Neoadjuvant Durvalumab and Chemotherapy Followed by Surgery/CRT and Durvalumab in Borderline Resectable Stage III NSCLC

Inclusion Criteria

• •1\. Participant must be ≥ 18 years, at the time of screening. 2. Histologically or cytologically documented NSCLC. 3. Deemed borderline resectable at baseline, confirmed by MDT evaluation at diagnosis.
• •4\. Previously untreated and pathologically confirmed stage III (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology2016)
• •1. Nodal status should be investigated with whole body FDG-PET, plus contrast-enhanced computed tomography, and it is optional and decided by investigator that nodal status be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy.
• •2. Mandatory brain MRI with IV contrast, if not available, it is mandatory to take brain computed tomography with IV contrast at the time of staging.
• •5\. WHO or ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dose.
• •6\. Participants must have been confirmed as EGFR/ALK wild type via an appropriately validated local test. Participants with known sensitising EGFR mutations or ALK rearrangements are excluded from the study.
• •7\. At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography or MRI and is suitable for accurate repeated measurements.
• •8\. Adequate organ and bone marrow function as follows:
• •Haemoglobin ≥ 9.0 g/dL.
• •Absolute neutrophil count ≥ 1.5 × 109/L.
• •Platelet count ≥ 100×109/L.
• •Serum bilirubin ≤ 1.5×the ULN or ≤ 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinaemia).
• •Alanine aminotransferase and AST ≤ 2.5×ULN.
• •Calculated CrCL \> 40 mL/min as determined by Cockcroft Gault (using actual body weight).
• •Males:
• •CrCL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)
• •Females:
• •CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85 72 × serum creatinine (mg/dL) 9. Minimum life expectancy of 12 weeks. 10. The participant should be deemed to have adequate cardiac and lung function, according to a multidisciplinary assessment. A pre- or post-bronchodilator FEV1 of 1.0 L and \>40% post-operative predicted value. Use of these cut-off values to assess candidacy for resection on pre-treatment risk assessment. (Surgical Eligible) 11. Minimum body weight of 30 kg. 12. Negative pregnancy test (serum) for FOCBP for female. 13. Male participants who intend to be sexually active with a female partner of child-bearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening, while receiving study intervention, SoC Chemotherapy or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period.
• •14\. Female participants must be for 1 year or more post-menopausal, surgically sterile, or using at least one highly effective method of contraception: a highly effective method of contraception is defined Non-hormonal
• •Total sexual abstinence (evaluate in relation to the duration of the clinical study and the preferred and usual lifestyle choice of the participant)
• •Vasectomised sexual partner (with participant assurance that partner received post-vasectomy confirmation of azoospermia)
• •Tubal occlusion Intrauterine device (provided coils are copper banded) Hormonal
• •Implants: Etonogestrel-releasing implants (e.g. Implanon® or Norplant®)
• •Intravaginal devices: Ethinylestradiol/etonogestrel-releasing intravaginal devices (e.g. NuvaRing®)
• •Injection: Medroxyprogesterone injection (e.g. Depo-Provera®)a
• •Combined Pill: Normal and low dose combined oral contraceptive pill
• •Patch: Norelgestromin/ethinylestradiol-releasing transdermal system (e.g. Ortho Evra®)
• •Mini pill: Progesterone based oral contraceptive pill using desogestrel: Cerazette® is currently the only highly effective progesterone-based Levonorgestrel-releasing intrauterine system (e.g., Mirena®)
• •1. Females \< 50 years old are considered post-menopausal if they have been amenorrhoeic for 12 months or more prior to enrolment following cessation of exogenous hormonal treatment and follicle-stimulating hormone (FSH) levels in the post-menopausal range.
• •2. Females ≥ 50 years old are considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment, or had radiation-induced menopause with last menses \> 1 year ago, or had chemotherapy-induced menopause with last menses \> 1 year ago.
• •3. Female participants of child-bearing potential must agree to use at least one highly effective method of birth control (see Appendix G for complete list of highly effective birth control methods). They should have been stable on their chosen method of birth control for a minimum of 3 months prior to enrollment (screening), while receiving study intervention, SoC Chemotherapy or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents. Cessation of birth control after this point should be discussed with a responsible physician.
• •4. Non-sterilised male partners of a female participant of child-bearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening their female partner, while their female partner is receiving study intervention, SoC Chemotherapy or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents.
• •5. Periodic abstinence, as well as the rhythm and withdrawal methods are not acceptable methods of birth control..
• •15\. Capable of giving signed informed consent as described in Appendix which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
• •16\. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.
• •17\. Patient 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.
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• •1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• •22\. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
• •(2) History of allogenic organ transplantation. (3) History of leptomeningeal carcinomatosis