Patient case: 49-year-old female with lung cancer; genetic feature: ERBB2

Clinical trial: Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

Summary: This randomized phase II trial studies the side effects and how well nintedanib works compared to a placebo in treating against radiation-induced pneumonitis (inflammation of the lungs) in patients with non-small cell lung cancer that cannot be removed by surgery and are undergoing chemoradiation therapy. Nintedanib may help shrink or slow the growth of radiation-induced pneumonitis by blocking some of the enzymes needed for cells to grow and may prevent the growth of new blood vessels. It may also help reduce the recurrence of non-small cell lung cancer.

Detailed description: PRIMARY OBJECTIVES:
  I. To compare the rate of symptomatic radiation pneumonitis in patients with unresectable Stage II/III/ oligometastatic IV non-small cell lung carcinoma (NSCLC) who completed chemoradiation followed by nintedanib versus placebo.
  SECONDARY OBJECTIVES:
  I. To compare the quality of life (QOL) in patients who received nintedanib versus placebo during active treatment until 6 months after completion of treatment.
  II. To compare the progression-free survival, overall survival and 1-year progression-free survival rate in patients who received nintedanib versus placebo.
  III. To compare pulmonary function test (PFT) results and radiation pneumonitis (RP) score in patients who received nintedanib versus placebo.
  IV. To compare the composite index (based on PFT, RP score and QOL) at the end of active treatment and 6 months after completion of treatment between patients who received nintedanib versus placebo.
  V. To investigate blood-based biomarkers in evaluating risk of developing radiation pneumonitis as well as the efficacy of nintedanib.
  OUTLINE: Patients are randomized to 1 of 2 arms.
  ARM I: Beginning 4-6 weeks after completion of radiation therapy, patients receive nintedanib orally (PO) twice daily (BID) on days 1-30. Treatment repeats every 30 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  ARM II: Beginning 4-6 weeks after completion of radiation therapy, patients receive placebo capsules PO BID on days 1-30. Treatment repeats every 30 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up at 30 days, between 76-97 days, between 166-187 days, and then between 2-2.5 years.

Eligibility: Inclusion Criteria:
  -  Histologically or cytologically-proven NSCLC; mixed histology with small cell lung carcinoma (SCLC) component not allowed
  -  Patients with stage II - IV NSCLC who received at least 54 Gy of total planned thoracic radiation dose will be eligible; patients must have received at least one cycle of chemotherapy concurrently during the course of thoracic radiation; regimens allowed are platinum combinations with either etoposide or a taxane regardless of histology subtype; platinum with pemetrexed for patients with nonsquamous NSCLC only; patients with oligometastatic stage IV cancer are eligible if they have received only one line of systemic therapy for their stage IV cancer prior to the concurrent chemoradiation phase
  -  Patient must have had a CR/PR/SD, 4-6 weeks after completing last fraction of chemotherapy / radiation therapy.
  -  Eastern Cooperative Oncology Group (ECOG) performance score 0-2 at the time of randomization
  -  Absolute neutrophil count (ANC) >= 1,500/uL
  -  Platelet count >= 100,000/uL
  -  Hemoglobin >= 9 g/dL
  -  Total bilirubin =< 1.5 times upper limit of normal (ULN) OR direct bilirubin normal (per institute standards)
  -  Aspartate aminotransferase (AST) =< 1.5 x ULN; alanine aminotransferase (ALT) and AST =< 3 x ULN is acceptable if there is liver metastasis
  -  Fertile patients must use adequate contraception
  Exclusion Criteria:
  -  Whole-brain radiotherapy (WBRT) < 14 days from the anticipated start of nintedanib/placebo administration
  -  Unable to start nintedanib/placebo treatment between 4 - 6 weeks after completing the last dose of thoracic radiation
  -  Active untreated brain or leptomeningeal metastases; in patients with treated central nervous system (CNS) metastases, eligible if symptoms controlled for at least 4 weeks; dexamethasone allowed if total daily dose does not exceed 2 mg
  -  Major injuries or surgery (e.g., craniotomy) < 28 days from the start of nintedanib/placebo administration; wound should be healed prior to starting therapy
  -  Second malignancies are allowed as long as the disease does not require active treatment with concomitant systemic cytotoxic chemotherapy, investigational or biologic therapy (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] or human epidermal growth factor receptor 2 [HER2] monoclonal antibodies); hormone-related therapies (e.g., gonadotrophin releasing hormone (LHRH) agonists, tamoxifen, etc.) are allowed
  -  Concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would increase the risk associated with study participation and/or limit compliance with study requirements
  -  Inability to swallow study medication
  -  Presence of malabsorption disorder or history of extensive small bowel resection
  -  Known bleeding or thrombotic diathesis
  -  History of arterial or venous thromboembolic event within 12 months prior to study participation
  -  Active hemoptysis or history of clinically relevant hemoptysis as determined by the treating physician; patients who had history of transient minor hemoptysis after bronchoscopic biopsy are eligible unless deemed otherwise by the treating physician
  -  Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher proteinuria
  -  Systemic therapy or investigational agent administered < 28 days prior to treatment with nintedanib
  -  Known chronic active hepatitis B or hepatitis C; human immunodeficiency virus (HIV)-positive patients receiving or are candidates for antiretroviral therapy are also excluded
  -  Pregnancy or breast feeding; female patients with child-bearing potential must have a negative pregnancy test (beta-human chorionic gonadotropin [B-HCG] test in urine or serum) prior to commencing study treatment
  -  Creatinine > 1.5 x ULN or creatinine clearance levels (CrCL) < 45 mL/min
  -  Centrally located tumors with radiographic evidence (computed tomography [CT] or magnetic resonance imaging [MRI]) of local invasion of major blood vessels
  -  Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day)

Relevance to patient case: not relevant