Health Condition 1: null- Unresectable Non-small Cell Lung Cancer (Stage III)
Conditions
Interventions
Intervention1: Durvalumab: Patients will be in a 2:1 ratio to either durvalumab plus SoC CRT or placebo plus SoC CRT. Patients with CR, partial response (PR), or stable disease (SD
based on Investigator assessment) at the 16-week tumor evaluation following completion of SoC CRT will continue to receive durvalumab/placebo as consolidation treatment
Control Intervention1: Placebo:
Sponsors
AstraZeneca AB
Eligibility
Inclusion criteria
Inclusion criteria: Informed consent 1. 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. 2. Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses. 3. 18 years or older at the time of signing the ICF. In Japan, patients must be 20 years or older at the time of signing the ICF. 4. Histologically or cytologically documented NSCLC who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology 2016]). ? Except for overt cT4 disease, nodal status N2 or N3 should be proven by biopsy, via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. Absent biopsy, nodal status should be confirmed with whole body F-fluoro-deoxyglucose positron emission tomography, plus contrast-enhanced computed tomography (CT) in addition to or in combination with PET. ? Mandatory brain magnetic resonance imaging (MRI preferred) or high-quality brain CT with IV contrast at the time of staging. 5. World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment and randomization. 6. Patients with at least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 Target Lesion (TL) at baseline. Tumor assessment by CT or MRI must be performed within 28 days prior to randomization. 7. Tumor sample requirements: i. Mandatory provision of an archived tumor tissue block (or at least 15 newly cut unstained slides) less than or equal to 3 years old. If an archival sample is not available, provision of a recent (less than or equal to 3 months) tumor biopsy is mandated. ii. The provision of an additional recent (less than or equal to 3 months) tumor biopsy is optional, provided that a biopsy procedure is technically feasible and the procedure is not associated with unacceptable clinical risk. 8. Must have a life expectancy of at least 12 weeks at randomization 9. Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or greater than 40 percentage predicted value and diffusing capacity of the lung for carbon monoxide greater than 30 percentage predicted value. Pulmonary function testing results for up to 8 weeks prior to registration are permitted. 10. Adequate organ and marrow function at enrollment and randomization as defined below: iii. Hemoglobin greater than or equal to 9.0 g/dL iv. Absolute neutrophil count greater than 1.5 × 109/L v. Platelet count greater than 100 × 109/L vi. Serum bilirubin less than or equal to 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. vii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 × ULN; for patients with hepatic metastases, ALT and AST less than or equal to 5 × ULN. viii. Measured creatinine clearance (CL) greater than 40 mL/min or calculated CL greater than 40 mL/min as determined by Cockcroft-Gault (using actual body weight) 11. Genetics research study (optional) For inclusion in the optional (DNA) genetics research
Exclusion criteria
Exclusion criteria: Patients should not enter the study if any of the following exclusion criteria are fulfilled: Medical conditions 1. History of allogeneic organ transplantation 2. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [example colitis or Crohns 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: i. Patients with vitiligo or alopecia ii. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement iii. Any chronic skin condition that does not require systemic therapy iv. Patients without active disease in the last 5 years at randomization may be included but only after consultation with the study physician v. Patients with celiac disease controlled by diet alone 3. 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 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 4. History of another primary malignancy except for vi. Malignancy treated with curative intent and with no known active disease greater than or equal to 5 years before the first dose of IP and of low potential risk for recurrence vii. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease viii. Adequately treated carcinoma in situ without evidence of disease 5. History of leptomeningeal carcinomatosis 6. History of active primary immunodeficiency 7. Active infection including tuberculosis (TB) (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 (HCV), 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 antibody are eligible only if polymerase chain reaction is negative for HCV RNA 8. Mixed small cell and NSCLC histology. 9. Known allergy or hypersensitivity to any of the IPs or any of the IP excipients. 10. Any medical contraindication to treatment with platinum-based doublet chemotherapy as listed in the local labelling. 11. Patients whose radiation treatment plans are likely to encompass a volume of whole lung receiving greater than or equal to 20 Gy in total (V20) of more than 35 percentage of lung volume. V20s up to 37% will be permitted and viewed as a minor deviation, provided that the treating radiation oncologist believes this level of exposure is within patient tolerance. 12. Planned radiation cardiac dose V50 greater than 25 percentage. 13. Patients who have disease considered for surgical treatment as part of their care plan, s
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess the efficacy of durvalumab + Standard of Care Chemo Radiation Therapy compared with placebo + Standard of Care Chemo Radiation in terms of Progression Free Survival and Objective Response RateTimepoint: Approximately 4 years | — |
Secondary
| Measure | Time frame |
|---|---|
| To assess patients’ overall impression of the severity of their cancer symptoms using PGISTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To assess the efficacy of durvalumab PLUS SoC CRT compared with placebo PLUS SoC CRT Timepoint: OS- Proportion of patients alive at 24 months from randomization CR- Complete response at 24 Months DCR- Disease control rate at 24 weeks, PFS2- Time from randomization to second progression TTDM- Time to death or distant metastasis ;To assess the PK of durvalumab when in combination with CRTTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To assess the safety and tolerability profile of durvalumab plus SoC CRT compared with placebo plus SoC CRTTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To collect and store DNA from tissue and/or blood according to each country’s local and ethical procedures for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability, and efficacy) to IPs and/or susceptibility to disease (optional)Timepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To collect blood and tissue samples, or leverage residual samples, for analysis of peripheral and tumoral biomarkersTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To describe and evaluate resource use associated with durvalumab treatment and underlying diseaseTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To explore the impact of treatment and disease state on health state utility using the EQ-5D-5LTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To explore the relationship(s) between a patient’s biomarker status and durvalumab PK exposure and clinical outcomes before and after treatmentTimepoint: Overall Survival (OS) (Time frame-Approximately 4 years);To investigate the immunogenicity of durvalumabTimepoint: Overall Survival (OS) (Time frame-Approximately 4 y | — |
Countries
Brazil, Hungary, India, Japan, Mexico, Peru, Philippines, Poland, Republic of Korea, Russian Federation, Thailand, Turkey, Ukraine, Viet Nam
Contacts
Public ContactMr Sandeep AV
AstraZeneca Pharma India Ltd.
Outcome results
None listed