Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The study is intended to assess the safety and efficacy of perioperative treatment with Durvalumab in combination with Oleclumab, Monalizumab or AZD0171 and platinum doublet chemotherapy; or MEDI5752 in combination with platinum doublet chemotherapy or datopotamab deruxtecan (Dato-DXd) in combination with durvalumab and single agent platinum chemotherapy in participants with resectable, early-stage non-small cell lung cancer.

Detailed Description
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This is a open-label, multi-arms, multicentre, randomised study, eligible participants will be enrolled and randomised to one of the following treatment regimens. Arm 1: Participants will receive Oleclumab + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and Oleclumab + durvalumab as adjuvant treatment. Arm 2: Participants will receive Monalizumab + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and Monalizumab + durvalumab as adjuvant treatment. Arm 3: Participants will receive MEDI5752 + platinum doublet chemotherapy as neoadjuvant treatment and MEDI5752 as adjuvant treatment. Arm 4: Participants will receive Dato-DXd + durvalumab + single agent platinum chemotherapy as neoadjuvant treatment and durvalumab as adjuvant treatment. Arm 5: Participants will receive AZD0171 + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and AZD0171 + durvalumab as adjuvant treatment.

Official Title
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A Phase II, Open-label, Multicentre, Randomised Study of Neoadjuvant and Adjuvant Treatment in Patients With Resectable, Early-stage (II to IIIB) Non-small Cell Lung Cancer (NeoCOAST-2)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Oleclumab
* Drug: Monalizumab
* Drug: MEDI5752
* Drug: Dato-DXd
* Drug: AZD0171
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed/Cisplatin
* Drug: Pemetrexed/Carboplatin
* Drug: Carboplatin/Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed NSCLC patients with resectable disease (Stage IIA to Stage IIIB). WHO or Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate organ and bone marrow function. Provision of tumour samples (newly acquired or archival tumour tissue [≤ 6 months old]) to confirm Programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR), or anaplastic lymphoma kinase (ALK) status. Adequate pulmonary function. Exclusion Criteria: Participants with sensitising EGFR mutations or ALK translocations. History of allogeneic organ transplantation. Active or prior documented autoimmune or inflammatory disorders. Uncontrolled intercurrent illness, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active bleeding diseases, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement. History of another primary malignancy. Participants with small-cell lung cancer or mixed small-cell lung cancer. History of active primary immunodeficiency. History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. Participants who have preoperative radiotherapy treatment as part of their care plan. Participants who require or may require pneumonectomy, segmentectomies, or wedge resections, as assessed by their surgeon at baseline, to obtain potentially curative resection of primary tumour. QTcF (QT interval corrected by Fridericia's formula) interval ≥ 470 ms. Any medical contraindication to treatment with chemotherapy as listed in the local labelling. Participants with moderate or severe cardiovascular disease. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Receipt of live attenuated vaccine within 30 days prior to the first dose of study interventions. Prior exposure to approved or investigational immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies. Participants who received agents targeting the adenosine pathway, anti-NKG2A, anti-HLA-E agents, and anti-LIF agents are also excluded. Participants who have received previous treatment with a TROP2 targeting ADC or with another ADC containing a chemotherapy agent that inhibits TOP1 activity are also excluded. Current or prior use of immunosuppressive medication within 14 days before the first dose of study interventions. Active or uncontrolled infections including HBA, HBV, HCV, and HIV.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 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 |
| --- | --- |
| Experimental: Oleclumab + Durvalumab + Platinum doublet chemotherapy<br>Participants will receive Durvalumab + Oleclumab + platinum doublet chemotherapy as neoadjuvant treatment and Durvalumab + Oleclumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin | Drug: Durvalumab<br>* Participants will receive Durvalumab via intravenous route.<br>* Other names: MEDI4736, IMFINZI;Drug: Oleclumab<br>* Participants will receive Oleclumab via intravenous route.<br>* Other names: MEDI9447;Drug: Pemetrexed/Cisplatin<br>* Pemetrexed/Cisplatin as chemotherapy<br>Drug: Pemetrexed/Carboplatin<br>* Pemetrexed/Carboplatin as chemotherapy<br>Drug: Carboplatin/Paclitaxel<br>* Carboplatin/Paclitaxel, as chemotherapy<br>|
| Experimental: Monalizumab + Durvalumab + Platinum doublet chemotherapy<br>Participants will receive Durvalumab + Monalizumab + platinum doublet chemotherapy as neoadjuvant treatment and Durvalumab + Monalizumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin | Drug: Durvalumab<br>* Participants will receive Durvalumab via intravenous route.<br>* Other names: MEDI4736, IMFINZI;Drug: Monalizumab<br>* Participants will receive Monalizumab via intravenous route.<br>* Other names: IPH2201;Drug: Pemetrexed/Cisplatin<br>* Pemetrexed/Cisplatin as chemotherapy<br>Drug: Pemetrexed/Carboplatin<br>* Pemetrexed/Carboplatin as chemotherapy<br>Drug: Carboplatin/Paclitaxel<br>* Carboplatin/Paclitaxel, as chemotherapy<br>|
| Experimental: MEDI5752 + Platinum doublet chemotherapy<br>Participants will receive MEDI5752 + platinum doublet chemotherapy as neoadjuvant treatment and MEDI5752 as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin | Drug: MEDI5752<br>* Participants will receive MEDI5752 via intravenous route.<br>Drug: Pemetrexed/Cisplatin<br>* Pemetrexed/Cisplatin as chemotherapy<br>Drug: Pemetrexed/Carboplatin<br>* Pemetrexed/Carboplatin as chemotherapy<br>Drug: Carboplatin/Paclitaxel<br>* Carboplatin/Paclitaxel, as chemotherapy<br>|
| Experimental: Dato-DXd + durvalumab + single agent platinum<br>Participants will receive Dato-DXd + durvalumab + single agent platinum as neoadjuvant treatment and durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on physician choice of as part of their treatment regimen prior to surgery: Carboplatin or Cisplatin | Drug: Durvalumab<br>* Participants will receive Durvalumab via intravenous route.<br>* Other names: MEDI4736, IMFINZI;Drug: Dato-DXd<br>* Participants will receive datopotamab deruxtecan (Dato-DXd) via intravenous route.<br>Drug: Carboplatin<br>* Carboplatin as chemotherapy<br>Drug: Cisplatin<br>* Cisplatin as chemotherapy<br>|
| Experimental: AZD0171 + durvalumab + platinum doublet chemotherapy<br>Participants will receive AZD0171 + durvalumab + platinum doublet chemotherapy as neoadjuvant treatment and AZD0171 + durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin | Drug: Durvalumab<br>* Participants will receive Durvalumab via intravenous route.<br>* Other names: MEDI4736, IMFINZI;Drug: AZD0171<br>* Participants will receive AZD0171 via intravenous route.<br>Drug: Pemetrexed/Cisplatin<br>* Pemetrexed/Cisplatin as chemotherapy<br>Drug: Pemetrexed/Carboplatin<br>* Pemetrexed/Carboplatin as chemotherapy<br>Drug: Carboplatin/Paclitaxel<br>* Carboplatin/Paclitaxel, as chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with pathological complete response (pCR) |  | From randomization to approximately 15 weeks after the first dose of study interventions | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) |  | Until Day 90 after the last dose of study interventions (Up to approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants experiencing an event-free survival (EFS) event |  | Up to approximately 3 years | 
| Number of participants experiencing a disease-free survival (DFS) event |  | Up to approximately 3 years | 
| Number of participants having surgical resection |  | From randomization to approximately 15 weeks after the first dose of study interventions | 
| Number of participants with major pathological response (mPR) |  | From randomization to approximately 15 weeks after the first dose of study interventions | 
| Number of participants with Objective response rate (ORR) |  | From randomization to approximately 15 weeks after the first dose of study interventions | 
| Overall survival (OS) |  | Up to approximately 3 years | 
| Serum concentration of study interventions (Durvalumab/Oleclumab/Monalizumab/MEDI5752) |  | From randomization to last dose of study interventions (Up to approximately 3 Years) | 
| Number of participants with anti-study drug antibodies (ADA) |  | From randomization to 3 months after last dose of study interventions (Up to approximately 3 Years) | 
| Baseline PD-L1 expression |  | At Screening/ baseline | 
| Changes in circulating tumour DNA (ctDNA) |  | From randomization to up to 24 months after last dose of study interventions (Up to approximately 3 Years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oleclumab, Monalizumab, Lung Cancer, early-stage, Durvalumab, AZD0171, Datopotamab Deruxtecan, Neoadjuvant, Adjuvant, Chemotherapy, MEDI5752