Overview

Aim of this phase 2 study is to evaluate the safety and the efficacy of the combination of induction chemotherapy plus durvalumab followed by reduced-dose hypo-fractionated thoracic RT (concurrent with durvalumab) and durvalumab maintenance for stage 3 unresectable NSCLC patients candidate to sequential chemo-RT.

Eligibility

Inclusion Criteria:

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses.

   Age

3. 18 years or older at the time of signing the ICF. Type of patient and disease characteristics
4. Histologically- or cytologically-documented NSCLC with locally-advanced, unresectable Stage III disease (according to the IASLC Staging Manual Version 8 [IASLC 2016]). Positron emission tomography (PET)/CT, MRI of the brain, and endobronchial ultrasound with biopsy are highly encouraged at diagnosis.
5. Patients with measurable disease assessed at baseline by CT/MRI will be entered in this study.
6. Must have a life expectancy of at least 12 weeks at enrolment.
7. WHO/ECOG PS 0-1.
8. Patient not eligible for concurrent chemo radiation according to investigator assessment
9. Adequate organ and marrow function at enrollment as defined below. These parameters should be achieved without augmentation by growth factors, transfusions, or infusions within 28 days of screening unless required for SoC:
   1. Haemoglobin ≥9.0 g/dL;
   2. Absolute neutrophil count >1.0 × 109/L;
   3. Platelet count >75 × 109/L;
   4. Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician.
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
   6. Measured creatinine clearance >40 mL/min or calculated creatinine clearance >40 mL/min as determined by Cockcroft-Gault (using actual body weight) (Cockcroft and Gault 1976).

      Males

             Creatinine clearance (mL/min) = [Weight (kg) × (140 - Age)] / 72 × serum creatinine
             (mg/dL)
             Females:
             Creatinine clearance (mL/min) = [Weight (kg) × (140 - Age) × 0.85] / 72 × serum
             creatinine (mg/dL)
         10. Body weight >30 kg at enrollment
         11. Male or female. Reproduction
         12. 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:
               1. 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).
               2. Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all 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).
        Exclusion Criteria:Patients should not enter the study if any of the following exclusion
        criteria are fulfilled:
          1. Patients who have disease considered for surgical treatment as part of their care
             plan, such as Pancoast or superior sulcus tumors.
          2. Mixed small-cell lung cancer and NSCLC histology.
          3. History of allogeneic organ transplantation.
          4. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
             exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
             Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:
               1. Patients with vitiligo or alopecia.
               2. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement.
               3. Any chronic skin condition that does not require systemic therapy.
               4. Patients without active disease in the last 5 years at enrolment may be included
                  but only after consultation with the Study Physician.
               5. Patients with celiac disease controlled by diet alone.
          5. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated
             with diarrhoea, 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.
          6. History of another primary malignancy except for:
               1. Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of IP and of low potential risk for recurrence.
               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.
               3. Adequately treated carcinoma in situ without evidence of disease.
          7. History of leptomeningeal carcinomatosis.
          8. History of active primary immunodeficiency.
          9. Active infection including hepatitis B (known positive hepatitis B surface antigen
             [HbsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
             (positive HIV 1/2 antibodies). Patients with a past or resolved hepatitis B virus
             (HBV) infection (defined as the presence of hepatitis B core antibody [anti-HBc] and
             absence of HbsAg) are eligible. Patients positive for hepatitis C antibody are
             eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
         10. Any unresolved toxicity of NCI CTCAE Grade ≥2 from previous anticancer therapy with
             the exception of alopecia, vitiligo, and the laboratory values defined in the
             inclusion criteria.
               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.
               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the Study
                  Physician.
         11. Known allergy or hypersensitivity to durvalumab or any of the IP excipients.
             Prior/concomitant therapy
         12. Prior chemo-radiotherapy for lung cancer. Prior surgical resection (ie, Stage I or II)
             is permitted.
         13. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
             Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up
             to 30 days after the last dose of IP.
         14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP.
        Note: Local surgery of isolated lesions for palliative intent is acceptable.