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CTRI Number  CTRI/2019/01/017034 [Registered on: 10/01/2019] Trial Registered Prospectively
Last Modified On: 22/05/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Study of Durvalumab or Durvalumab and Tremelimumab, and Placebo in Stage I-III Limited Disease Small-Cell Lung Cancer Patients 
Scientific Title of Study   A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, International Study of Durvalumab or Durvalumab and Tremelimumab as Consolidation Treatment for Patients with Stage I-III Limited Disease Small-Cell Lung Cancer Who Have Not Progressed Following Concurrent Chemoradiation Therapy (ADRIATIC) 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
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, India

Bangalore
KARNATAKA
560045
India 
Phone  918067748006  
Fax    
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, India

Bangalore
KARNATAKA
560045
India 
Phone  918067748006  
Fax    
Email  Tapankumar.Shah@astrazeneca.com  
 
Source of Monetary or Material Support  
AstraZeneca AB, 151 85 Södertälje, Sweden 
 
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, India  
 
Countries of Recruitment     Argentina
Belgium
Canada
China
Czech Republic
Germany
India
Italy
Japan
Netherlands
Republic of Korea
Russian Federation
Spain
Taiwan
Turkey
United States of America
Viet Nam  
Sites of Study
Modification(s)  
No of Sites = 7  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Samit Purohit  Action Cancer Hospital  Senior Consultant Medical Oncologist, Dept. of Medical Oncology, A4, Paschim Vihar, New Delhi
North
DELHI 
01149222222
01145024287
samitmedonc@gmail.com 
Dr Rejiv Rajendranath   Apollo Speciality Hospital  Senior Consultant Medical Oncologist Dept. of Medical Oncology No: 320, Padma Complex, Anna Salai, Nandanam
Chennai
TAMIL NADU 
04424336119
04424329044
rejivr@yahoo.co.in 
Dr Hari Goyal  Artemis Hospitals  Consultant Medical Oncologist Department of Medical Oncology Sector-51, 122001
Gurgaon
HARYANA 
9958715678
01246767701
drgoyalhari@hotmail.com 
Dr Priyanka Srivastava  Manibhai Shivabhai Patel Cancer Centre, Shree Krishna Hospital and Medical Research Centre  Consultant Medical Oncologist Dept. of Medical Oncology Shree Krishna Hospital and Medical Research Centre, H M Patel Centre for Medical Care & Education, (Managed by: Charutar Arogya Mandal) Gokal Nagar
Anand
GUJARAT 
917574868577
02692223466
priyankass@charutarhealth.org 
Dr L K Rajeev  Shettys Hospital  Dept. of Medical Oncology Plot No. 11 & 12, 12th F Main Kaveri Nagar, Bommanahalli Bangalore -560068
Bangalore
KARNATAKA 
9880585797

lkrajeev@gmail.com 
Dr Satheesh CT  Sri Venkateshwara Hospital  Consultant Medical Oncologist, Dept. of Medical Oncology, # 27, 29th Main Road, Rashtra Kuvempu Nagara, BTM 2nd stage, BTM layout, PIN-560076
Bangalore
KARNATAKA 
08041508702
08040416700
drsatheeshct@gmail.com 
Dr Bivas Biswas  Tata Medical Centre  Dept of Medical Oncology 14-MAR (EW), New Town, Rajarhat, PIN–700160
Kolkata
WEST BENGAL 
919830922005

bivas.biswas@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 7  
Name of Committee  Approval Status 
Action Cancer Hospital Ethics Committee, Action Cancer Hospital, A-4, Paschim Vihar, New Delhi- 110063  Approved 
Artemis Health Sciences Institutional Ethics Committee Artemis Health Institute, Sector – 51, Gurgaon – 122001, Haryana  Approved 
Ethics Committee Sri Venkateshwara Hospital, # 27, 29th Main Road, Rashtra Kuvempu Nagara, BTM 2nd stage, BTM layout, PIN- 560076, Karnataka  Approved 
Institutional Ethics Committee H. M. Patel Centre for Medical Care and Education (Managed by Charutar Arogya Mandal) Office: Department of Forensic Medicine & Toxicology Pramukhswami Medical College, Gokal Nagar, Karamsad-388325, Gujarat, India.  Approved 
Institutional Ethics committee – Clinical Studies,Apollo Hospitals Enterprise Limited, 21, Greams Lane, Off Greams Road,Chennai – 600006, Tamil Nadu  Approved 
Shetty’s Hospital Ethics Committee Plot No.11 & 12, 12th “F” Main, Kaveri Nagar, Kodichikkanahalli, Bommanahalli, Bangalore- 560068, Karnataka  Approved 
Tata Medical Centre Institutional Ethics Committee, Kolkata  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  C349||Malignant neoplasm of unspecifiedpart of bronchus or lung,  
 
Intervention / Comparator Agent
Modification(s)  
Type  Name  Details 
Intervention  Durvalumab monotherapy: Durvalumab in combination with placebo saline solution IV q4w for up to 4 doses/cycles each, followed by durvalumab q4w. A total of 26 cycles. Durvalumab in combination with tremelimumab: Durvalumab in combination with tremelimumab q4w for up to 4 doses/cycles each, followed by durvalumab q4w. A total of 26 cycles  patient will be randomized into 1:1:1 either Durvalumab:durvalumab with Tremelimumab:placebo 
Comparator Agent  Placebo saline solution (IV) q4w in combination with a second placebo saline solution (IV) q4w for up to 4 doses/cycles each, followed by a single placebo saline solution q4w. A total of 26 cycles.  patient will be randomised into 1:1:1 ratio  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  75.00 Year(s)
Gender  Both 
Details  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 genetic informed consent prior to collection of sample for genetic analysis.
4.Age 18 to 75 years at the time of screening. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.

Type of patient and disease characteristics

5. Histologically or cytologically documented limited-stage SCLC (Stage I-III SCLC [T any, N any, M0] according to the American Joint Committee on Cancer Staging Manual [AJCC Cancer Staging Manual, 8th Edition] or the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology 2016]), ie, patients whose disease can be encompassed within a radical radiation portal. Patients who are Stage I or II must be medically inoperable.

6.World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment and randomization.

7.Received 4 cycles of platinum-based chemotherapy concurrent with RT, which must be completed within 1 to 42 days prior to randomization and the first dose of IP.
i.The chemotherapy regimen must contain platinum and etoposide, as per local standard-of-care regimens.
ii.For patients who are recovering from toxicities associated with initial treatment or for whom PCI is indicated by local standard of care, the first dose of IP may be delayed by up to 42 days from the end of the CRT.
iii.Radiotherapy must have commenced no later than the end of Cycle 2 of chemotherapy.
iv. Receipt of 3 cycles of platinum-based chemotherapy concurrent with RT will be permitted if the patient achieved disease control and Investigators judge no additional benefit will be expected with additional cycle of chemotherapy.
8.Patients must have achieved CR, PR, or SD and not have progressed following definitive, platinum-based, concurrent CRT.

9.Received a total dose of radiation of 60 to 66 Gy for standard QD radiation schedules or 45 Gy for hyperfractionated BID radiation schedules. Sites are encouraged to adhere to mean organ radiation dosing as follows:
i. Mean lung dose <20 Gy and/or V20 must be <35%
ii.Heart V50 <25%
10.Tumor sample requirements:
i. Provision of an archived tumor tissue block (or at least 15 newly cut unstained slides, where available) ≤3 years old, where such samples exist in a quantity sufficient to allow for analysis (refer to the Laboratory Manual for details)
ii. A recent (≤3 months) tumor biopsy (taken following completion of the most recent therapy) is an optional requirement, provided that a biopsy procedure is technically feasible, and the procedure is not associated with unacceptable clinical risk.
11. Adequate organ and marrow function independent of transfusion, infusion, or growth factor support for at least 14 days prior to screening, defined as 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 (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), 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 CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight)

12. Must have a life expectancy of at least 12 weeks

Weight
13. Body weight >30 kg

Sex
14. Male or female
 
 
ExclusionCriteria 
Details  Patients are eligible to be included in the study only if none of the following exclusion criteria apply:

Medical conditions

1. Mixed SCLC and NSCLC histology
2. Extensive-stage SCLC
3. Patients with Grade ≥2 pneumonitis from prior CRT
4. History of allogeneic organ transplantation
5. 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
6. 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 GI 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

7. 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
8. History of leptomeningeal carcinomatosis

9. History of active primary immunodeficiency

10. 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 HBV surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved 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 RNA.
11. Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from previous CRT with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
i. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
ii. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician
12. Brain metastases or spinal cord compression. All patients will have an MRI (preferred) or CT, preferably with IV contrast of the brain, prior to study entry.
13.Mean QT interval corrected for heart rate using fridericia formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
14. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

15. Patients who received sequential CRT for LD-SCLC (no overlap of RT with chemotherapy)

16. Patients whose conditions have progressed while on concurrent CRT Prior/concomitant therapy

17. Receipt of consolidation chemotherapy after radiation. (Treatment with etoposide and platinum after radiation is acceptable as 1 regimen for 1 to 2 cycles; chemotherapy regimens other than etoposide and platinum as consolidation are not permitted.)
18. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
19. 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.
20. 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.

21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.

Note:
Patients, if randomized, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.

22. Major surgical procedure (as defined by the Investigator) within 42 days prior to the first dose of IP.

23. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. 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
ii. Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)

Prior/concurrent clinical study experience

24. Participation in another clinical study with an investigational product administered in the last 4 weeks.

25. Previous IP assignment in the present study

26. 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.

27. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment group assignment.
28. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

Other exclusions

29. Female patients who are pregnant or breastfeeding and male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of IP.

30. Judgment by the Investigator that the patient should not participate in the study because the patient is unlikely to comply with study procedures, restrictions, and requirements.

31. Genetics research study (optional): Exclusion criteria for participation in the optional (DNA) genetics research component of the study include:

i. Previous allogeneic bone marrow transplant
ii. Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection


 
 
Method of Generating Random Sequence   Stratified block randomization 
Method of Concealment   Centralized 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
To assess the efficacy of durvalumab monotherapy as well as durvalumab in
combination with tremelimumab therapy compared to placebo in terms of PFS

• PFS using BICR assessments according to RECIST 1.1

To assess the efficacy of durvalumab in combination with tremelimumab therapy
compared to placebo in terms of OS

•OS 
During the Treatment period and Follow up period (Time frame-Approximately
4 years) 
 
Secondary Outcome  
Outcome  TimePoints 
•To assess the efficacy of durvalumab monotherapy compared to placebo in terms of OS
•To assess the efficacy of durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to placebo in terms of ORR, PFS18a, PFS24a, TTDM, OS24, OS36, and PFS2


 
os 4 years 
•To assess the efficacy of durvalumab and tremelimumab combination therapy compared to durvalumab monotherapy in terms of PFS, OS,and ORR
•To assess disease-related symptoms and HRQoL in patients treated with durvalumab monotherapy or durvalumab and tremelimumab combination therapy compared to placebo using the EORTC, QLQ-C30 v3 and QLQ-LC13
•To assess the PK of durvalumab monotherapy and durvalumab and tremelimumab combination therapy

 
OS 4 years 
•To investigate the immunogenicity of durvalumab monotherapy and durvalumab and tremelimumab combination therapy
•To investigate the relationship between a patient’s tumor mutational burden (TMB) measured in tumor and/or blood and efficacy outcomes with
durvalumab and durvalumab and tremelimumab combination therapy 
OS 4 years 
Safety objectives:

• To assess the safety and tolerability profile of durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to
placebo in patients with LD-SCLC.

 
OS 4 years 
Exploratory objectives:

• To assess treatment-related side effects in patients treated with durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to placebo using PRO-CTCAE

 
OS 4 YEARS 
•To assess the patients’ overall impression of the severity of their cancer symptoms using PGIS

• To describe and evaluate health resource use associated with durvalumab monotherapy and durvalumab and tremelimumab combination therapy and underlying disease

• To explore the impact of treatment and disease state on health state utility using the EQ-5D-5L
 
OS 4 YEARS 
• To collect blood and tissue samples, or leverage residual samples, for analysis of peripheral and tumoral biomarkers

• To investigate the relationship between a patient’s PD-L1 expression and spatial distribution within the tumor microenvironment and clinical
outcomes with durvalumab monotherapy or durvalumab and tremelimumab
combination therapy

 
OS 4 YEARS 
To explore the relationship(s) between patient biomarker status and durvalumab PK exposure and clinical outcomes before and after treatment.

• To explore irRECIST as assessment methodologies for clinical benefit of durvalumab monotherapy and durvalumab and tremelimumab combination therapy compared to placebo with assessment by BICR.


 
OS 4 YEARS 
• To collect and store DNA from tissue and/or blood according to each country’s local and ethical procedures for future exploratory research
into genes/genetic variation that may influence response (ie, distribution, safety, tolerability, and efficacy) to IPs and/or susceptibility to disease
(optional) 
OS 4 YEARS 
 
Target Sample Size   Total Sample Size="600"
Sample Size from India="30" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   18/01/2019 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  27/09/2018 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="4"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Open to Recruitment 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   not yet 
Brief Summary  

This is a Phase III, randomized, double-blind, placebo-controlled, multi-center study assessing the efficacy and safety of durvalumab or durvalumab and tremelimumab combination therapy versus placebo as consolidation treatment in patients with LD-SCLC who have not progressed following definitive, platinum-based, concurrent CRT.

 

To be eligible for this study, patients must have achieved CR, PR, or SD and have not progressed following definitive, platinum-based, concurrent CRT. This CRT treatment, and PCI treatment if received per local standard of care, must be completed within 1 to 42 days prior to randomization and the first dose of investigational product (IP; ie, durvalumab, tremelimumab,or placebo) in this study.In addition,the baseline efficacy assessment must be performed post-CRT as part of the screening procedures within 42 days before randomization and the first dose of IP.

 

Approximately 750 patients will be recruited in order to enroll and randomize approximately 600 patients in a 1:1:1 ratio to 1 of 3 treatment groups: durvalumab monotherapy, durvalumab and tremelimumab combination therapy, or placebo.  Randomization will be stratified by TNM stage (I/II versus III) and receipt of PCI (yes versus no). Recruitment for patients with TNM Stage III disease will be limited to up to 85% of the targeted global population. Patients will receive their assigned treatment until clinical/RECIST 1.1-defined radiological progression, until intolerable toxicity, or for a maximum of 24 months (26 doses/cycles), whichever occurs first.

 
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