Nintedanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer
Condition: Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Nintedanib
Intervention MeSH terms: Nintedanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      There has been limited benefit with angiogenesis inhibitor drugs in molecularly unselected
      patients in non-small cell lung cancer (NSCLC). The investigators propose that patients who
      are molecularly selected for treatment with nintedanib based on the presence of mutations in
      the following genes: VEGFR1-3, PDGFR-A, PDGFR-B, FGFR1-3, and TP53, will have clinically
      meaningful benefit in terms of response rate (RR) and progression-free survival (PFS).
      Furthermore the investigators plan to correlate outcomes with specific mutations and evaluate
      mechanisms of resistance.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of advanced (metastatic or unresectable) NSCLC with
             mutations, rearrangement and fusion involving RET oncogene, or abnormalities
             (non-synonymous SNV or amplification) in the nintedanib target genes VEGFR1-3, TP53,
             PDGFR-A, PDGFR-B, and FGFR1-3. CLIA certified lab testing for nintedanib target genes
             using cell free DNA from peripheral blood and/or assays performed on tumor tissues are
             acceptable.

          -  Patients with EGFR mutations or ALK rearrangements must have disease progression on
             appropriate FDA-approved therapy for these genomic aberrations prior to enrollment.

          -  Disease progression on platinum-doublet chemotherapy prior to enrollment.

          -  At least one measurable lesion or evaluable disease. Measurable disease is defined as
             lesions that can be accurately measured in at least one dimension (longest diameter to
             be recorded) as ≥10 mm with CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers
             by clinical exam.

          -  Prior treatment of cancer (chemotherapy, radiation therapy, and surgery) is allowed if
             completed at least 3 weeks prior to start of treatment with nintedanib and if all
             treatment-related toxicities are resolved.

          -  At least 18 years of age.

          -  ECOG performance status 0-1

          -  Normal bone marrow and organ function as defined below:

               -  Leukocytes ≥ 3,000/mcL

               -  Absolute neutrophil count ≥ 1,500/mcL

               -  Platelets ≥ 100,000/mcL

               -  Hemoglobin ≥ 9.0 g/dL

               -  INR < 2.0

               -  PT and PTT < 50% of deviation from IULN

               -  Total bilirubin ≤ 1.5 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN for patients without liver metastases and ≤ 2.5
                  x IULN for patients with liver metastases

               -  Urine protein < 2+

               -  Creatinine within normal institutional limits OR Creatinine clearance > 45 mL/min
                  for patients with creatinine levels above institutional normal

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry, for
             the duration of study participation, and for 3 months after the end of treatment.
             Should a woman become pregnant or suspect she is pregnant while participating in this
             study, she must inform her treating physician immediately.

          -  Able to understand and willing to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Prior treatment with VEGFR tyrosine kinase inhibitors.

          -  A history of other malignancy ≤ 5 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only or
             carcinoma in situ of the cervix.

          -  Currently receiving any other investigational agents, or received an investigational
             agent within 3 weeks of the first dose of nintedanib.

          -  Radiotherapy to the target lesion within the past 3 months prior to baseline imaging.

          -  Symptomatic brain metastases. Patients with known brain metastases are eligible if the
             metastases are asymptomatic and previously treated.

          -  Leptomeningeal disease.

          -  Radiographic evidence of cavitary or necrotic tumors.

          -  Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of
             major blood vessels.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to nintedanib or other agents used in the study.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure > NYHA II, active coronary artery
             disease, unstable angina pectoris, serious cardiac arrhythmia, uncontrolled
             hypertension (defined as systolic pressures > 150 mmHg or diastolic pressure > 90
             mmHg), pericardial effusion, uncontrolled seizure disorder, or psychiatric
             illness/social situations that would limit compliance with study requirements.

          -  Major injuries and/or surgery with then past 4 weeks prior to the start of study
             treatment with incomplete wound healing and/or planned surgery during the on-treatment
             study period.

          -  History of clinically significant hemorrhagic or thromboembolic event in the past 6
             months.

          -  Known inherited predisposition to bleeding or thrombosis.

          -  History of cardiac infarction within the past 12 months prior to the start of study
             treatment.

          -  Receiving therapeutic anticoagulation (except low-dose heparin and/or heparin flush as
             needed for maintenance of an in-dwelling intravenous device) or anti-platelet therapy
             (except for low-dose therapy with acetylsalicylic acid < 325 mg QD).

          -  Pregnant and/or breastfeeding. Patients of childbearing potential must have a negative
             pregnancy test within 14 days of study entry.

          -  Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the
             trial.

          -  Known active or chronic hepatitis B or C infection.

          -  Active alcohol or drug abuse.

          -  Gastrointestinal disorder or abnormality that would interfere with absorption of the
             study drug.

          -  Known HIV-positivity on combination antiretroviral therapy because of the potential
             for pharmacokinetic interactions with nintedanib. In addition, these patients are at
             increased risk of lethal infections when treated with marrow-suppressive therapy.
             Appropriate studies will be undertaken in patients receiving combination
             antiretroviral therapy when indicated.