Durvalumab (MEDI4736) With or Without SBRT in Clinical Stage I, II and IIIA Non-small Cell Lung Cancer
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Durvalumab; Durvalumab plus SBRT
Intervention description: Intravenously; Intravenously plus radiotherapy
Intervention MeSH terms: Durvalumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Lung neoplasms; Bronchial Neoplasms; Carcinoma, bronchogenic; Neoplasms; Neoplasms by site; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms

Summary:

      The purpose of this study is to find out the effectiveness of the drug durvalumab (MEDI4736)
      with or without stereotactic body radiation therapy (SBRT) as treatment for stage I (tumors >
      2cm), II, and IIIA non-small cell lung cancer (NSCLC) prior to surgery and one year following
      surgery.
    

Eligibility criteria:

        Inclusion Criteria

          1. Patient has histologically or cytologically proven clinical stages I (tumors > 2 cm),
             II, and IIIA NSCLC and is considered eligible for surgical resection with curative
             intent. Patients with 2 primary non-small cell lung cancers are allowed.

          2. Measureable disease, as defined by RECIST v1.1.

          3. Written informed consent and HIPAA obtained from the subject prior to performing any
             protocol-related procedures.

          4. Age > 18 years at time of study entry

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          6. Adequate normal organ and marrow function as defined below:

               -  Haemoglobin ≥ 9.0 g/dL

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)

               -  Platelet count ≥ 100 x 109/L (>100,000 per mm3)

               -  Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not
                  apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
                  hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
                  or hepatic pathology), who will be allowed only in consultation with their
                  physician.

               -  AST (SGOT)/ALT (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit
                  of normal (ULN).

               -  Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
                  1976) or by 24-hour urine collection for determination of creatinine clearance:

          7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

             Women <50 years of age would be considered post-menopausal if they have been
             amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
             and if they have luteinizing hormone and follicle-stimulating hormone levels in the
             post-menopausal range for the institution or underwent surgical sterilization
             (bilateral oophorectomy or hysterectomy).

             Women ≥50 years of age would be considered post-menopausal if they have been
             amenorrheic exogenous hormonal treatments, had radiation-induced menopause with last
             menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago,
             or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy
             or hysterectomy).

          8. Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

          9. No prior therapy for their lung cancer.

        Exclusion Criteria

        Subjects should not enter the study if any of the following exclusion criteria are
        fulfilled:

          1. Participation in another clinical study with an investigational product during the
             last 3 weeks.

          2. History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease ≥3 years
                  before the first dose of study drug and of low potential risk for recurrence.

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               -  Adequately treated carcinoma in situ without evidence of disease eg, cervical
                  cancer in situ, in-situ urinary bladder cancer , treated localized prostate
                  cancer and ductal carcinoma-in situ.

               -  Indolent hematological malignancies

          3. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab, with the exceptions of intranasal,inhaled, topical steroids, or
             local steroid injections (e.g., intra articular injection), corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid, and steroids as premedication for
             hypersensitivity reactions (e.g., CT scan premedication).

          4. Any unresolved toxicity (CTCAE grade 2) from therapy for a prior malignancy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria.

               -  Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.

               -  Subjects with irreversible toxicity that is not reasonably expected to be
                  exacerbated by the investigational product may be included (e.g., hearing loss,
                  peripherally neuropathy).

          5. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1.

          6. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease systemic lupus
             erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
             polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). No
             active diverticulitis within the previous 3 months. The following are exceptions to
             this criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               -  Patients with celiac disease controlled by diet alone

          7. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis).

          8. History of active primary immunodeficiency.

          9. History of allogeneic organ transplant.

         10. History of hypersensitivity to durvalumab or any excipient.

         11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, serious chronic gastrointestinal conditions
             associated with diarrhea, or psychiatric illness/social situations that would limit
             compliance with study requirement, substantially increase risk of incurring AEs or
             compromise the ability of the patient to give written informed consent.

         12. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and TB testing in line with
             local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
             hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
             with a past or resolved HBV infection (defined as the presence of hepatitis B core
             antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

         13. History of leptomeningeal carcinomatosis.

         14. Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab.

         15. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy.

         16. Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

         17. Subjects with uncontrolled seizures.

         18. History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis
             (including drug induced), or evidence of active pneumonitis on screening chest CT
             scan.

         19. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
             need for a major surgical procedure during the course of the study.

         20. Receipt of the last dose of therapy (chemotherapy, immunotherapy, endocrine therapy,
             targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, or
             other investigational agent) for an accepted other malignancy as defined in Section
             3.3.2 within 30 first dose of study drug for lung cancer.

         21. Prior randomisation or treatment in a previous durvalumab clinical study regardless of
             treatment arm assignment.