Regorafenib and Methotrexate in Treating Participants With Recurrent or Metastatic KRAS Mutated Non-Small Cell Lung Cancer
Condition: KRAS Gene Mutation; Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer AJCC v7
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms
Intervention: Methotrexate; Pharmacokinetic Study; Regorafenib
Intervention description: Given PO; Correlative studies; Given PO
Intervention MeSH terms: Methotrexate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well regorafenib works together with methotrexate in treating
      participants with metastatic non-squamous non-small cell lung cancer with tumors that harbor
      a KRAS mutation. Regorafenib is a targeted therapy that works on different cancer pathways to
      stop the growth of tumor cells and stop them from spreading. Methotrexate may stop the growth
      of tumor cells by blocking some of the enzymes needed for cell growth. Giving regorafenib and
      methotrexate together may work in treating participants with KRAS mutated non-small cell lung
      cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologic or cytologic confirmed diagnosis of non-squamous non-small cell lung cancer
             that is recurrent or metastatic.

          -  Documentation of pathogenic KRAS mutation

          -  Previous receipt of at least one systemic therapy for recurrent or metastatic disease
             OR previous receipt of adjuvant systemic therapy within 6 months of enrollment; there
             is no limit on number of prior therapies allowed

          -  Prior systemic therapy must be completed within 2 weeks of study treatment, with
             either improvement of clinically significant treatment-related toxicities to grade 0-1
             OR stabilized to a new baseline

          -  Previously treated OR asymptomatic non-progressing < 1 cm untreated brain metastases
             are allowed

          -  Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
             version 1.1 criteria

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Absolute neutrophil count (ANC) ≥ 1500/mm^3

          -  Platelet count ≥ 100,000 /mm^3

          -  Hemoglobin (Hb) ≥ 9 g/dL

          -  Serum creatinine ≤ 1.5x upper limit of normal (ULN) OR calculated (Cockcroft Gault
             formula) or measured creatinine clearance ≥ 50 mL/min for patients with creatinine
             levels > 1.5x ULN

          -  Total bilirubin ≤ 1.5x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin
             levels > 1.5x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x ULN (≤ 5x ULN
             for patients with liver involvement of their cancer)

          -  Must be able to swallow and retain oral medication

          -  Women patients of childbearing potential and men patients with women partners of
             childbearing potential must agree to use adequate contraception or agree to abstain
             from heterosexual activity beginning at the time of signing informed consent until at
             least 3 months after the last dose of study treatment; post-menopausal women (defined
             as no menses for at least 1 year) and surgically sterilized women are not considered
             childbearing

        Exclusion Criteria:

          -  Previously treated with regorafenib

          -  Known allergy to regorafenib or methotrexate

          -  Currently receiving another systemic standard or investigational anti-cancer therapy;
             prior investigational therapy must be completed within 4 half-lives (if known) or 2
             weeks, whichever is longer; the maximal washout of investigational therapy will not
             exceed 4 weeks prior to study treatment; bone medications such as bisphosphonates and
             receptor activator of nuclear factor kappa-Β (RANK) ligand inhibitors permitted

          -  Leptomeningeal disease as documented by cerebrospinal fluid (CSF) cytology

          -  Clinically significant cardiovascular related disease including:

               -  Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure >
                  90 mmHg on repeated measurements, i.e., 3 or more separate days within one week)
                  despite optimal medical management

               -  Congestive heart failure - New York Heart Association (NYHA) class III or greater

               -  Active coronary artery disease (i.e., unstable or new onset angina within 3
                  months of study treatment; myocardial infarction within 6 months of study
                  treatment)

               -  Clinically significant cardiac arrhythmias other than atrial flutter/fibrillation

               -  Stroke, including transient ischemic attacks, within 6 months of study treatment

               -  Other clinically significant arterial events, except for controlled asymptomatic
                  pulmonary embolism, within 6 months of study treatment

          -  Clinically significant hemorrhage or bleeding event within 1 month of study treatment

          -  Uncontrolled symptomatic pleural effusion or ascites

          -  Known active additional malignancy that is undergoing or expected to undergo systemic
             treatment during duration of study participation

          -  Known history of human immunodeficiency virus (HIV) infection or known current active
             hepatitis B (i.e., hepatitis [Hep] B deoxyribonucleic acid [DNA] positive in prior 3
             months) or hepatitis C infection (i.e., Hep C ribonucleic acid [RNA] positive in prior
             3 months)

          -  Major surgical procedure (e.g., involving the opening of a major body cavity) within 4
             weeks of study treatment; this does not apply to low risk procedures (i.e.,
             thoracentesis; paracentesis; chest tube / PleurX catheter placement; line placement;
             needle biopsy of tumor; and bronchoscopy)

          -  Presence of a clinically significant non-healing wound, non-healing ulcer, or bone
             fracture

          -  Concomitant therapy required at time of first dose of study treatment, including:

               -  Strong CYP3A4 inhibitors and CYP3A4 inducers

               -  Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump
                  inhibitors, and probenecid

          -  Women who are pregnant or breast feeding

          -  Any condition which, in the investigator's opinion, including substance abuse,
             medical, psychological or social conditions that makes the patient unsuitable for
             trial participation or may interfere with the patient's participation in the study