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CTRI Number  CTRI/2019/02/017798 [Registered on: 25/02/2019] Trial Registered Prospectively
Last Modified On: 04/11/2023
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 treatment with Durvalumab or Placebo in patients with locally advanced and surgically non-removable Non-Small Cell Lung Cancer (Stage III) whose disease has not progressed after platinum-based chemotherapy and radiation 
Scientific Title of Study   A Phase III Randomized Double-Blind Placebo-Controlled Multicenter study of Durvalumab as Consolidation Therapy in patients with locally advanced unresectable Non-Small Cell Lung Cancer (Stage III) who have not progressed following definitive platinum-based chemoradiation therapy  
Trial Acronym  PACIFIC 5 
Secondary IDs if Any
Modification(s)  
Secondary ID  Identifier 
D933YC00001 Version 3.0, dated 07 May 2019  Protocol Number 
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
Modification(s)  
Name  Mr Sandeep AV 
Designation  Senior Director, Oncology Country Head Site Management and Monitoring – India  
Affiliation  AstraZeneca Pharma India Ltd 
Address  AstraZeneca Pharma India Ltd Block N1 12th Floor Manyata Embassy Business Park Rachenahalli Outer Ring Road Bangalore

Bangalore
KARNATAKA
560045
India 
Phone  91-9845079472  
Fax  91-8067748857  
Email  Sandeep.AV@astrazeneca.com  
 
Details of Contact Person
Public Query
Modification(s)  
Name  Mr Sandeep AV 
Designation  Senior Director, Oncology Country Head Site Management and Monitoring – India  
Affiliation  AstraZeneca Pharma India Ltd 
Address  AstraZeneca Pharma India Ltd Block N1 12th Floor Manyata Embassy Business Park Rachenahalli Outer Ring Road Bangalore

Bangalore
KARNATAKA
560045
India 
Phone  91-9845079472  
Fax  91-8067748857  
Email  Sandeep.AV@astrazeneca.com  
 
Source of Monetary or Material Support  
AstraZeneca AB 151 85 Sodertalje Sweden 
 
Primary Sponsor  
Name  AstraZeneca AB  
Address  151 85 Sodertalje Sweden 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     China
India
Mexico
Philippines
Poland
Russian Federation
Taiwan
Turkey
Republic of Korea  
Sites of Study
Modification(s)  
No of Sites = 8  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Madras Ananthanarayanan Raja   Apollo Speciality Hospital  Department of Oncology No 320 Padma Complex Anna Salai Chennai 600035
Chennai
TAMIL NADU 		 18605001066
04424362424
drmaraja@gmail.com 
Dr Nirav Asarawala   Manibhai Shivabhai Patel Cancer Centre  Shree Krishna Hospital and Medical Research Centre H M Patel Centre for Medical Care and Education Department of Oncology Clinical research room Ground floor Gokul Nagar Karamsad 388325
Anand
GUJARAT 		 02692222130
02692223466
niravna@charutarhealth.org 
Dr Shailesh Bondarde  Shatabdi Hospital   Department of Oncology Suyojit City Centre Opp Mahamarga Bus stand Mumbai Naka Nashik 422005
Nashik
MAHARASHTRA 		 02532501888
02532502105
shaileshbondarde1971@gmail.com 
Dr Rajeev Lakkavalli Krishnappa  Shettys Hospital   Department of Oncology 11 and 12 12 Main Kaveri Nagar Kodichikkanahalli Bommanahalli Bangalore 560068
Bangalore
KARNATAKA 		 08079485545
08040943039
lkrajeev@gmail.com 
Dr Kartikeya Jain  Shree Himalaya Cancer hospital and Research Institute  Department of Oncology 3rd Floor Room No. 301 4 Vinod Baugh Jetalpur Bridge Road Alkapuri Vadodara 390007
Vadodara
GUJARAT 		 07043220905
02656542151
divahogclinic@gmail.com 
Dr Satheesh CT  Sri Venkateshwara Hospital   Department of Oncology # 27, 29th Main Road, Rashtra Kuvempu Nagara, BTM 2nd stage, BTM layout PIN - 560076
Bangalore
KARNATAKA 		 08049730808

drsatheeshct@gmail.com 
Dr Bivas Biswas  Tata Medical Centre  Drpt of Medical Oncology 14-MAR (EW), New Town, Rajarhat, PIN 700160
Kolkata
WEST BENGAL 		 919830922005

bivas.biswas@gmail.com 
Dr Nithya Sridharan   V. S. Hospital  Department of Oncology 13 East Spur Tank Road Chetpet Chennai Tamil Nadu 600031
Chennai
TAMIL NADU 		 04442001000
04442172604
drnithya.vsh@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 8  
Name of Committee  Approval Status 
Ethics Committee V S Hospital   Approved 
Institutional Ethics Committee Clinical Studies   Approved 
Institutional Ethics Committee H M Patel Centre for Medical Care and Education   Approved 
Institutional Ethics Committee Shree Himalaya Cancer Hospital and Research Centre  Approved 
Shatabdi Hospital Ethics Committee  Approved 
Shettys Hospital Ethics Committee  Approved 
Sri Venkateshwara Hospital Ethics Committee  Approved 
Tata Medical Centre Institutional Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI
Modification(s)  
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   Patients will be randomized in a 2:1 ratio to either Durvalumab or Placebo Patients with complete response Partial response or stable disease at 8 weeks tumor evaluation will receive Durvalumab or placebo as consolidation therapy 
Comparator Agent  Placebo   Placebo as consolidation therapy  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  1. Capability to give signed informed consent that 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

Histologically or cytologically documented NSCLC and present with locally
advanced unresectable (Stage III) disease (according to Version 8 of the (IASLC
Staging Manual in Thoracic Oncology]). Positron emission tomography/CT, MRI of
the brain, and endobronchial ultrasound with biopsy are highly encouraged at
diagnosis.
4. Receipt of concurrent or sequential chemoradiation therapy, which must be completed within 1 to 28 days prior to first dose of IP in the study.
-For cCRT, patients must have received at least 2 cycles of platinum-based
chemotherapy concurrent with radiation therapy. The last dose of chemotherapy
must be prior to, or concurrent with, the final dose of radiation. Consolidation
chemotherapy after radiation is not permitted, but no more than 2 cycles of
induction chemotherapy prior to cCRT is acceptable.

-For sCRT, patients must have received at least 2 cycles of platinum-based
chemotherapy before radiation therapy. The interval between administration of
the last dose of chemotherapy regimen and start of RT must be no more than
6 weeks. Consolidation chemotherapy after radiation is not permitted.
(i) Note: If a patient receives only 1 cycle of platinum-based chemotherapy
concurrent with radiation treatment, this patient will be eligible for the
study to participate in the sCRT stratum.
-The platinum-based chemotherapy regimen must contain cisplatin or carboplatin
and 1 of the following agents: etoposide, vinblastine, vinorelbine, a taxane
(paclitaxel or docetaxel), or pemetrexed, according to the local SoC regimens.
(Gemcitabine is not included.)
-Patients must have received a total dose of radiation of 60 Gy ±10% (54 to 66 Gy)
to be randomised as part of the chemoradiation therapy. Study sites are
encouraged to adhere to the following mean organ radiation dosing:
(i) Mean lung dose must be <20 Gy, and/or V20 must be <35%
(ii) Mean oesophagus dose must be <34 Gy
(iii) Heart V45 must be <35%, or V30 must be <30%
 Study sites should be aware of the recent RTOG 0617 Trial data demonstrating
that doses higher than 60 Gy may be associated with greater toxicity and worse
efficacy.

5. No progression following definitive, platinum-based, concurrent or sequential chemoradiation therapy

6. Tumor PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a reference laboratory, must be known prior to randomization. Patient with unknown PD-L1 status is not eligible for the study. “Unknown” refers to (1) insufficient sample which is not able to be analyzed, or (2) sample could be analyzed but results not interpretable.

7. Documented EGFR and ALK status (locally or centrally) at Screening. If the local laboratory will perform the test, a well-validated, local regulatory-approved kit must be used.

- EGFR and ALK status must be available prior to randomisation. After approximately 15% EGFR or ALK mutant patients have been randomised, the incoming patients with EGFR or ALK mutation will not be enrolled.

8. Tumour sample requirements are as follows: Provision of a tumour tissue sample (newly acquired sample ≤3 months old is preferred, but an archived sample ≤6 months old is acceptable) in a quantity sufficient to allow for analysis. Study subject should not have received any intervening systemic therapy other than chemoradiotherapy for Stage III disease as described above.

9. World Health Organization (WHO) PS of 0 or 1 at enrolment
10. No prior exposure to any anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines
11. Adequate organ and marrow function as defined below. Absolute neutrophil count, platelet count, and haemoglobin criteria cannot be met with transfusion or growth factor support administered within 14 days before randomisation.
- Haemoglobin ≥9 g/L
- Absolute neutrophil count >1.5 × 109/L (1500 per mm3)
- Platelet count >100 × 109/L (100000 per mm3)
- 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 that is predominantly unconjugated in the absence of evidence of haemolysis or hepatic pathology), who will be allowed in consultation with their primary physician.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN
- Serum creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine CL

12. Life expectancy of at least 12 weeks at Day 1

13. WT >30 kg

 
 
ExclusionCriteria 
Details  Patients should not enter the study if any of the following exclusion criteria are fulfilled:
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 [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). 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 interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, 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
History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigation product (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 clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus(positive human immunodeficiency virus [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.

7. Mixed small cell and NSCLC histology

8. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from the prior chemoradiation therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included (eg, hearing loss) after consultation with the AstraZeneca Study Physician.

9. Patients with Grade ≥2 pneumonitis from prior chemoradiation therapy

10. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients

Prior/concomitant therapy
11. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment other than those under investigation in this study
12. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
13. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent and placement of vascular access are acceptable.
14. 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)

- Systemic steroid administration required as prophylaxis against or to manage toxicities arising from chemotherapy and/or radiotherapy delivered as part of the chemoradiation therapy for locally advanced NSCLC
Prior/concurrent clinical study experience
15. Participation in another clinical study with an IP administered in the last 4 weeks prior to randomization.
16. Previous IP assignment in the present study
17. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the Follow-up Period of an interventional study
18. Prior randomisation or treatment in a previous durvalumab ± tremelimumab clinical study regardless of treatment arm assignment
Other exclusions
19. 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 monotherapy
20. 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.
 
 
Method of Generating Random Sequence   Stratified randomization 
Method of Concealment   Centralized 
Blinding/Masking   Double Blind Double Dummy 
Primary Outcome  
Outcome  TimePoints 
To assess the efficacy of Durvalumab treatment compared with placebo in terms of Progression Free Survival   Progression Free Survival Time frame approximately 5 years 
 
Secondary Outcome  
Outcome  TimePoints 
To further access the efficacy of Durvalumab compared with Placebo in terms of OS   OS analysis will occur when approximately 255 death events have occurred 
• To further assess the efficacy of durvalumab compared with placebo in terms of OS24, ORR, DoR, PFS12, PFS18, PFS2, and TTDM

 		 Time Frame Approximately 5 years  
To assess the PK of Durvalumab   Time Frame approximately 5 years  
To investigate the immunogenicity of Durvalumab   Time Frame Approximately 5 years  
To assess symptoms and health related quality of life in patients treated with Durvalumab compared with placebo using EORTC QLQ C30 v3 and QLQ LC13   Overall Survival Time Frame approximately 5 years  
To investigate the relationship between a patients tissue TMB and efficacy outcomes with Durvalumab   Time frame approximately 5 years  
To investigate the relationship between a patients baseline tumor PD L1 expresssion and efficacy outcome with durvalumab compared with placebo   Time Frame approximately 5 years  
 
Target Sample Size   Total Sample Size="360"
Sample Size from India="15" 
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)   18/03/2019 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  27/11/2018 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="5"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Open to Recruitment 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   None as yet  
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary
Modification(s)  

This study is a Phase III, randomised, double-blind, placebo-controlled, multicentre study assessing the efficacy and safety of durvalumab compared with placebo as consolidation therapy in patients with locally advanced, unresectable NSCLC (Stage III) who have not progressed following definitive, platinum-based, chemoradiation therapy.

Approximately 360 patients with locally advanced, unresectable NSCLC (Stage III) who received cCRT or sCRT will be randomised globally. These patients will be in complete response (CR), partial response (PR), or have stable disease (SD) following definitive, platinum based, concurrent or sequential chemoradiation therapy.

Patients must have histologically or cytologically documented NSCLC and present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology. The number of patients with an EGFR mutation or ALK rearrangement will be capped at approximately 15% of the total number of patients randomised. The study will maintain a balance of approximately 1:1 between the cCRT and sCRT patient population with the majority of patients to be recruited in China.

 

Patients will be randomised in a 2:1 ratio (durvalumab to placebo) to 1 of 2 arms:

·       Durvalumab q4w intravenously [IV] until clinical progression/deterioration or confirmed radiological progression)

·       Placebo (matching placebo) for infusion q4w IV until clinical progression/deterioration or confirmed radiological progression)

Randomisation will be stratified by the level of PD-L1 expression (PD-L1 <1% or PD-L1≥1%] and prior therapy (cCRT or sCRT). Patients must not have progressed following definitive, platinum-based, concurrent or sequential CRT. For those patients randomised to the placebo arm, no crossover to the durvalumab arm is permitted; similarly, those patients randomised to the durvalumab arm cannot crossover to the placebo arm.

Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) will be performed. RECIST 1.1 measurements (using BICR assessments) will be used to derive the primary variable of PFS and secondary variables of ORR, DoR, PFS12, and PFS18.

 
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