Durvalumab vs Placebo With Stereotactic Body Radiation Therapy in Early Stage Unresected Non-small Cell Lung Cancer (NSCLC) Patients / Osimertinib Following SBRT in Patients With Early Stage Unresected NSCLC Harboring an EGFR Mutation

Study Overview
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Brief Summary
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This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study assessing the efficacy and safety of durvalumab with SoC SBRT versus placebo with SoC SBRT in patients with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC. An additional cohort will assess Osimertinib following SBRT in patients with early stage unresected T1 to T3N0M0 NSCLC harbouring an EGFR mutation.

Detailed Description
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Patients who are to receive SoC SBRT as definitive treatment of Stage I/II lymph node-negative NSCLC and confirmed to meet all eligibility criteria will be randomized 1:1 to Durvalumab or placebo. The primary objective of main cohort is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of PFS. Key secondary is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of Overall Survival (OS). In addition, a study cohort with a sufficient number of patients harboring an EGFR mutation, will receive Osimertinib treatment after completion of SoC SBRT as definitive treatment of Stage I/II lymph node-negative NSCLC. The primary objective of Osimertinib cohort is to assess efficacy of Osimertinib following SoC SBRT in terms of 4years-PFS. Key secondary objectives include safety, OS and efficacy of Osimertininb treatment with SBRT.

Official Title
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A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab With Stereotactic Body Radiation Therapy (SBRT) for the Treatment of Patients With Unresected Stage I/II, Lymph-node Negative Non-small Cell Lung Cancer (PACIFIC-4/RTOG-3515) Osimertinib Following SBRT, a Single Arm Cohort for Patients With Unresected Stage I/II, Lymph Node Negative NSCLC Harboring a Sensitizing EGFR Mutation

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Durvalumab
* Other: Placebo
* Drug: Osimertinib (single-arm, open-label)


Participation Criteria
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Eligibility Criteria
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Main Cohort Key Inclusion Criteria: Age ≥18 years Planned SoC SBRT as definitive treatment WHO/ECOG PS of 0, 1 or 2 Life expectancy of at least 12 weeks Body weight >30 kg Submission of tumor tissue sample if available Adequate organ and marrow function required Patients with central or peripheral lesions are eligible Staging studies must be done during screening (PET-CT within 10 weeks) Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions Main Cohort Key Exclusion Criteria: Mixed small cell and non-small cell cancer History of allogeneic organ transplantation History of another primary malignancy with exceptions History of active primary immunodeficiency Epidermal growth factor receptor local testing is strongly recommended prior to enrollment. Patients with a tumor harboring an EGFRm per local testing will be excluded from the main cohort Prior exposure to immune-mediated therapy with exceptions Osimertinib Cohort Key Inclusion Criteria Age ≥18 years Planned SoC SBRT as definitive treatment World Health Organization (WHO)/ECOG PS of 0, 1, or 2 Patients with central or peripheral lesions are eligible Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions Staging studies must be done during screening (PET-CT within 10 weeks) Submission of available tumor tissue sample Confirmation by local laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R) Adequate bone marrow reserve or organ function required Female patients should be using highly effective contraceptive measures Male patients should be asked to use barrier contraceptives (ie, condoms) during sex with all partners during the trial and avoid procreation Osimertinib Cohort Key Exclusion Criteria Mixed small cell and non-small cell cancer Patients currently receiving potent inducers of CYP3A4 Patients with known or increased risk factor for QTc prolongation Treatment with any of the following: Preoperative or adjuvant platinum-based or other chemotherapy for the disease under investigation Prior treatment with neoadjuvant or adjuvant EGFR TKI Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib Any of the following cardiac criteria Mean resting corrected QT interval >470 msec, obtained from 3 ECGs Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained -sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SoC SBRT + Durvalumab Therapy (Main Cohort)<br>SBRT Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks [q4w] intravenously [iv] for up to 24 months or until progression or other discontinuation criteria are met. | Drug: Durvalumab<br>* Durvalumab 1500 mg every 4 weeks [q4w] intravenously [iv] for up to 24 months or until progression or other discontinuation criteria are met.<br>* Other names: MEDI4736;|
| Placebo Comparator: SoC SBRT + Placebo Therapy (Main Cohort)<br>SBRT Placebo (matching placebo for infusion every 4 weeks iv for up to 24 months or until progression or other discontinuation criteria are met. | Other: Placebo<br>* Matching placebo for infusion every 4 weeks iv for up to 24 months or until progression or other discontinuation criteria are met.<br>|
| Experimental: SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, separate cohort)<br>SBRT Osimertinib 80mg every day [qd] for oral administration up to 36 months or until progression. Osimertinib treatment should start within 7 to 14 days after completion of SBRT | Drug: Osimertinib (single-arm, open-label)<br>* Osimertinib 80 mg every day [qd] orally for up to 36 months or until progression or other discontinuation criteria are met. Osimertinib treatment should start from 7 to 14 days after completion of SBRT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 in subpopulation of patients with Stage I/II NSCLC | Main Cohort | from randomization up to 6 years | 
| 4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria | Osimertinib Cohort | from randomization up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 in all randomised patients with Stage I/II NSCLC | Main Cohort | from randomization up to 6 years | 
| Overall Survival (OS) | Main Cohort | from randomization up to 7 years | 
| Maximum Plasma concentration (Cmax) | Main Cohort | 12 weeks after last dose | 
| Detection of ADA neutralising antibodies titers | Main Cohort | up to 6 months after last dose | 
| Health-related quality of life in patients treated with durvalumab with SoC SBRT compared to placebo with SoC SBRT using the EORTC QLQ-C30 | Main Cohort | from randomization up to 7 years | 
| Proportion of patients alive and progression free at 24 months from randomisation (PFS24) assessed by BICR according to RECIST 1.1 | Main Cohort | at 24 months following randomization | 
| Time to progression (TTP) assessed by BICR according to RECIST 1.1 | Main Cohort | from randomization up to 6 years | 
| Time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1 | Main Cohort | from randomization up to 6 years | 
| Time from randomisation to second progression (PFS2) as defined by local standard clinical practice | Main Cohort | from randomization up to 7 years | 
| Trough Concentration (Ctrough) | Main Cohort | up to 3 months after last dose | 
| Assessment of AEs by CTCAE v 5.0 as measures of the safety and tolerability of Durvalumab with SoC SBRT compared to placebo with SoC SBRT | Main Cohort | up to 3 months after last dose | 
| Assessment of AEs by CTCAE v 5.0 as measures of the safety, tolerability and compliance of osimertinib with SoC SBRT therapy | Osimertinib Cohort | Up to 35 days after last dose | 
| WHO performance status | Osimertinib Cohort | from randomization Up to 5 years | 
| ECG QT interval | Osimertinib Cohort | Up to 156 weeks of treatment or treatment discontinuation | 
| Overall Survival | Osimertinib Cohort | from randomization Up to 5 years | 
| Time To Progression (TTP) | Osimertinib Cohort | from randomization Up to 5 years | 
| Time to CNS progression | Osimertinib Cohort | from randomization Up to 5 years | 
| PFS2 | Osimertinib Cohort | from randomization up to 5 years | 
| Site(s) of disease progression | Osimertinib Cohort | from randomization up to 5 years | 
| PFS by ICR using RECIST 1.1 | Osimertinib Cohort | from randomization up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PFS, NSCLC, Early-Stage NSCLC, Lung cancer, Double- Blind, PD-L1, MEDI4736, Durvalumab, Osimertinib, OS, Unresected lung cancer, Inoperable, Operable, SBRT, SABR, EGFR