Targeted Treatment for ALK Positive Patients Who Have Previously Been Treated for Non-squamous Non-small Cell Lung Cancer
Condition: Lung Non-Squamous Non-Small Cell Carcinoma; Stage IV Lung Cancer AJCC v8; Stage IVA Lung Cancer AJCC v8; Stage IVB Lung Cancer AJCC v8
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Alectinib; Brigatinib; Carboplatin; Ceritinib; Cisplatin; Crizotinib; Ensartinib; Lorlatinib; Pemetrexed
Intervention description: Given PO; Given PO; Given IV; Given PO; Given IV; Given PO; Given PO; Given PO; Given IV
Intervention MeSH terms: Cisplatin; Carboplatin; Pemetrexed; Crizotinib; Ceritinib; Ensartinib; Tyrosine Protein Kinase Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This National Cancer Institute (NCI)-NRG ALK Protocol phase II trial studies how well a
      combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK
      positive non-squamous non-small cell lung cancer. Lorlatinib, ceritinib, alectinib,
      brigatinib, ensartinib, and crizotinib may stop the growth of tumor cells by blocking some of
      the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed,
      cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either
      by killing the cells, by stopping them from dividing, or by stopping them from spreading. It
      is not yet known whether a combination of biomarker/ALK inhibitors or chemotherapy may work
      better in treating patients with ALK positive non-squamous non-small cell lung cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  PRIOR TO STEP 1 REGISTRATION

          -  Patients must have histologically or cytologically confirmed stage IV ALK-positive
             non-squamous non-small cell lung carcinoma (NSCLC) (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 (FDA) approved assay
             (Vysis fluorescence in situ hybridization [FISH] or Ventana immunohistochemistry
             [IHC]) or by next generation sequencing (NGS)

          -  Patient must be willing and able to undergo a fresh biopsy or if patient has a biopsy
             after progression on current tyrosine-kinase inhibitor (TKI) within 3 months of study
             enrollment (and has continued TKI for clinical benefit per treating physician) this
             tissue may be used. Must have sufficient tissue

          -  Patient must have progressive disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1 after one second generation ALK inhibitor, including LDK378
             (ceritinib), alectinib, ensartinib, and brigatinib (may not have received more than
             one second-generation ALK inhibitor). Patient may have received prior crizotinib;
             however, the second generation ALK inhibitor received must be the last treatment given
             prior to study enrollment

               -  Prior lorlatinib (third-generation ALK inhibitor) is not allowed

          -  Prior chemotherapy is not allowed except for one prior cycle received at the time of
             original diagnosis of metastatic NSCLC with no evidence of disease progression
             following the cycle. NOTE: prior adjuvant or neoadjuvant chemotherapy is allowed if
             last dose was received more than 12 months prior to enrollment

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to Step 1 Registration

          -  PRIOR TO STEP 2 REGISTRATION

          -  Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 28 days prior to step 2
             registration)

          -  Platelets >= 100,000 cells/mm^3 (within 28 days prior to step 2 registration)

          -  Estimated creatinine clearance >= 60 mL/min by the Cockcroft Gault formula (within 28
             days prior to step 2 registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with
             documented Gilbert's syndrome) (within 28 days prior to step 2 registration)

          -  Aspartate aminotransferase (AST) =< 2.5 x ULN; =< 5 x ULN if liver metastases are
             present (within 28 days prior to step 2 registration)

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN; =< 5 x ULN if liver metastases are
             present (within 28 days prior to step 2 registration)

          -  Patients with asymptomatic treated or untreated brain metastases are eligible. 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 7 days prior to step 2 registration. Anticonvulsants are allowed
             as long as the patient is neurologically stable and not deteriorating

          -  Patients enrolled with asymptomatic brain metastases (mets) must have at least one
             measurable target extracranial lesion according to RECIST 1.1

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  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)

          -  Not taking any medications that may interact with selected study medication based on
             stratification

          -  Patients must be able to take oral medications (i.e. swallow whole tablets/capsules)

          -  All females of childbearing potential must have a blood test or urine study within 14
             days prior to Step 2 Registration to rule out pregnancy. A female of childbearing
             potential is any woman, regardless of sexual orientation or whether they have
             undergone tubal ligation, who 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

        Exclusion Criteria:

          -  Major surgery within 2 weeks of study entry. Minor surgical procedures (e.g., port
             insertion, pleurex catheter placement) are allowed and all wounds must not show signs
             of infection or draining

          -  Palliative RT (< 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 RT or other palliative RT must have
             been completed at least 2 weeks prior to study entry

          -  Prior dose of next generation ALK inhibitor (LDK378 [ceritinib], alectinib,
             ensartinib, lorlatinib) within 5 days prior to step 2 registration. Prior dose of
             brigatinib within 7 days prior to step 2 registration

          -  History of interstitial lung disease or interstitial fibrosis, including a history of
             pneumonitis, obliterative bronchiolitis, pulmonary fibrosis. Patients with a history
             of prior radiation pneumonitis are not excluded

          -  Active inflammatory gastrointestinal disease (such as Crohns, ulcerative colitis),
             chronic diarrhea, symptomatic diverticular disease, or any gastrointestinal disease
             that would affect the absorption of oral medications or increase the risk of toxicity

          -  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 6 months

          -  Active and clinically significant bacterial, fungal, or viral infection

          -  Patients with active or chronic pancreatitis based on lipase elevation, symptoms, and
             radiographic findings

          -  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

          -  Patients must not plan to receive any other investigational agents during the course
             of therapy

          -  Patients with active malignancy other than ALK-positive non-squamous NSCLC within the
             last 2 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 2 years are eligible)

          -  No chemotherapy and/or immunotherapy allowed after step 1 registration