Study of Durvalumab or Placebo given along with Standard Chemotherapy in Patients with Non-small Cell Lung Cancer (Stage II-III) who’s tumor has been removed through surgery
Scientific Title of Study
A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled Study to Determine the Efficacy of Adjuvant Durvalumab in Combination with Platinum-based Chemotherapy in Completely Resected Stage II-III NSCLC (MeRmaiD-1)
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
D910LC00001 Version 1.0 dated 09 MAR 2020
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Mr Tapankumar M Shah
Designation
Director, Site Management and Monitoring – India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road.
Bangalore
Bangalore KARNATAKA 560045 India
Phone
91-9535104975
Fax
91-8067748857
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Mr Tapankumar M Shah
Designation
Director, Site Management and Monitoring – India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road.
Bangalore
Bangalore KARNATAKA 560045 India
Phone
91-9535104975
Fax
91-8067748857
Email
tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Sodertalje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy
Business Park Rachenahalli, Outer Ring Road,
Bangalore – 560045
Countries of Recruitment
Argentina Australia Belgium Brazil Bulgaria Canada Czech Republic Denmark France Germany Greece Hong Kong Hungary India Israel Italy Japan Mexico Netherlands Peru Poland Republic of Korea Romania Russian Federation Singapore Spain Sweden Switzerland Taiwan Thailand Turkey United Kingdom United States of America Viet Nam
Department of Medical Oncology, ACI Cumballa Hill Hospital,
93/95, Kemp’s Corner,
August Kranti Maidan,
Grant Road, Mumbai – 400036,
INDIA Mumbai MAHARASHTRA
9638179656
suhas.aagre@gmail.com
Dr Sachin Khurana
All India Institute of Medical Sciences, Delhi
Dept. of Medical Oncology,
Ansari Nagar, PIN - 110029 New Delhi DELHI
9769030180
dr.sachinkhurana@gmail.com
Dr Viveka B K
Fortis Hospital Ltd
Department of Medical Oncology, 154/9, Bannerghatta Road, Opp to IIM-B, PIN -560076 Bangalore KARNATAKA
9945056718
vivekquest@gmail.com
Dr Shruti Kate
HCG Manavata Cancer Centre
Department of Medical Oncology,
HCG Manavata Cancer Centre,
Behind Shivang Auto, Mumbai Naka,
PIN-422002 Nashik MAHARASHTRA
7506117343
drshruti@mcrinasik.com
Dr Satheesh CT
HealthCare Global Enterprises Ltd
Department of Medical Oncology,
HCG Tower, # 8, P. Kalinga Rao Road,
Sampangi Ram Nagar, PIN 560027
Bangalore KARNATAKA
9242698750
drsatheeshct@gmail.com
Dr Sewanti Limaye
Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute
Dept. of Medical Oncology,
Rao Saheb, Achutrao Patwardhan Marg, Four Bungalows, Andheri West, PIN 400053 Mumbai MAHARASHTRA
9619607339
sewanti@yahoo.com
Dr Gautam Goyal
Max Super Speciality Hospital, Chandigarh
Dept. of Medical Oncology,
Phase 6, Sector 56, Chandigarh, PIN 160055
Chandigarh CHANDIGARH
8195849111
gautam3636@gmail.com
Dr Ajay Sharma
Max Super Speciality Hospital, Shalimar Bagh
Dept. of Medical oncology, FC-50, C and D Block, Shalimar Bagh, New Delhi, PIN 110088
New Delhi DELHI
9999379838
ajaysharma04@rediffmail.com
Dr Pragnya Coca
Mazumdar Shaw Medical Center (A unit of Narayana Health)
Department of Medical Oncology, No 258/A, Bommasandra Industrial Area, Anekal Taluk, PIN - 560099 Bangalore KARNATAKA
8050004989
pragnya.11@gmail.com
Dr Ullas Batra
Rajiv Gandhi Cancer Institute & Research Centre
Department of Medical Oncology,
Rajiv Gandhi Cancer Institute & Research Centre,
D-18, Sector-V, Rohini,
PIN-110085
New Delhi DELHI
9711080001
ubclinicaltrial@gmail.com
Dr Shyam Aggarwal
Sir Ganga Ram Hospital
Dept. of Medical Oncology,
Old Rajinder Nagar, Rajinder Nagar, New Delhi, PIN 110060 New Delhi DELHI
9811075870
drshyam_aggarwal@yahoo.com
Dr Bivas Biswas
Tata Medical Center, Kolkata
Dept. of Medical Oncology,
14 Major arterial road E-W New Town Rajarhat PIN 700160 Kolkata WEST BENGAL
9830922005
bivas.biswas@tmckolkata.com
Dr CS Pramesh
Tata Memorial Hospital, Mumbai
Dept. of Medical Oncology,
Dr. E, Dr Ernest Borges Rd, Parel, Mumbai, PIN 400012 Mumbai MAHARASHTRA
Institutional Ethics Committee – New Healthcare Nursing Home
Approved
Institutional Ethics Committee, All India Institue of Medical Sciences, New Delhi
Approved
Institutional Ethics Committee, Kokilaben
Approved
Institutional Ethics Committee, Max Super Specialty Hospital, Mohali
Approved
Institutional Review Board Rajiv Gandhi Cancer Institute and Research Centre
Approved
Institutional Review Board, Tata Medical Center, Kolkata
Approved
Manavata Clinical Research Institute Ethics Committee HCG Manavata Cancer Centre
Approved
Max Healthcare Ethics Committee, Delhi
Approved
Narayana Health Medical Ethics Committee
Approved
TMH, Institutional Ethics Committee I and II
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C349||Malignant neoplasm of unspecifiedpart of bronchus or lung,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Durvalumab with Platinum based chemotherapy
Durvalumab with Platinum based chemotherapy (paclitaxel PLUS
carboplatin (squamous patients only), pemetrexed PLUS carboplatin (non-squamous patients only), or pemetrexed PLUS cisplatin (non-squamous patients only)
Comparator Agent
Placebo with Platinum based chemotherapy
Placebo with Platinum based chemotherapy (paclitaxel PLUS
carboplatin (squamous patients only), pemetrexed PLUS carboplatin (non-squamous patients only), or pemetrexed PLUS cisplatin (non-squamous patients only)
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Informed consent
Criteria and procedures initiated with the signing of ICF1
1 ICF1 must be signed and dated prior to any study procedures and prior to the planned surgical resection of the primary NSCLC, with the exception noted below.
i. Exception: Patients will be permitted to sign ICF1 after surgery. In this case, a post surgical whole blood sample and resected tumor tissue must be collected as soon as possible for development of the personalized panel. The plasma sample to determine MRD status must still be collected between Weeks 3 and 4 post-surgery, even if creation of the personalized panel for MRD detection is delayed. Only patients identified as MRD+ based on the post-surgery plasma sample may be randomized in the study, provided all additional inclusion and none of the exclusion criteria are met.
ii. Patients randomized to the MRD- cohort must have had a plasma sample collected prior to surgery and will not be eligible for the study if they signed ICF1 after surgery. Patients will not be excluded from randomization based on the results of the pre-surgical sample.
Age
2 Age ≥18 years at the time of screening.
Sex
3 Male and/or female.
Type of patient and disease characteristics
4. Individuals who have diagnosis of histologically confirmed NSCLC with resectable (stage II-III) disease, Select (ie, T3N2 or T4N2) stage IIIB patients will be eligible, provided that they are upstaged to T3N2 or T4N2 based on confirmed pathology. Patients who are staged as T3N2 or T4N2 prior to surgery are not eligible.
The following criteria must be met prior to surgery or at the time of the surgery:
5 A contrast-enhanced CT/MRI scan of the chest and abdomen (including liver and adrenal glands) 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 in order to rule out detectable extrathoracic, extracranial metastasis and to assess for potential mediastinal lymph node involvement prior to surgery. If only CT is available, or FDG-PET reveals suspicious lymph node mediastinal involvement, it is recommended that invasive pre-operative mediastinal staging is performed according to the algorithm of the European Society of Thoracic Surgeons guidelines (algorithm to follow for primary mediastinal staging if only pre-operative CT is available, algorithm to follow for primary mediastinal staging when PET-CT is available). Brain MRI (preferred) or brain CT with IV contrast is required for complete staging of the tumor. Imaging should occur within 6 weeks prior to surgery.
Complete resection of the primary NSCLC is mandatory. The primary tumor must be deemed resectable by a multidisciplinary evaluation that must include a thoracic surgeon certified or trained according to local standards and who performs lung cancer surgery as a significant part of their practice. Surgical resection of the 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.
At a minimum, the following parameters should be met for a tumor to be declared completely resected:
(a) The surgeon performing the resection should remove all gross disease by the end of surgery. All surgical margins of resection must be negative for tumor.
(b) Pathology and/or operative reports must include the examination of at least 2 different mediastinal lymph node (N2) levels, one of which is the subcarinal node group (level 7) and the second of which is lobe-specific (defined below).
(c) No extracapsular nodal extension of the tumor is observed in resected mediastinal N2 lymph nodes.
7 Collection of a pre-surgical plasma sample for MRD evaluation is preferred for all patients but is mandatory in order for any MRD- patient to be randomized
The following criteria must be met post-surgery and prior to signing ICF2:
8 Confirmation of suitable resected tumor tissue and whole blood sample for WES of tumor and germline DNA, respectively, and creation of Sponsor-approved personalized panel for MRD determination. Tumor tissue and whole blood samples must be provided to the diagnostic laboratory for development of the personalized panel as soon as possible following pathology confirmation. Germline sequencing of whole blood is mandatory.
9 Established MRD status (+/-) based on Sponsor-approved personalized assay of a plasma sample collected between Weeks 3 and 4 post-surgery.
10 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.
11 Post-operative CT scan of the chest and abdomen (including liver and adrenal glands) performed within 28 days prior to randomization. If clinically indicated, additional scans (such as brain MRI [preferred] or brain CT with IV contrast) should be performed to confirm no evidence of metastasis.
Criteria and procedures initiated with the signing of ICF2 (and optional genetic consent)
12 ICF2 must be signed and dated after MRD status is determined; within the 12 weeks (±7 days) following surgery; and prior to initiation of any study-specific procedures, sampling, and analyses per study protocol
13 WHO/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
14 Complete postoperative 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 or chemotherapy according to the Investigator’s judgment.
15 Eligible to tolerate 4 cycles of platinum-based adjuvant chemotherapy
16 Adequate organ and marrow function as defined below:
i. Hemoglobin ≥9.0 g/dL
ii. Absolute neutrophil count ≥1.5 × 109/L
iii. Platelet count ≥100 × 109/L
iv. 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.
v. ALT and AST ≤2.5 × ULN
vi. Measured creatinine clearance (CL) ≥40 mL/min or Calculated creatinine CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight)
17 Must have a life expectancy of at least 12 weeks
Weight
18 Body weight >30 kg
ExclusionCriteria
Details
Diagnostic assessments
1 Post-operative imaging demonstrating unequivocal evidence of disease recurrence or tissue biopsy-proven disease recurrence. 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. If pathological confirmation of lymph-node metastasis is not technically feasible and imaging appearance are deemed unequivocal for relapse, the patient will be excluded.
2 EGFR-mutant and/or ALK-translocation as assessed either from the tumor biopsy taken prior to surgery (preferred) or the resected tumor tissue (if biopsy was not evaluable). If a pre surgery biopsy is not available, testing will be conducted as soon as possible post surgery on the resected tumor tissue while the personalized panel is in development; patients will still be allowed to continue with study procedures while testing is ongoing but will be excluded from randomization if their resected tumor tissue tests positive for EGFR mutations and/or ALK translocations. Testing must be performed using a well validated, local regulatory approved test. EGFR/ALK may be tested centrally if local testing is unavailable.
3 Mixed small cell and NSCLC histology.
4 Require 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.
5 Patients who are candidates to undergo only wedge resections.
Medical conditions
6 History of allogeneic organ or bone marrow transplantation.
7 Non-leukocyte-depleted whole blood transfusion within 120 days of genetic sample collection.
8 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 [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
i. Patients with vitiligo or alopecia
ii. 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
9 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 requirements, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
10 History 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
11 History of active primary immunodeficiency
12 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 (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.
13 Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
14 Any medical contraindication to treatment with platinum-based doublet chemotherapy as listed in the local labeling.
Prior/concomitant therapy
15 Received any prior adjuvant therapy for NSCLC or any prior exposure to durvalumab.
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 IP.
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/placebo. The following are exceptions to this criterion:
i. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
ii. 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
21 Participation in another clinical study with an IP administered since completion of surgery.
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 group assignment.
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 durvalumab/placebo.
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.
To assess the efficacy of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy as measured by DFS in MRD positive patients
To assess the efficacy of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy as measured by DFS in MRD positive patients - 4.5 years
To assess the efficacy of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy as measured by DFS in all patients
DFS in FAS using Investigator assessments according to RECIST 1.1 - 4.5 years
To assess the efficacy of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy as measured by DFS in MRD positive patients and in all patients
DFS using BICR assessments according to RECIST 1.1
in MRD positive analysis set and in FAS - 4.5 years
To assess the efficacy of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy as measured by OS in MRD positive patients and in all patients
OS in MRD positive analysis set and in FAS - 4.5 years
To assess patient-reported symptoms, functioning, and HRQoL in MRD positive patients treated with durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy
Change from baseline and time to deterioration in EORTC QLQC30 and EORTC QLQ LC13 - 4.5 years
To assess the PK of durvalumab
Concentration of durvalumab - 4.5 years
To investigate the immunogenicity of durvalumab
Presence of ADAs for durvalumab - 4.5 years
Safety objective:
To assess the safety and tolerability profile of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy in MRD plus patients and in all patients
AEs physical examinations vital signs and
laboratory findings - 4.5 years
Exploratory Objective
o assess the efficacy of durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy on post recurrence outcomes
PFS using local standard practice - 4.5 years
To assess the efficacy of durvalumab PLUS SoC chemotherapy to clear ctDNA compared to placebo PLUS chemotherapy in MRD PLUS patients
Correlation of polymorphisms with variation in PK, pharmacodynamics, safety or response observed in patients treated with osimertinib plus chemotherapy- 4.5 Years
To assess relationship between treatment effect on DFS and treatment effect on ctDNA endpoints
ctDNA endpoints (as defined above) and DFS - 4.5 years
To assess prognostic significance of MRD detection as determined by ctDNA in NSCLC
Time from randomization to DFS
in MRD positive vs MRD negative
- 4.5 years
To assess the association of TMB with efficacy of durvalumab PLUS SoC chemotherapy compared with placebo PLUS SoC chemotherapy
DFS, OS in patients with TMB - 4.5 years
To investigate the relationship between a patients baseline PD-L1 TC expression and efficacy outcomes with durvalumab PLUS SoC chemotherapy compared with placebo PLUS SoC chemotherapy
IHC analysis of PDL1 TC expression and spatial distribution within the tumor microenvironment relative to efficacy outcomes ie DFS and OS - 4.5 years
To investigate the effect of baseline colonic microbiome on response to treatment and the effect of treatment on the microbiome over time
Microbiome profiling and metabolome analysis of stool samples - 4.5 years
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
Exploratory markers within the peripheral and tumoral compartments.
TMB and somatic mutations in tissue and or blood or plasma.
Changes in RNA DNA or protein will be compared at baseline, on treatment, post-treatment and or at recurrence
Attributes of tumor microenvironment that could be assessed using various methods with spatial resolution such as Mass Spectroscopy or other technologies
- 4.5 years
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 explore the impact of treatment and disease on health care resource use
Prespecified items on the PRO CTCAE
Patient global assessments
EQ 5D 5L descriptor and VAS
Health care resource use will be captured, including inpatient admissions ICU admissions and length of stay in the hospital. Study mandated visits are excluded from this assessment
Target Sample Size
Total Sample Size="332" Sample Size from India="18" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a Phase III, multicenter, randomized, double-blind,
placebo-controlled, parallel-arm study to evaluate the efficacy and safety of
durvalumab plus SoC chemotherapy compared to placebo plus SoC chemotherapy in
patients with completely resected stage II-III NSCLC who are MRD+ post-surgery.
The study will screen approximately 2225 patients and randomize
approximately 332 patients with stage II-III NSCLC (select stage IIIB patients
with T3N2 or T4N2 disease may be eligible, whose tumors are EGFR and ALK wild
type, and who have undergone complete resection.
Randomized patients will include approximately 232 MRD+ and 100 MRD-
patients. The number of MRD- patients will be capped at 100. There will be a
split of approximately 30%/70% of Asian/non-Asian patients within the MRD-
randomized population.
The study will be conducted in approximately 250 centers globally.
The Investigator will decide before randomization which chemotherapy regimen
(carboplatin/pemetrexed or cisplatin/pemetrexed) a patient would receive in
case the patient is assigned to the osimertinib plus chemotherapy arm.
Approximately 332 patients
will be randomized 1:1 to treatment with durvalumab for 4 cycles plus SoC
chemotherapy for up to 4 cycles or placebo for 4 cycles plus SoC chemotherapy
for up to 4 cycles followed by durvalumab or placebo for up to an additional 10
cycles (for a total of 12 months of treatment), until disease recurrence, or
until other specific treatment discontinuation criteria are met (whichever
occurs first).