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Submitted by: Ranelle Lou Dorado N/A Last Updated by: Ranelle Lou Dorado 2020-05-20 11:19:29


A Phase III, Double-blind, Placebo-controlled, Multi-center International Study of Neoadjuvant/Adjuvant Durvalumab for the Treatment of Patients with Resectable Stages II and III Non-small Cell Lung Cancer 

PHRR190321-002089

D9106C00001

2019-CT0477

A Phase III, Double-blind, Placebo-controlled, Multi-center International Study of Neoadjuvant/Adjuvant Durvalumab for the Treatment of Patients with Resectable Stages II and III Non-small Cell Lung Cancer (AEGEAN)

This is a Phase III, double-blind, placebo-controlled, multi-center international study of neoadjuvant/adjuvant durvalumab for the treatment of patients with resectable Stages II and III NSCLC.The study will plan to enroll approximately 545 patients in order to randomize 300 eligible patients. Patients will be randomized in a 1:1 ratio to receive either durvalumab plus platinum-based chemotherapy before surgery followed by durvalumab post-surgery (Arm 1) or placebo plus platinum-based chemotherapy before surgery followed by placebo post-surgery (Arm 2). Patients will be stratified by disease stage (Stage II versus Stage III) and by PD-L1 expression status (umonectomy as determined by the attending surgeon based on the intraoperative findings. Patients who are candidates to undergo only segmentectomies or wedge resections at eligibility assessment are not eligible for this study. All patients must be staged and managed according to the National Comprehensive Cancer Network 2018 Guidelines (version 4).

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development
Start Date Duration in Months Target Completion Date Actual Completion Date
2019-03-01 84 2026-03-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Region
AstraZeneca AB Sweden
AstraZeneca Pharmaceuticals (Philippines) Inc. NCR
Name E-Mail Institution and Institution Address
Mary Grace Arbues MaryGrace.Arbues@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name E-Mail Institution and Institution Address
Mary Grace Arbues MaryGrace.Arbues@astrazeneca.com 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name Expertise Affiliation
Adrian Manapat, MD Thoracic and Cardiovascular Surgeon Makati Medical Center
Arthur Gregory Lui, MD Oncology Metro Davao Medical and Research Center
Eugenio Emmanuel Regala, MD Oncology University of Santo Tomas Hospital
Guia Elena Imelda R. Ladrera, MD Oncology Lung Center of the Philippines
Project Location Institutional Ethics Review Board
Makati Medical Center Makati Medical Center Institutional Review Board
Metro Davao Medical and Research Center Metro Davao Medical and Research Center – Ethics Review Committee
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee

Resectable Stages II and III Non-small Cell Lung Cancer

mPR (10% or less residual viable tumor tissue in lung primary tumor after neoadjuvant treatment at the time of resection) in FAS

pCR (absence of any residual viable tumor in the primary lung lesion and lymph nodes at the time of surgical resection) in FAS and PD-L1-TC≥1% patients mPR in PD-L1-TC≥1% patients EFS, DFS, OS Change from baseline in EORTC QLQ-C30 and EORTC QLQ-LC13 Concentration of durvalumab Presence of ADAs for durvalumab

Recruiting

Clinical Trial

D9106C00001

20181116125642

2019-02-20

0000-00-00

15

Unspecified

Unspecified

01 Mar 2019

Inclusion Criteria

Patients are eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria apply:
Informed consent
1 Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

2 Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses
3 Provision of signed and dated written ICF prior to collection of sample for genetic analysis
The ICF process is described in Appendix A 3.
Age
4 Age ≥18 years at the time of screening. For patients aged Type of patient and disease characteristics
5 Histologically or cytologically documented NSCLC with resectable (Stage IIA to select [ie, N2] Stage IIIB) 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 2016]).
 At screening, complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a multidisciplinary evaluation, which must include a thoracic surgeon who performs lung cancer surgery as a prominent part of his/her practice.
 Nodal status should be investigated with whole body 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET), plus contrast-enhanced computed tomography (CT) in addition to or in combination with PET before surgery. If PET/CT scan is positive in the mediastinum, or if scan is negative but there is T>3 cm, central tumor, or clinical N1 (cN1), then nodal status should be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. See surgery eligibility below and Section 6.1.3 (preoperative mediastinal lymph node staging) for more details.
 Mandatory brain magnetic resonance imaging (MRI; preferred) or brain CT with IV contrast at the time of staging.
6 World Health Organization (WHO)/ECOG PS of 0 or 1 at enrollment
7 At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by CT or MRI scan must be performed within 28 days prior to randomization.
8 No prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
9 Adequate organ and marrow function as defined below:
 Hemoglobin ≥9.0 g/dL
 Absolute neutrophil count ≥1.5 × 109/L
 Platelet count ≥100 × 109/L

 Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician.
 ALT and AST ≤2.5 × ULN
 Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL >40 mL/min as determined by Cockcroft-Gault (using actual body WT)
Males
Creatinine CL=WT (kg) × (140-Age)
(mL/min) 72 × serum creatinine (mg/dL)
Females:
Creatinine CL=WT (kg) × (140-Age) × 0.85
(mL/min) 72 × serum creatinine (mg/dL)
10 Must have a life expectancy of at least 12 weeks
Weight
11 Body WT >30 kg
Sex
12 Male and/or female
Tumor sample requirements:
13 Confirmation of a patient’s tumor PD-L1 status must occur prior to randomization using Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay applied to formalin fixed paraffin embedded tissue sample with testing completed by the central laboratory. Samples for PD-L1 testing may include the following:
 Newly acquired tumor tissue (preferred) or archival tissue ( If the patient’s PD-L1 status has already been assessed using the analytically validated Ventana assay as a part of the screening process for another AstraZeneca/MedImmune study, this test result can be used for the determination of eligibility.
14 Documented EGFR and ALK status (local testing is preferred; if not feasible, central testing will be performed). If the local laboratory will perform the test, a well-validated, local regulatory-approved kit must be used. EGFR/ALK status must be available prior to randomization. If the number of patients with EGFR or ALK mutations (ie, the total number of patients summed across both types of mutations) reaches approximately 20% of the total randomization target patient number, the incoming patients with EGFR/ALK mutations will not be randomized.
Surgery eligibility (these criteria must be assessed within 30 days prior to surgery, following neoadjuvant treatment)
15 Surgery to be performed will be lobectomy, sleeve resection, bilobectomy, or pneumonectomy, as determined by the attending surgeon based on the intraoperative findings.
16 Received 3 cycles of platinum-based chemotherapy concurrent with durvalumab or placebo

 Receipt of 2 cycles of platinum-based chemotherapy concurrent with durvalumab or placebo will be permitted only if the patient experienced chemotherapy related toxicities and Investigators judge additional safety issue will be expected with additional cycles of chemotherapy.
17 Surgery should happen within 40 days from the last IP administration
18 Patients must have recovered from all acute, reversible toxic effects from chemotherapy (excluding alopecia) and durvalumab or placebo that could potentially adversely impact the surgical procedure or outcome according to the Investigator’s judgement.
19 A contrast enhanced CT/MRI scan of chest and abdomen (including the entire liver and both adrenals) are required for RECIST 1.1 assessment and for surgical planning prior to surgery. A supplemental (whole body or chest alone) FDG-PET scan may also be acquired prior to surgery in order to help identify mediastinal lymph node involvement.
20 If preoperative CT and/or PET are suspicious for mediastinal nodal involvement, or should those be negative for mediastinal lymph node but there is T>3 cm, cN1, or central tumor, then it is recommended that invasive mediastinal staging with mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration be performed if those were not performed at screening and/or according to the multidisciplinary evaluation and Investigator’s judgment.
21 Complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a multidisciplinary evaluation, which must include a thoracic surgeon who perform lung cancer surgery as a prominent part of his/her practice.
22 Deemed adequate cardiac and lung function, according to the multidisciplinary assessment. A pre- or post-bronchodilator forced expiratory volume in 1 second (FEV1) of 1.0 L or >40% postoperative predicted value and diffusing capacity of the lungs for carbon monoxide (DLCO) >40% predicted value is recommended.
Post-surgery durvalumab or placebo administration eligibility (these criteria must be assessed within 10 weeks from surgery, prior to starting adjuvant treatment)
23 Patients must have recovered from all acute, reversible toxic effects from previous treatments that could potentially adversely impact further administration of durvalumab or placebo according to the Investigator’s judgement.
24 Patients should be able to start durvalumab or placebo administration as soon as clinically feasible and within 10 weeks from surgery. A minimum of 3 weeks is recommended between NSCLC surgery and durvalumab/placebo treatment start (first post-surgical scan must be performed prior to starting adjuvant treatment). Complete post-operative wound healing must have occurred following any surgery.
25 Patients with N2 disease or patients with R1/2 post-surgical findings can receive adjuvant post-operative radiation therapy (within 8 weeks after surgery) and are eligible to receive post-surgery durvalumab/placebo (within 3 weeks from end of post-operative radiation therapy). The post-operative radiation therapy must be completed prior to durvalumab/placebo administration.
26 Patients who require re-resection according to Investigator’s judgement will not be allowed to receive post-surgery treatment with durvalumab.

Exclusion Criteria

Medical conditions
1 History of allogeneic organ transplantation
2 Active 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 [eg, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, or uveitis]). The following are exceptions to this criterion:
 Patients with vitiligo or alopecia
 Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
 Any chronic skin condition that does not require systemic therapy
 Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician
 Patients with celiac disease controlled by diet alone
3 Uncontrolled 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 requirement, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent
4 History of another primary malignancy, except for the following:
 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
 Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
 Adequately treated carcinoma in situ without evidence of disease
5 History of active primary immunodeficiency
6 Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B virus surface antigen [HBsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
7 Deemed unresectable NSCLC by multidisciplinary evaluation that must include a thoracic surgeon who perform lung cancer surgery as a significant part of their practice
8 Patients who have pre-operative radiotherapy treatment as part of their care plan
9 Patients who have brain metastases or spinal cord compression. All patients will have an MRI (preferred) or high-quality CT with IV contrast of the brain, prior to study entry.

10 Stage IIIB N3 and Stages IIIC, IVA, and IVB NSCLC
11 Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
12 Mixed small cell and NSCLC histology
13 Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
14 Any medical contraindication to treatment with platinum-based doublet chemotherapy as listed in the local labelling
15 Patients who are candidates to undergo only segmentectomies or wedge resections
Prior/concomitant therapy
16 Any 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.
17 Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
18 Receipt of live attenuated vaccine within 30 days prior to 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.
19 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
20 Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
 Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
 Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
Prior/concurrent clinical study experience
21 Participation in another clinical study with an IP administered in the last 4 weeks
22 Previous IP assignment in the present study
23 Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
24 Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment
Diagnostic assessments
Other exclusions
25 Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of IP.

26 Judgment 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.
27 Exclusion criteria for participation in the optional (DNA) genetics research component of the study include the following:
 Previous allogeneic bone marrow transplant
 Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection

Interventional

Durvalumab + chemotherapy

Durvalumab is a human mAb of the immunoglobulin G 1 kappa subclass that blocks the interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on immune cells. It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The proposed mechanism of action for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation of interferon-γ (Stewart et al 2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. To date, durvalumab has been given to more than 6000 patients as part of ongoing studies either as monotherapy or in combination with other anticancer agents. Details on the safety profile of durvalumab monotherapy are summarized in Section 4.3.1 and Section 8.3.12. Refer to the current durvalumab IB for a complete summary of pre-clinical and clinical information including safety, efficacy, and PK.    The use of combination chemotherapy is a mainstay of oncology therapy. The goal of combination chemotherapy is to utilize agents that affect cancer cells by different mechanisms, thus reducing the risk of developing resistance. Current studies are now adding immunotherapeutics to chemotherapeutics to broaden antitumor responses (see Section 2.2.3).In addition to the PD-1/PD-L1 chemotherapy combination studies mentioned in Section 2.2.3, data for durvalumab ± tremelimumab with standard platinum-based chemotherapy in advanced cancers are being generated from 2 ongoing Phase I studies: the internal Study D419SC00001 (n=6) and a Phase Ib study (NCT02537418) run by the Canadian Cancer Trials Group (CCTG; n=118; Daaboul et al 2017). The combinations tested are tolerable and toxicities are manageable. Preliminary results from the CCTG study were presented for the NSCLC cohorts at the International Association for the Study of Lung Cancer 2016 meeting; the overall ORR in NSCLC cohort (n=24) was 52.9% (Juergens et al 2017a). See Section 2.3.1.2 for more details.Additionally, a Phase III study of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy for first-line treatment of patients with metastatic NSCLC is currently ongoing (Study D419MC00004). Regular scheduled safety IDMC reviews have been conducted, and no safety concerns were raised; the study is continuing as planned.

Date Amendment Classification Reason
2019-02-20 Amendments related to the trial arrangements Change of the principal investigator or addition of new ones

Randomized

Double Blind

Unspecified

Parallel

To assess the activity of durvalumab + chemotherapy administered prior to surgery compared with placebo + chemotherapy administered prior to surgery in terms of mPR

Phase III

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