Immunochemotherapy, Surgery or Chemoradiation, and Durvalumab for Stage IIIA/B NSCLC

Prospective Randomized Phase II Trial on Induction Immunochemotherapy Followed by Surgery or Definitive Chemoradiation and Consolidation Durvalumab (MEDI4736) in Resectable and Borderline Resectable Stage IIIA/B NSCLC

The hypothesis of the study is that induction immunochemotherapy, followed by surgery or chemoradiation and consolidation Durvalumab immunotherapy, can significantly improve event-free survival in patients with resectable or borderline resectable NSCLC at stage IIIA/B compared to existing treatment methods.

Inclusion Criteria:

1. Patient is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.

2. Patient is willing and able to comply with the protocol for the duration of the study 3. Age ≥ 18 years and < 75 years. 4. All sex and gender. 5. Female patients of childbearing potential as well as male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to the Clinical Trials Facilitation and Coordination Group (CTFG) during the course of this study and for at least 90 days after the last dose of durvalumab or 6 months after the last dose of chemotherapy, whichever occurs last.

6. Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause.

7. Histologically and / or cytologically proven NSCLC (EGFRm-, ALK-). 8.

Selected patients with NSCLC stage IIIA/B:

1. IIIA: one or more lymph node levels involved at EBUS/mediastinoscopy T1/T2 N2.

2. IIIB: one or more lymph node levels involved at EBUS/mediastinoscopy T3/T4 N2. 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 10. Given technical/oncologic complete resectability (R0) at the time of inclusion. 11. Sufficient functional reserves for the planned surgery 12. Fulfilment of adequate criteria for functional and medical resectability as described in the European Respiratory Society (ERS)/ European Society of Thoracic Surgeons (ESTS) guidelines (Brunelli et al. 2009) and acceptable general clinical condition for multimodality treatment (interdisciplinary committee).

   13. Life expectancy of > 12 weeks. 14. Body weight > 30 kg. 15.

   Adequate normal organ and bone marrow function as defined below:

a. Hemoglobin ≥ 9.0 g/dL. b. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L. c. Platelet count ≥ 100 × 109/L. d. Serum bilirubin ≤ 1.5 × institutional upper limit of normal (ULN). (This will not apply to patients 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.

e. Alanine aminotransferase (ALT/SGPT) and aspartate aminotransferase (AST/SGOT) ≤ 2.5 × institutional ULN.

f. Measured creatinine clearance (CL) ≥ 60 mL/min or calculated creatinine CL ≥ 60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

16. Stable cardiac function (no myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV).

17. Discussion in a multidisciplinary tumor board which supports participation in this clinical trial, indicating that both chemoradiotherapy and surgery are possible local treatments.

Patients should only be randomized if all of the following inclusion criteria are fulfilled at the time of randomization:

1. Given technical/oncologic complete resectability (R0) at the time of randomization.

2. Sufficient functional reserves for the planned surgery

3. Adequate normal organ and bone marrow function as defined before

   Exclusion Criteria:

1. Unresectable disease. 2. Mixed histology with areas of small cell carcinoma (neuroendocrine markers). 3. ALK+/ EGFRm disease. 4. Clinically symptomatic vena cava superior syndrome. 5. Diffuse mediastinal involvement. 6. Patients with N3 tumors (IASLC/UICC 8). 7. Invasion of the thoracic aorta (T4 - aorta) or the heart (except left atrium - T4 - heart) or the esophagus (T4 - esophagus), or invasion of spine (T4 - spine) NOTE: T4 with invasion of diaphragm are eligible. 8. Pancoast-syndrome in tumors of the superior sulcus (T3-4 Nx). 9. Metastatic disease (M1). 10. Endobronchial tumor extension to the contralateral main stem bronchus. 11. Lung or heart function not allowing the intended surgical procedure at the time of inclusion.

12. Prior treatments including prior mediastinal irradiation. 13. Insufficient patients' compliance (e.g., symptomatic psychiatric disorder) or missing written informed consent or definitive refusal for participation.

14. Prior randomization of treatment in a previous durvalumab clinical study regardless of treatment arm assignment.

15.

Patients who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4:

1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.

2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.

3. Must not have experienced a ≥ Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy.

   NOTE: Patients with endocrine AE of ≤ Grade 2 are permitted to be enrolled if they are stably maintained on appropriate replacement therapy and are asymptomatic.

4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.

   16. Participation in another clinical study with an investigational product during the last 12 months.

   17. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.

   18. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.

   19. Any concurrent chemotherapy (other than study therapy), Investigational Product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

   20. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab.

   21. History of allogenic organ transplantation or a stem cell transplantation. 22.

   Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., 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:

a. Vitiligo or alopecia b. Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Celiac disease controlled by diet alone e. Patients without active disease in the last 5 years may be included but only after consultation with the study physician 23. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, 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.

24. History of another primary malignancy except for

a. Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of durvalumab and of low potential risk for recurrence b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease c. Adequately treated carcinoma in situ without evidence of disease 25. History of active primary immunodeficiency. 26. History of leptomeningeal carcinomatosis. 27. Known 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, hepatitis C, or human immunodeficiency virus (positive HIV-1 or HIV-2). 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.

28.

Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 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 (e.g., CT scan premedication) 29. Current or prior use of immunostimulatory agents within 14 days before the first dose of durvalumab 30. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 90 days after the last dose of study treatment.

   31. 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 or 6 months after the last dose of chemotherapy, whichever occurs last.

   32. Known allergy or hypersensitivity to any of the study drugs or any of the study drugs excipient.

   33. Any medical contraindication to treatment with platin-based doublet chemotherapy as listed in the applying SmPCs.

   34. 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.

   Patients should not be randomized if any of the following exclusion criteria are fulfilled at the time of randomization:

   1. Complete remission after induction immunochemotherapy. 2.

   Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous immunochemotherapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:

a. Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.

b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician (exception: alopecia).

3. Allergy or hypersensitivity to durvalumab or concurrent chemotherapy drugs or any excipient appearing for the first time during previous immunochemotherapy.