NRG-LU003: A biomarker-driven protocol for previously treated ALK-positive non-squamous NSCLC patients: The NCI-NRG ALK Protocol

Including patients who:

Prior to step one registration

• Have histologically or cytologically confirmed stage IV ALK-positive non-squamous non-small cell lung carcinoma (NSCLC) (Notes: Includes M1a, M1b, M1c stage disease, American Joint Committee on Cancer [AJCC] 8th edition; ALK rearrangement must have been demonstrated by a Food and Drug Administration approved assay [Vysis fluorescence in situ hybridization or Ventana immunohistochemistry or by next generation sequencing.]
• Must be willing and able to undergo a fresh biopsy or if patient has a biopsy after progression on current tyrosine-kinase inhibitor (TKI), and has continued TKI for clinical benefit per treating physician, this tissue may be used
• Must have progressive disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 after a second generation ALK inhibitor, including LDK378 (ceritinib), alectinib, ensartinib, and brigatinib or third generation ALK inhibitor referring to lorlatinib (Notes: The next generation ALK inhibitor must be the last ALK inhibitor given. Prior crizotinib is allowed.)
• Have received a cycle of chemotherapy at the time of original diagnosis of metastatic NSCLC, if they have received a next generation ALK inhibitor
• Must provide study-specific informed consent

Prior to step two registration

• Have, within 28 days to step two registration:

• Absolute neutrophil count (ANC) >= 1500 cells/mm^3
• Platelets >= 100,000 cells/mm^3
• Estimated creatinine clearance >= 60 mL/min by the Cockcroft Gault formula
• Total bilirubin =< 1.5 x upper limit of normal (ULN), except for patients with documented Gilbert's syndrome
• Aspartate aminotransferase (AST) =< 2.5 x ULN; =< 5 x ULN if liver metastases are present
• Alanine aminotransferase (ALT) =< 2.5 x ULN; =< 5 x ULN if liver metastases are present

• Have asymptomatic treated or untreated brain metastases. (Notes: Treated brain metastases are eligible as long as patients have measurable disease outside the brain according to RECIST 1.1. Patients must be on a stable or decreasing dose of steroids for at least seven days prior to step two registration. Anticonvulsants are allowed as long as the patient is neurologically stable and not deteriorating
• Have at least one measurable target extracranial lesion according to RECIST 1.1, if enrolled with asymptomatic brain metastases
• Have Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Have acute effects of any prior therapy resolved to baseline severity or to Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 (except for alopecia, hearing loss)
• Are not taking any medications that may interact with selected study medication based on stratification
• Must be able to take oral medications (i.e. swallow whole tablets/capsules)
• If female of childbearing potential, must have a blood test or urine study within 14 days prior to step two registration to rule out pregnancy

• If female of childbearing potential, any woman, regardless of sexual orientation or whether they have undergone tubal ligation, meets the following criteria:
  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from ALK inhibitors and the unknown risk. Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study

Excluding patients who:

• Had major surgery within two weeks of study entry. (Note: Minor surgical procedures, such as port insertion, pleurex catheter placement, are allowed and all wounds must not show signs of infection or draining.)
• Had radiation therapy (except palliative radiation therapy to relieve bone pain) within two weeks of study entry. (Note: Palliative radiation therapy (< 10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have completed at least 1 week prior to study entry. Whole brain radiation therapy must have completed at least two weeks prior to study entry.)
• Had a prior dose of next generation ALK inhibitor (ceritinib, alectinib, ensartinib, lorlatinib) within five days prior to step two registration or prior dose of brigatinib within seven days prior to step two registration
• Have a history of interstitial lung disease or interstitial fibrosis, including a history of pneumonitis, obliterative bronchiolitis, pulmonary fibrosis. (Note: Patients with a history of prior radiation pneumonitis are not excluded.)
• Have active inflammatory gastrointestinal disease, such as Crohn’s disease or ulcerative colitis, or chronic diarrhea, symptomatic diverticular disease, or any gastrointestinal disease that would affect the absorption of oral medications or increase the risk of toxicity
• Have clinically significant cardiovascular abnormalities, as determined by the treating/registering physician, such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within six months
• Have active and clinically significant bacterial, fungal, or viral infection
• Have active or chronic pancreatitis based on lipase elevation, symptoms, and radiographic findings
• Have other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug
• Do not plan to receive any other investigational agents during therapy
• Have active malignancy other than ALK-positive non-squamous NSCLC within the last two years are excluded (Note: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, papillary thyroid cancer treated with curative intent, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years are eligible.)
• Have not had chemotherapy and/or immunotherapy after step 1 registration