Study to Assess Neoadjuvant Durvalumab (D) and Platinum-Based Chemotherapy (CT), Followed by Either Surgery and Adjuvant D or CRT and Consolidation D, in Resectable or Borderline Resectable Stage IIB-IIIB NSCLC (MDT-BRIDGE)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess efficacy and safety of neoadjuvant durvalumab in combination with platinum-based chemotherapy (CT) given as initial therapy after cancer diagnosis followed by either surgery and adjuvant durvalumab or chemoradiotherapy (CRT) and consolidation durvalumab given alone as further therapy in participants with resectable and borderline resectable stage IIB-IIIB NSCLC.

Detailed Description
-----------------
This will be a multicentre, Phase II, single-arm, global study assessing the efficacy and safety of neoadjuvant durvalumab and platinum-based CT, given intravenously, followed by either surgery and adjuvant durvalumab or definitive CRT and consolidation durvalumab in participants with resectable and borderline resectable stage IIB-IIIB NSCLC. Neoadjuvant Period A: All participants will initially receive 2 cycles of neoadjuvant durvalumab + CT (investigator's choice platinum-based) every three weeks. Participants will be assessed for resectability by a multidisciplinary team. Neoadjuvant Period B: Cohort 1: Participants who are deemed eligible for surgery will receive study intervention every three weeks for an additional one and up to two cycles, followed by surgery. CRT: Cohort 2: Participants with unresectable tumours (according to MDT re-assessment) will receive definitive CRT (6 one-week cycles) for approximately six weeks. Both cohorts will then go on to receive durvalumab every four weeks until disease progression or recurrence or up to one year.

Official Title
-----------------
A Multicentre, Phase II, Single-Arm, Interventional Study of Neoadjuvant Durvalumab and Platinum-based Chemotherapy (CT), Followed by Either Surgery and Adjuvant Durvalumab or Chemoradiotherapy (CRT) and Consolidation Durvalumab, in Participants With Resectable or Borderline Resectable Stage IIB-IIIB Non-small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Durvalumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Deemed resectable or borderline resectable at baseline, confirmed by MDT evaluation at diagnosis. Previously untreated and pathologically confirmed Stage IIB to select [i.e.N2] Stage IIIB by AJCC v8. Nodal status confirmed with whole body FDG-PET and biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. Mandatory brain MRI. EGFR and ALK wild-type. Medically operable: adequate cardiac and lung function to undergo resection. Participant must be ≥ 18 years, at the time of screening. Histologically or cytologically documented NSCLC. Minimum life expectancy of 12 weeks. Minimum body weight of 30 kg. Male and female participants must be willing to use acceptable methods of contraception. Female participants of childbearing potential must have negative pregnancy test. Exclusion Criteria: Unresectable NSCLC confirmed by MDT evaluation at baseline Stage IIIC patients Participants whose planned surgery at enrollment is a wedge resection Known EGFR mutation or ALK translocation Participants contraindicated for surgical intervention due to comorbid conditions Participants who are allergic to study intervention. Participants with more than one primary tumour. Known active hepatitis infection, positive HCV antibody, HBsAg or HBV core antibody (anti-HBc), at screening. Female participants who are pregnant or breastfeeding. Judgement by the investigator that the participant should not participate in the study. Previously infected or tested positive for human immunodeficiency virus.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab<br>Durvalumab will be administered to the participants via intravenous infusion (IV) | Drug: Durvalumab<br>* Participants that go on to receive surgery, will receive durvalumab for up to four cycles prior to surgery. Participants that go on to receive CRT will receive durvalumab for up to two cycles prior to CRT. All participants will receive durvalumab every four weeks until disease progression or recurrence or up to 12 months following surgery/CRT, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.<br>* Other names: MEDI4736;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resection rate | Resection rate is defined as the proportion of all participants who underwent definitive surgery. Participants who undergo (ie, start) surgery with the goal of complete tumour resection will be counted as meeting this endpoint. | At day of surgery (Within 40 days of the last dose of neoadjuvant treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resection rate | Resection rate will be further assessed separately in participants deemed resectable at baseline and participants deemed borderline resectable at baseline. | At the day of surgery (within 40 days after the last dose of neoadjuvant treatment ) | 
| R0, R1, R2 resection rates | The R0, R1, and R2 resection rates are defined as the proportion of resected participants with resection margins assessed as R0, R1, and R2 respectively. R0 corresponds to resection for cure or complete remission, R1 to microscopic residual tumour, R2 to macroscopic residual tumour. | At the day of surgery (within 40 days after the last dose of neoadjuvant treatment) | 
| Pathological complete response (pCR) | pCR will be defined as the proportion of participants who undergo surgery and have 0% residual viable tumour cells in resected lung and lymph nodes. | At the day of surgery (within 40 days after the last dose of neoadjuvant treatment) | 
| Overall Survival (OS) | OS will be defined as the time from first dose of study intervention until the date of death due to any cause. | From first dose of study intervention until death, withdrawal of consent, or the end of the study (approximately 3.5 years) | 
| Overall Survival (OS) rate | The proportion of participants alive at 12 and 24 months. | At 12 months and 24 months | 
| Event-free survival (EFS) | EFS is defined as the time from the first dose of study intervention to any of the following events: PD that precludes surgery, progression or recurrence of disease after surgery, PD in the absence of surgery, disease progression, recurrence, or death due to any cause. | From first dose of study intervention until progression of disease (PD), recurrence or death, withdrawal of consent, or the end of the study (approximately 3.5 years) | 
| Event-free survival (EFS) rate | The proportion of participants alive and event-free at 12 and 24 months. | At 12 months and 24 months | 
| Progression Free Survival (PFS) | PFS is defined as the time from the first dose of study intervention to RECIST 1.1-defined PD, as assessed by the investigator, or death due to any cause. | From first dose of study intervention until disease progression, death, withdrawal of consent, or the end of the study (approximately 3.5 years) | 
| Progression Free Survival (PFS) rate | The proportion of participants alive without disease progression at 12 and 24 months. | At 12 months and 24 months | 
| Objective response rate (ORR) pre-surgery/pre-chemoradiotherapy (CRT) | ORR is defined as the proportion of participants who have unconfirmed complete response or partial response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | From first dose of study intervention until death, surgery/start of CRT | 
| ORR after definitive CRT | ORR is defined as the proportion of participants who have unconfirmed complete response or partial response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | From MDT decision timepoint (baseline for this endpoint) until the first tumour assessment after definitive CRT | 
| Percentage of all participants with circulating tumor DNA (ctDNA) clearance | Circulating tumour DNA clearance (ie, cMR) will be defined as a change from detectable ctDNA to undetectable ctDNA (ctDNA concentration less than limit of detection) at specified timepoints. The percentage of all biomarker-evaluable participants with ctDNA clearance will be assessed. | From Cycle 1 Day 1 up to pre-surgery/CRT (within 7 to 14 days pre-surgery/CRT) [Each cycle is of 3 weeks] | 
| Number of participants with adverse events | Safety and tolerability will be evaluated in terms of adverse events and serious adverse events. | From enrollment up to at least 90 days after last dose of study intervention | 
| Surgical safety: Surgical delays | Time from last neoadjuvant treatment dose to surgery. | Time from last neoadjuvant treatment dose to surgery | 
| Surgical safety: Duration of surgical procedure | Time from start of surgery to end of surgery. | Time from start of surgery to end of surgery | 
| Surgical safety: Length of hospital stay | Time from the beginning of the surgery/procedure to the discharge of hospital. | Time from the beginning of the surgery/procedure to the discharge of hospital | 
| Surgical safety: Intended surgical approach | Intended surgical approach at baseline (minimally invasive vs open thoracotomy). | At baseline | 
| Surgical safety: Actual surgical approach | Actual surgical approach (minimally invasive vs open thoracotomy). | At surgery | 
| Surgical safety: Intended surgical procedure | Intended surgical procedure (lobectomy vs bilobectomy vs sleeve resection vs pneumonectomy). | At baseline | 
| Surgical safety: Actual surgical procedure | Actual surgical procedure (lobectomy vs bilobectomy vs sleeve resection vs pneumonectomy) | At surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neoadjuvant, Durvalumab, Chemoradiotherapy, Surgery, Adjuvant, Consolidation, Multidisciplinary team (MDT)