A Phase III, Open-label, Randomized Study to Investigate the Efficacy and Safety of MPDL3280A (Anti-PD-L1 Antibody) Compared With Best Supportive Care Following Adjuvant Cisplatin-based Chemotherapy in PD-L1-Selected Patients With Completely Resected Stage IB-IIIA Non-small Cell Lung Cancer

The primary efficacy objective of the study is to evaluate the efficacy of 16 cycles of Atezolizumab (MPDL3280A) treatment compared with best supportive care as measured by disease-free survival (DFS) as assessed by the investigator.
Cancer (Oncology) - Lung, Cancer (Oncology)
Howard West, MD
Swedish Cancer Institute
Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Inclusion Criteria for Enrollment Phase

  • Age >/= 18 years
  • Ability to comply with protocol
  • ECOG performance status of 0 or 1
  • Histological or cytological diagnosis of Stage IB (tumors >/= 4 cm) -IIIA (T2-3 N0, T1-3 N1, T1-3 N2) NSCLC (per the UICC/AJCC staging system, 7th edition; Detterbeck et al. 2010)
  • Patients must have had complete resection of NSCLC 6-12 weeks (>/= 42 days and </= 84 days) prior to enrollment and must be adequately recovered from surgery
  • Complete mediastinal lymph node dissection (MLND) is required. If mediastinoscopy was not performed preoperatively, it is required that, at a minimum, mediastinal lymph node systematic sampling will have occurred. Systematic sampling is defined as removal of at least one representative lymph node at specified levels. MLND entails resection of all lymph nodes at those same levels. For a right thoracotomy, sampling or MLND is required at levels 4 and 7 and for a left thoracotomy, levels 5 and/or 6 and 7. If there is clear documentation in the operative report or in a separately submitted addendum by the surgeon of exploration of the required lymph node areas, the patient will be considered eligible if no lymph nodes are found in those areas. If patients have documented N2 disease in one level (per the UICC/AJCC staging system, 7th edition; Detterbeck et al. 2010), not all levels need to be sampled.
  • Eligibility to receive a cisplatin-based chemotherapy regimen
  • Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to enrollment
  • Women who are not postmenopausal (>/= 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of cisplatin-based chemotherapy.

Inclusion Criteria for Randomized Phase

- Women who are not postmenopausal (>/= 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug or BSC

Exclusion Criteria:

Exclusion Criteria for Enrollment Phase

  • Pregnant and lactating women
  • Treatment with prior systemic chemotherapy at any time
  • Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years before enrollment
  • Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrollment
  • Patients with hearing impairment
  • Known sensitivity to any component of the chemotherapy regimen the patient will be assigned to, or to mannitol
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Interstitial lung disease or history of pneumonitis
  • Malignancies other than NSCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the MPDL3280A formulation
  • History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
  • Positive test for HIV
  • Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
  • Active tuberculosis
  • Significant cardiovascular disease, such as New York Heart Association cardiac disease(Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
  • Prior allogeneic bone marrow transplantation or solid organ transplant
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

Specific Exclusions for Pemetrexed Treatment

  • Patients with squamous cell histology
  • Patients who are receiving concurrent nonsteroidal anti-inflammatory agents (NSAIDs) and are unable to discontinue treatment

Exclusion Criteria for Randomized Phase

  • Signs or symptoms of infection within 14 days prior to randomization (severe infection within 28 days prior to randomization), including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Received therapeutic oral or IV antibiotics within 14 days prior to randomization
  • Major surgical procedure within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study
  • Administration of a live, attenuated vaccine within 28 days prior to randomization or anticipation that such a live attenuated vaccine will be required during the study
  • Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to randomization
  • Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium >ULN)
  • For patients who are receiving denosumab prior to randomization, unwillingness or ineligibility to receive a bisphosphonate instead while in the study
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