Study of Durvalumab or Placebo in Patients with Non-small Cell Lung Cancer (Stage II-III) who’s has residual disease after surgery and chemotherapy.

Phase 3

Recruiting

• Conditions: Malignant neoplasm of unspecifiedpart of bronchus or lung,

• Registration Number: CTRI/2021/01/030611
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase III, randomized, multicenter, double-blind, placebo-controlledstudy to evaluate the efficacy and safety of durvalumab adjuvant therapycompared to placebo in patients with stage II-III NSCLC who have undergonecurative intent therapy (complete resection ± neoadjuvant and/or adjuvanttherapy), who have no evidence of RECIST 1.1- defined disease recurrence, andwho become MRD+ during a 96-week surveillance period.

 The study will screen approximately 1500 patients and randomizeapproximately 284 MRD+ patients with stage II-III NSCLC (select Stage IIIB[T3N2 or T4N2] patients) whose tumors are EGFR and ALK wild type, and who havecompleted curative intent therapy. The study will be conducted in approximately250 centers globally.

 Approximately 284 MRD+patients will be randomized 1:1 to treatment with Durvalumab monotherapy orplacebo every 4 weeks (q4w) intravenously (IV). Patients will be treated for upto a total of 24 months (26 cycles), until disease recurrence, or until other specifictreatment discontinuation criteria are met (whichever comes first). This studywill be fully blinded

Detailed Description

Not available

Study Timeline

• Study Start: 2021-01-25
• Last Update Posted: 2023-05-11

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 284

Inclusion Criteria

• Informed consent 1 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICFs and in this protocol.
• 2 Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses.
• ICF1 must be signed and dated prior to initiation of the first screening and surveillance activities.
• ICF2a must be signed and dated prior to initiation of the second screening activities and randomization.
• ICF2b must be signed and dated prior to initiation of the study-specific observation period and procedures.
• 3 Provision of signed and dated written optional genetic informed consent prior to collection of the optional sample for genetic analysis.
• This consent should be signed at the time of second screening.
• This optional sample and analyses are separate from the mandatory genetic testing consent included in ICF1.
• 4 Age ≥18 years at the time of screening.
• 5 Male and/or female.
• 6 Histologically confirmed NSCLC with resectable stage II-III disease (according to IASLC Staging Manual in Thoracic Oncology v8.0) who have undergone curative intent therapy (complete resection of the primary tumor ± neoadjuvant and/or adjuvant therapy) per SoC.
• Select stage IIIB (ie, T3N2 or T4N2) patients will be eligible, provided they are upstaged to T3N2 or T4N2 based on confirmed pathology after surgery.
• Patients who are staged as T3N2 or T4N2 prior to surgery are not eligible.
• 7 A contrast-enhanced CT/MRI scan of the chest and abdomen (including liver and adrenal glands) along with brain MRI (preferred) or brain CT with IV contrast must have been done for surgical planning prior to surgery.
• It is recommended that patients undergo combined FDG-PET (18F-Fluoro-deoxyglucose positron emission tomography) and CT scan (computerized tomography) within the 6 weeks prior to surgery in order to rule out detectable extrathoracic, extracranial metastasis and to assess for potential mediastinal lymph node involvement prior to surgery.
• 8 Complete resection of the primary NSCLC is mandatory.
• Invasive (pre-operative or intraoperative) exploration of hilar and mediastinal lymph nodes must have been performed to confirm primary tumor nodal status (prior to or after surgery).
• primary NSCLC can occur by open thoracotomy or by video-assisted thoracic surgery (VATs) and resection can be achieved by segmentectomy, lobectomy, sleeve resection, bilobectomy or pneumonectomy.
• Patients undergoing wedge resection are not eligible for this study.
• 9 Patients should have completed (or be undergoing) curative intent therapy (surgery ± neoadjuvant and/or adjuvant therapy; adjuvant therapy can include PORT) with exceptions noted below: i.
• Patients who discontinue chemotherapy and/or PORT for toxicity prior to completion of all planned therapy are eligible.
• Patients who have not received any neoadjuvant and/or adjuvant chemotherapy, and meet all other eligibility criteria, may be eligible under the following circumstances: iii.
• All patients who are eligible for adjuvant chemotherapy MUST be offered adjuvant chemotherapy.
• The patient has declined adjuvant chemotherapy, and in the opinion of the Investigator, this is the patient s final decision after receiving appropriate information and adequate time to make the decision.
• The patient s refusal of adjuvant chemotherapy must be documented.
• If in the view of the Investigator, adjuvant chemotherapy is contraindicated due to an underlying intercurrent illness/laboratory abnormality, which is not considered reversible within a reasonable timeframe for the patient to be eligible for adjuvant therapy, which must be documented.
• 10 Confirmation of suitable biosamples for WES and central PD-L1 testing.
• Resected tumor tissue and whole blood samples must be provided to the diagnostic laboratory for WES of tumor and germline DNA, respectively as soon as possible following pathology confirmation.
• Samples must be sent no later than 1-2 weeks after completion of adjuvant therapy or 3-5 weeks after surgery (if no adjuvant therapy is given) for development of the Sponsor-approved personalized panel for MRD detection at a central reference laboratory.
• Germline sequencing of whole blood is mandatory.
• must also be provided for PD-L1 testing at a central reference laboratory (see inclusion criteria 15).
• If scans were not performed post-curative intent therapy, additional scans must be done prior to start of surveillance.
• 12 Consents to be accessible for q6w±3d plasma sample collection for MRD evaluation and for q12w±1w CT scans during the 96-week surveillance period.
• 13 The plasma sample that marks the start of surveillance must be collected 8±1 weeks after completion of adjuvant therapy (if administered) or 12±1 weeks after surgery (where adjuvant therapy is not given).
• A patient who is determined to be MRD- based on analysis of this plasma sample (ie, MRD- at the start of surveillance) may continue in surveillance provided all other eligibility criteria are met.
• A patient who is determined to be MRD+ based on analysis of this plasma sample (ie, MRD+ at the start of surveillance) may be eligible for immediate randomization provided all other eligibility criteria are met.
• A patient who becomes MRD+ during surveillance is eligible to enter the second screening period and may be randomized in the study if all other eligibility criteria are met.
• 14 CT scan of the chest and abdomen (including liver and adrenal glands) and brain MRI [preferred] or brain CT with IV contrast performed within the 28 days ± 7 days prior to randomization to confirm no evidence of RECIST 1.1-defined disease recurrence and/or metastasis.
• 15 Known tumor PD-L1 status determined at a central reference laboratory testing service using a validated Ventana SP263 PD-L1 immunohistochemistry (IHC) assay prior randomization.
• Patients with unknown PD-L1 status are not eligible for the study.
• 16 WHO/Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• 17 Complete post-operative wound healing must have occurred prior to randomization; patients must have recovered from all acute, reversible toxic effects from prior treatments (excluding alopecia) that could potentially adversely impact further administration of durvalumab/placebo according to the Investigator s judgment.
• 18 Must have recovered from all acute, reversible toxic effects from chemotherapy that could potentially adversely impact further administration of durvalumab or placebo according to the Investigator s judgment 19 Adequate organ and marrow function as defined below: i.
• Hemoglobin ≥9.0 g/dL ii.
• Platelet count ≥100 × 109/L iv.
• Serum bilirubin ≤1.5 × the upper limit of normal (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN Measured creatinine clearance (CL) ≥30 mL/min or Calculated creatinine CL >30 mL/min as determined by Cockcroft-Gault (using actual body weight) 20 Must have a life expectancy of at least 12 weeks 21 Body weight >30 kg 22 No evidence of RECIST 1.1-defined disease recurrence or metastasis confirmed by CT scan of the chest and abdomen (including liver and adrenal glands) and a brain MRI (preferred) or brain CT with IV contrast.
• MRD- status, as determined by testing the last plasma sample collected during the 96- week surveillance period.

Exclusion Criteria

• Diagnostic assessments 1EGFR and/or ALK mutant as assessed either from the tumor biopsy taken prior to surgery or the resected tumor tissue.
• Testing must be performed using a well-validated, local regulatory-approved test.
• EGFR/ALK may be tested centrally if local testing is unavailable.
• 2Mixed small cell and NSCLC histology.
• 3Require re-resection or are deemed to have unresectable NSCLC by a multidisciplinary evaluation that must include a thoracic surgeon who performs lung cancer surgery as a significant part of their practice.
• 4Baseline imaging demonstrating unequivocal evidence of RECIST 1.1-defined disease recurrence or evidence of clinical recurrence outside of imaging prior to randomization.
• In the event of lymphadenopathy on imaging that would lead to exclusion, histopathological confirmation of lymph node metastasis should be obtained prior to excluding a patient from the study.
• Medical conditions 5History of allogeneic organ or bone marrow transplantation.
• 6Non-leukocyte-depleted whole blood transfusion within 120 days of genetic sample collection.
• 7Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
• The following are exceptions to this criterion: i.
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement iii.
• Any chronic skin condition that does not require systemic therapy iv.
• Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician v.
• Patients with celiac disease controlled by diet alone 8Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
• 9History of another primary malignancy, except for i.
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence ii.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease iii.
• Adequately treated carcinoma-in-situ without evidence of disease 10History of active primary immunodeficiency 11Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (HBV; known positive HBV surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus infection (positive HIV 1/2 antibodies).
• Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
• Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• 12Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
• Prior/concomitant therapy 13Received any prior adjuvant therapy for NSCLC or any prior exposure to durvalumab.
• 14Received any radiotherapy in the neoadjuvant setting.
• 15Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
• 16Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP.
• Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
• 18Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
• 19Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab/placebo.
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent iii.
• Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) Prior/concurrent clinical study experience 20Previous IP assignment in the present study.
• 21Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study, or during the follow-up period of an interventional study.
• 22Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• Female patients who become pregnant during the study will be withdrawn from surveillance and are not eligible for randomization.
• 24Male or female patients of reproductive potential who are not willing to employ effective birth control at the time of entry into second screening (initiated with the signing of ICF2a) until 90 days after the last dose of IP 25Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
placebo as measured by DFS in the PD-L1 TC≥1%	To assess the efficacy of durvalumab compared to | placebo as measured by DFS in the PD-L1 TC≥1% | analysis set. 5 years
analysis set	To assess the efficacy of durvalumab compared to | placebo as measured by DFS in the PD-L1 TC≥1% | analysis set. 5 years
To assess the efficacy of durvalumab compared to	To assess the efficacy of durvalumab compared to | placebo as measured by DFS in the PD-L1 TC≥1% | analysis set. 5 years

Secondary Outcome Measures

Name	Time	Method
To assess the efficacy of durvalumab compared to	placebo on post-recurrence outcomes
To investigate the relationship between a patient’s baseline PD-L1 TC expression and efficacy of study treatments	IHC analysis of PD-L1 TC expression and spatial distribution within the tumor microenvironment relative to efficacy outcomes (ie, DFS, OS) - 5.5 years
To assess the relationship between treatment effect	on DFS and treatment effect on ctDNA endpoints
To assess the association of TMB with efficacy of	durvalumab compared with placebo, and other
To investigate biomarkers in tumor and periphery at baseline, on treatment, post-treatment and/or at	recurrence wherever feasible to identify markers related to disease, mechanism of action of the drug and/or their associations with response and clinical endpoints
To assess the efficacy of durvalumab compared to placebo as measured by OS in the PD-L1 TC≥1% analysis set and in all randomized patients	OS in PD-L1 TC≥1% and in FAS - 5.5 years
To assess patient-reported symptoms, functioning,	and HRQoL in patients treated with durvalumab
Safety objective:	To assess the safety and tolerability profile of durvalumab monotherapy compared with placebo
Exploratory Objective	To assess the efficacy of durvalumab monotherapy to clear ctDNA compared to placebo
To evaluate patient-reported treatment-related	symptoms using PRO-CTCAE To assess the patient´s global impression of symptoms severity, and global treatment tolerability
To explore the impact of treatment and disease on	health state utility
To assess alternative methodologies for determining MRD	MRD determinations in screened patients - 5.5 years
To assess prognostic value of ctDNA quantification	at baseline
To assess prognostic value of MRD classification by comparing outcomes of randomized (MRD PLUS) placebo-treated patients to those of patients in surveillance and/or observation	i. MRD status as determined at screening and

Trial Locations

Locations (12)

ACI Cumballa Hill Hospital; 🇮🇳 Mumbai, MAHARASHTRA, India

All India Institute of Medical Sciences, Delhi; 🇮🇳 Delhi, DELHI, India

Fortis Hospital Ltd, Bannerghatta Road; 🇮🇳 Bangalore, KARNATAKA, India

HCG Manavata Cancer Centre; 🇮🇳 Nashik, MAHARASHTRA, India

HealthCare Global Enterprises Ltd; 🇮🇳 Bangalore, KARNATAKA, India

Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute; 🇮🇳 Mumbai, MAHARASHTRA, India

Max Super Specialty Hospital, Mohali; 🇮🇳 Chandigarh, CHANDIGARH, India

Max Super Specialty Hospital, Shalimar Bagh; 🇮🇳 Delhi, DELHI, India

Mazumdar Shaw Medical Center (A unit of Narayana Health); 🇮🇳 Bangalore, KARNATAKA, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

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ACI Cumballa Hill Hospital

🇮🇳Mumbai, MAHARASHTRA, India

Dr Suhas Vilasrao Aagre

Principal investigator

9638179565

suhas.aagre@gmail.com