A Study to Determine Safety of Durvalumab After Sequential Chemo Radiation in Patients With Unresectable Stage III Non-Small Cell Lung Cancer
Condition: Non-small Cell Lung Cancer (NSCLC)
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Durvalumab
Intervention description: Participants will receive 1500 mg Durvalumab monotherapy via IV infusion q4w for up to a maximum of 24 months with the last administration at Week 104.
Intervention MeSH terms: Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 117.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Stage III Non-Small Cell Lung Cancer; Durvalumab; IV infusion immunoglobulin G (IgG); Antibody-dependent cellular cytotoxicity; Complement-dependent cytotoxicity; Monotherapy

Summary:

      This is a Phase II, open-label, multi-centre study to determine the safety of a fixed dose of
      Durvalumab (MEDI4736) (1500 mg) every 4 weeks [q4w] in participants with unresectable Stage
      III Non-Small Cell Lung Cancer (NSCLC), who have not progressed following platinum-based
      sequential chemoradiation therapy (sCRT). This study will be conducted in Europe and North
      America.
    

Eligibility criteria:

        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.

          3. Provision of signed and dated written genetic informed consent prior to collection of
             sample for genetic analysis (optional).

          4. 18 years or older at the time of signing the ICF.

          5. 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.

          6. Receipt of sCRT which must have been completed within 42 days prior to first IP dose
             administration in the study.

               1. The platinum-based chemotherapy regimen must contain cisplatin or carboplatin and
                  1 of the following agents: etoposide, vinblastine, vinorelbine, a taxane
                  (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care
                  (SoC) regimens. Platinum-based chemotherapy containing cisplatin or carboplatin
                  and gemcitabine is permitted under certain conditions - refer to bullet point
                  6(b).

               2. Patients must have received at least 2 cycles of platinum-based chemotherapy
                  before radiation therapy. The interval between administration of the last dose of
                  chemotherapy regimen and start of radiation therapy must be no more than 6 weeks.
                  Consolidation chemotherapy after radiation is not permitted.

             (i) If the patient's platinum-based chemotherapy contained gemcitabine, no overlap
             between chemotherapy and radiation therapy is permitted.

             (ii) If the patient's platinum-based chemotherapy contained any of the agents listed
             in (a) other than gemcitabine, an overlap of 1 cycle of chemotherapy and radiation
             therapy is acceptable.

             (c) Patients must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66
             Gy). Sites are encouraged to adhere to mean organ radiation dosing as follows: (i)
             Mean lung dose <20 Gy and/or V20 <35%; (ii) Mean oesophagus <34 Gy; (iii) Heart V45
             <35% or V30 <30%. Note: Sites should be aware of the recent RTOG 0617 Study data
             demonstrating that doses higher than 60 Gy may be associated with greater toxicity and
             worse efficacy.

             (d) Patients with WHO/ECOG PS 2 or chronic lung disease (pulmonary emphysema or
             chronic obstructive pulmonary disease) must have received a V20 <25%.

          7. Patients must not have progressed following platinum-based sCRT, as per Investigator
             assessed RECIST 1.1 criteria. . In order to assess disease progression, the baseline
             imaging (CT/MRI) used for Screening purposes should be compared against the most
             recently performed scan that allows physician assessment as per RECIST 1.1 criteria.
             If an intermediate scan taken between chemotherapy and radiotherapy is available and
             that scan is suitable for physician assessment as per RECIST 1.1 criteria, then this
             scan should be used.

               1. Patients with measurable disease and/or non-measurable and/or no evidence of
                  disease (NED) assessed at baseline by CT/MRI will be entered in this study.

               2. Prior irradiated lesions may be considered measurable and selected as TLs
                  provided they fulfil the other criteria for measurability.

          8. Must have a life expectancy of at least 12 weeks at enrolment.

          9. WHO/ECOG PS ≤2.

         10. Adequate organ and marrow function at enrolment as defined below. These parameters
             should be achieved without augmentation by growth factors, transfusions, or infusions
             within 14 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)

        11 Body weight >30 kg at enrolment and first IP dose administration. 12 Male or female. 13
        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:

          1. Patients with locally-advanced NSCLC whose disease has progressed following platinum
             based sCRT.

          2. Patients who have disease considered for surgical treatment as part of their care
             plan, such as Pancoast or superior sulcus tumours.

          3. Mixed small-cell lung cancer and NSCLC histology.

          4. History of allogeneic organ transplantation.

          5. 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.

          6. 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.

          7. 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.

          8. History of leptomeningeal carcinomatosis.

          9. History of active primary immunodeficiency.

         10. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis testing in
             line with local practice), 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).

         11. 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 or Grade ≥2 lymphopenia 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 (MEDI4736) may be included only after consultation with
                  the Study Physician.

         12. Known allergy or hypersensitivity to durvalumab (MEDI4736) or any of the IP
             excipients.

         13. Patients who have received cCRT for locally-advanced NSCLC, or who received sCRT with
             at least 2 concomitant CRT cycles. Prior surgical resection (ie, Stage I or II) is
             permitted.

             Note: Patients whose platinum-based chemotherapy contained gemcitabine and who
             received sCRT with at least 1 concomitant CRT cycle are excluded from this study.

         14. 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.

         15. 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.

         16. Prior exposure to immune-mediated therapy, including but not limited to, other anti
             CTLA-4, anti-PD-1, anti-PD-L1, and anti PD L2 antibodies, excluding therapeutic
             anticancer vaccines.

         17. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of IP. The following are exceptions to this criterion:

               1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
                  articular injection);

               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent;

               3. Steroids as premedication for hypersensitivity reactions (eg, CT scan
                  premedication).

         18. Previous IP assignment in the present study.

         19. Concurrent enrolment in another clinical study, unless it is an observational
             (noninterventional) clinical study or the follow-up period of an interventional study.

         20. Participation in another clinical study with an IP during the 4 weeks prior to the
             first IP dose administration.

         21. Prior randomisation or treatment in a previous durvalumab (MEDI4736) ± tremelimumab
             clinical study regardless of treatment arm assignment.

         22. 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 IP.

         23. Judgment by the Investigator that the patient is unsuitable to participate in the
             study and the patient is unlikely to comply with study procedures, restrictions, and
             requirements.

         24. Genetic research study (optional):

        Exclusion criteria for participation in the optional (DNA) genetic research component of
        the study include:

          1. Previous allogeneic bone marrow transplant.

          2. Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample
             collection.