Ablative STEreotactic RadiOtherapy wIth Durvalumab (MEDI4736)

Study Overview
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Brief Summary
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This is a randomized multicentre open label phase II study of Durvalumab following Stereotactic Body Radiotherapy (SBRT) in patients with T1-2N0M0 NSCLC. Patients will be randomized 1:1 to follow up or receiving Durvalumab every 4th week for 12 months

Detailed Description
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This is a randomized multicentre open label phase II study of the PDL1 inhibitor Durvalumab following SBRT in patients with T1-2N0M0 NSCLC. It will enroll 106 patients aiming at a minimum of 5 subjects per site. The subjects will be randomized in a 1:1 fashion with performance status, gender and T-stage as stratification factors. Patients with peripheral lung tumors will receive SBRT usually between 3 and 4 fractions. The group randomized to immunotherapy will then receive Durvalumab, given with a fixed dose of 1500 mg i.v. every fourth week during 12 months. Both arms will be assessed according to the same follow-up schedule with radiology every third month.

Official Title
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Ablative STEreotactic RadiOtherapy wIth Durvalumab (MEDI4736). An Open Label Randomized Phase II Trial With Durvalumab Following Stereotactic Body Radiotherapy (SBRT) in Patients With Stage I Non-small Cell Lung Cancer (NSCLC)

Conditions
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NSCLC, Stage I

Intervention / Treatment
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* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained from the subject prior to performing any protocol- related procedures, including screening evaluations Histological or cytological diagnosis of NSCLC Stage I-IIA tumours ≤ 5 cm Peripheral tumours Medically inoperable patients or patients refusing surgery Received no prior chemotherapy or radiation therapy for NSCLC Age > 18 years at time of study entry, no upper age limit WHO performance status 0-2 Adequate normal organ and marrow function as defined below: Haemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) Platelet count ≥ 100 x 109/L (>100,000 per mm3) Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) AST/ALT ≤ 2.5 x institutional upper limit of normal Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by chrome-EDTA or Iohexol clearance Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects Subject 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 Exclusion Criteria: Centrally located tumours No regional or distant metastases are allowed (i.e. no stage II-IV disease) Oxygen usage or a FEV1 < 0.7 L and CO diffusion capacity < 30% Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study Participation in another clinical study with an investigational product during the last 4 weeks Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab Second primary residual malignancy. Other malignancy diagnosed and treated > 5 years ago without relapse is allowed. (Carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin < 5 years are allowed) Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 28 days prior to the first dose of study drug Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid Active or prior documented autoimmune or inflammatory disorders . The following are exceptions to this criterion: Subjects with vitiligo or alopecia Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Subjects without active disease in the last 5 years may be included but only after consultation with the study physician Subjects with celiac disease controlled by diet alone History of primary immunodeficiency History of allogeneic organ transplant History of hypersensitivity to durvalumab or any excipient Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (NYHA III-IV), uncontrolled hypertension, unstable angina pectoris, interstitial lung disease, cardiac arrhythmia, active peptic ulcer disease, active bleeding diatheses 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 (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab Female subjects who are pregnant or breastfeeding or male or female subjects of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm A<br>SBRT and follow-up | |
| Experimental: Arm B<br>SBRT followed by Durvalumab | Drug: Durvalumab<br>* durvalumab 1500 mg i.v. every fourth week for 12 months<br>* Other names: Medi4736;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TTP | Time to progression | From date of randomization until the date of first documented progression, assessed up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall survival | From date of randomization until the date of death from any cause, assessed up to 60 months | 
| LC | Local control | Assessed at scheduled timepoints every 3-6 months through study completion (60 months) | 
| QoL | QoL by LCSS | Measured at baseline and at three timepoints (6, 12 and 20 months) | 
| TTP by PDL1 expression | Time to progression related to level of PDL1expression | From date of randomization until the date of first documented progression, assessed up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SBRT, Immunotherapy