A Phase III, Double-Blind, Placebo-Controlled, Randomized, Multicenter, International Study to Determine the Efficacy of Durvalumab Plus Oleclumab and Durvalumab plus Monalizumab in Patients With Locally Advanced (Stage III), Unresectable Non-small Cell Lung Cancer (NSCLC) who Have Not Progressed Following Definitive, Platinum-Based Concurrent Chemoradiation Therapy.

Study ID: 50363
Short Title: PACIFIC 9
Trust Name: UHD
Recruitment Site: Poole Hospital
Disease Area: Lung cancer
Phase: III
Expected End Date: 30/05/2025
Postcode: BH15 2JB
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

1. Participants must have 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]). Initial staging procedures performed prior to initiation of any component of definitive treatment should include: - Whole-body Positron Emission Tomography – Computed Tomography (PET-CT) scan performed up to 42 days prior to the first dose of concurrent chemoradiotherapy (CRT). Brain imaging must be obtained to allow for appropriate staging. o - Except for overt cT4 disease, biopsy strongly preferred to prove nodal status N2 or N3 via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. 2. Tumour sample requirements as follows: Provision of a tumour tissue sample (≤ 3 months old is preferred; ≤ 6 months old is acceptable). An FFPE block sufficient for sectioning 20 slides (5 micron thickness) is the preferred sample type. 3. Tumour PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a central laboratory, must be known prior to randomization. Patients with unknown PD-L1 status are not eligible for the study. “Unknown” refers to (1) insufficient sample which is not able to be analysed, or (2) sample could be analyzed but results not interpretable. 4. Documented EGFR and ALK status (locally or centrally). If the local laboratory will perform the test, a well-validated, local regulatory-approved kit must be used. If performed locally, negative EGFR and ALK tests will be confirmed by central laboratory. EGFR and ALK status must be available prior to randomisation. Participants with sensitizing EGFR (e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 insertion or S768I mutation) or ALK rearrangements are excluded from the study. 5. Tumours harbouring mutations in any of the following genes, as determined by existing local test results: ROS1, RET, MET, BRAF, NTRK1, NTRK2, ERBB2 and KEAP1/NRF2 are excluded. 6. Patients must have not progressed following definitive, platinum-based, concurrent chemoradiation therapy as demonstrated by the following imaging studies performed after completion of CRT: - Screening baseline RECIST imaging of chest and abdomen by CT (preferred) or MRI (see schedule of assessments Table 1) - Brain magnetic resonance imaging (MRI, preferred) or high-quality brain CT with IV contrast (See schedule of assessments Table 1). 7. Participants must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 28 days prior to first dose of investigational product in the study (one cycle is defined as 21 or 28 days). . Sites are strongly encouraged to complete screening within the first 14 days of the 28 day screening period. 8. The platinum-based chemotherapy regimen must contain one of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care regimens. Gemcitabine is not permitted. 9. The last dose of chemotherapy must be administered prior to, or concurrently with, the final dose of radiation. Consolidation chemotherapy after radiation is not permitted. Up to 2 cycles of induction chemotherapy prior to cCRT is permitted. 10. Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique. Sites are encouraged to adhere to the following organ dosimetric specifications: - Mean lung dose must be < 20 Gy and/or V20 must be < 35% - Mean oesophagus dose must be < 34 Gy - Heart V45 < 35% or V30 < 50%. 11. WHO/ECOG PS of 0 or 1 at randomization. 12. Adequate organ and marrow function. 13. Minimum life expectancy of 12 weeks at randomization.

1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active interstitial lung disease/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol. 2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease > 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy, adequately treated carcinoma in situ or Ta tumors treated with curative intent and without evidence of disease. 3. Mixed small cell and non-small cell lung cancer histology. 4. Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced, unresectable NSCLC. 5. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy (excluding alopecia). Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead. 6. Participants with ≥ grade 2 pneumonitis from prior chemoradiation therapy. 7. Any prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1. 8. Investigator judgment of 1 or more of the following: a. Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening. b. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes (TdP). c. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden cardiac death under 40 years of age in first-degree relatives. 9. History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study clinical lead. 10. Subjects with a history of MI, TIA, stroke, or pulmonary embolism diagnosed in the past 6 months or venous thrombosis diagnosed in the past 3 months. 11. Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies, anti-CD73 antibodies, and anti NKG2A antibodies, excluding therapeutic anticancer vaccines.

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