inhibitors, or anti-cancer drugs that act on tumors. Some examples of these anti-cancer drugs are: KEYTRUDA® or ALECENSA®).

A significant population of Anaplastic Lymphoma Kinase (ALK) plus Non-small cell lung cancer patients exist that have progressed on or who were intolerant of second generation anaplastic lymphoma kinase inhibitor (e.g. ceritinib or alectinib). Brigatinib has demonstrated activity in patients who have progressed on crizotinib, but the activity of brigatinib in patients who have progressed on ceritinib, alectinib, or other second generation anaplastic lymphoma kinase inhibitors is unknown. Based on the preclinical data. 3, , brigatinib has activity against known secondary anaplastic lymphoma kinase mutations suggesting it may retain activity after second-generation anaplastic lymphoma kinase inhibitors.

Patients enrolled in ARI-AT-002 must have previously received a second generation Anaplastic lymphoma kinase inhibitor other than brigatinib. We have chosen 20% as a clinically meaningful response rate that would justify further study of brigatinib in previously treated anaplastic lymphoma kinase plus disease.

Inclusion Criteria:

Locally advanced or metastatic NSCLC that has been cytologically or histologically confirmed

ALK rearrangement based on FDA approved test (e.g. Vysis breakapart FISH or IHC using Ventana)

ECOG PS ≤2

Age of ≥ 18 years

Brain lesions may be used as target lesions if progressing, ≥10mm in longest diameter and if they were not previously treated with any of the following:

• Whole brain radiation therapy (WBRT) within 3 months
• Stereotactic radiosurgery (SRS)
• Surgical resection Availability of core biopsy of progressive lesion taken within 60 days prior to D1 of treatment under study therapy or willing to undergo tumor biopsy: NOTE:. 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.
• In the situation the patient undergoes biopsy within 60 days prior to D1. and there is insufficient tumor tissue subjects for the correlative science part of the protocol patient will be permitted to enroll on the study with prior approval of the study PI
• In the situation the patient undergoes molecular testing or next-generation sequencing as part of standard care there must be sufficient tumor sample available for participation in the study (i.e. a next generation sequencing report is not sufficient for enrollment)

Recovered from toxicities related to prior anticancer treatment to ≤Grade 2 or baseline with the exception of alopecia

Have normal QT interval on ECG evaluation QT corrected Fridericia (QTcF) of ≤ 450 ms in males or ≤ 470 ms in females

Adequate organ function defined as:

Absolute neutrophil count (ANC) ≥1500/µL Platelets ≥75,000/µL Hemoglobin≥ 10g/dL AST /ALT ≤ 2.5 x upper limit of normal (ULN); ≤ 5 x ULN if liver metastasis Total serum bilirubin ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x UNL Serum amylase ≤ 1.5 x UNL

At least 1 measurable lesion per RECIST version 1.1

Negative serum pregnancy test within 7 days of D1 of treatment in women of child bearing potential (WOCBP)

If fertile, willing to use highly effective form of contraception (defined as a combination of at least two of the following methods: condom or other barrier methods, oral contraceptives, implantable contraceptives, intrauterine devices) during the dosing period and for at least 4 months after

Ability to provide signed informed consent and willing and able to comply with all study requirements

Inclusion criteria for cohort assignment:

Cohort A: Progressive disease on any next generation ALK inhibitor except first line alectinib or brigatinib (any line)

Cohort B: Progressive disease on first-line therapy with alectinib, and no other ALK inhibitors

Cohort C: Previous treatment brigatinib at 180 mg daily for ≥4 weeks without > grade 2 drug-related toxicities and with radiographic evidence of progressive disease and no intervening systemic therapies such as chemotherapy, immunotherapy or another ALK inhibitor (radiation therapy allowed as intervening therapy). Patients who are treated on cohorts A and B will be allowed to enroll in cohort C if the meet the inclusion and exclusion criteria

Exclusion Criteria for cohorts A, B, and C:

Patients meeting any of the following exclusion criteria will not be able to participate in this study:

History or the presence of pulmonary interstitial disease, drug-related or immune-related pneumonitis, or radiation pneumonitis requiring medical management within 6 months of trial enrollment

Prior treatment with brigatinib for cohorts A and B

History of or active significant gastrointestinal (GI) bleeding within 3 months

Malabsorption syndrome or other GI illness that could affect oral absorption of the study drug

Received cytotoxic chemotherapy, investigational agents or radiation within 7 days prior to D1 of study treatment

Received prior ALK TKI therapy within 7 days prior to D1 of treatment under study drug. 7 day wash out period is required after prior ALK inhibitor treatment.

Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

• Myocardial infarction (MI) within 6 months of trial enrollment
• Unstable angina within 6 months of trial enrollment
• Congestive heart failure (CHF) with 6 months prior to trial enrollment
• Any history of ventricular arrhythmia
• Cerebrovascular accident or transient ischemic attack within 6 months of D1 of study treatment
• Clinically significant atrial arrhythmia or severe baseline bradycardia defined as resting heart rate < 60 beat per minute
• Uncontrolled hypertension defined as baseline SBP> 160 and DBP > 100 on 3 separate clinic visits or past history of hypertensive urgency, emergency or encephalopathy

Have been diagnosed with another primary malignancy within the past 3 years (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer, which are allowed within 3 years)

Have symptomatic CNS metastases which require an increasing dose of corticosteroids within the last 2 weeks to remain asymptomatic.

Have active infection requiring intravenous antibiotics

Pregnant or breastfeeding

Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with evaluation of the study drug.