Study of Durvalumab plus Domvanalimab in Stage III Unresectable Non-small Cell Lung Cancer Whose Disease has not Progressed Following Concurrent Chemoradiation Therapy
Scientific Title of Study
A Phase III, Randomised, Double blind, Placebo controlled, Multicentre, International Study of Durvalumab plus Domvanalimab (AB154) in Participants with Locally Advanced (Stage III), Unresectable Non-small Cell Lung Cancer Whose Disease has not Progressed Following Definitive Platinum based Concurrent Chemoradiation Therapy (PACIFIC-8)
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
D9075C00001, Version 3.0 Date 17 Dec 2021
Protocol Number
NCT05211895
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Senior Director, Oncology Country Head Site Management and Monitoring – India
Affiliation
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road.
Bangalore KARNATAKA 560045 India
Phone
91-9845079472
Fax
08067748857
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
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road, Bangalore –560045, Karnataka, India
Countries of Recruitment
Belgium Chile China Germany Greece Hungary India Ireland Japan Malaysia Mexico Norway Philippines Romania Russian Federation South Africa Taiwan Turkey Ukraine United States of America
Dept. of Medical Oncology
Sector-51, PIN122001 Gurgaon HARYANA
9911152107
vineet.gupta@artemishospitals.com
Dr Deepak Gupta
Bhagwan Mahaveer Cancer Hospital & Research Centre
Dept. of Medical Oncology
Jawahar Lal Nehru Marg,Jaipur, PIN-302017
Jaipur RAJASTHAN
9001795275
drdeepakgupta@yahoo.co.in
Dr Praveen Adusumilli
CARE Hospitals, Hyderabad
Hi- Tech City, Near Cyberbad Police Commissionerate, Hyderabad, PIN 500032 Hyderabad TELANGANA
9100755777
apraveenonco@gmail.com
Dr Harish V Reddy
Cytecare Cancer Hospital
Dept. of Medical Oncology
Near, Venkatala, Bagalur Cross, Yelahanka,
PIN- 560064
Bangalore KARNATAKA
7899105235
harish.reddy@cytecare.com
Dr Chandragouda Dodagoudar
Dr. B.L Kapur Memorial Hospital
Dept. of Medical Oncology
Pusa Road, PIN 110005
New Delhi DELHI
9958450124
drchandru1976@yahoo.co.in
Dr Satheesh CT
HealthCare Global Enterprises Limited
Department of Medical
Oncology, HCG Tower #8, P. Kalinga Rao Road, Sampangi
Ram Nagar PIN 560027, India
Bangalore Bangalore KARNATAKA
9242698750
drsatheeshct@gmail.com
Dr Anuj Gupta
Mahamana Pandit Madan Mohan Malaviya Cancer Centre
Department of Medical Oncology Sundar Bagiya, Near Nariya Gate,
Banaras Hindu University Campus,
Varanasi Uttar Pradesh – 221005, India
Varanasi UTTAR PRADESH
9588229594
dranuj.gupta24@gmail.com
Dr Gautam Goyal
Max Superspeciality Hospital, Mohali
Dept. of Medical Oncology
Max Superspeciality Hospital,
Chandigarh Road,Near Civil Hospital, Phase 6, Sector 56,
Sahibzada Ajit Singh Nagar, Punjab 160055
Chandigarh CHANDIGARH
8195849111
gautam3636@gmail.com
Dr Chandrakanth M V
Narayana Superspeciality Hospital, Howrah
Dept. of Medical Oncology
Narayana Superspeciality Hospital,
120/1, Andul Rd, near Nabanna, Shibpur,
Howrah, PIN 711103
Haora WEST BENGAL
7003206633
drmvch@gmail.com
Dr Sandeep Kumar Jasuja
R.K. Birla Cancer Center, SMS Medical and Attached Hospital
SMS Hospital, JLN Marg,
Jaipur, 302004, Rajasthan, India.
Jaipur RAJASTHAN
9660121475
sandeepjasuja@gmail.com
Dr Manasi Sharma
Rajiv Gandhi Cancer Institute and Research Centre
Dept. of Medical Oncology
Sir Chotu Ram Marg, Rohini Institutional Area,
Sector 5, Rohini, PIN 110085
New Delhi DELHI
9873008262
mansisharma08@gmail.com
Dr Lalit Mohan Sharma
Sri Ram Cancer & Super Speciaility Centre
Dept. of Medical Oncology
Mahatma Gandhi Medical College and Hospital,
RIICO Institutional Area, Sitapura, PIN-302022
Jaipur RAJASTHAN
9928602244
drlalit2003@gmail.com
Dr Somnath Roy
Tata Medical Centre, Kolkata
Dept. of Medical Oncology
14, MAR E-W, DH Block Newtown,
Action Area I, Newtown, PIN 700160
Kolkata WEST BENGAL
9051732283
somnath.roy1@tmckolkata.com
Dr Bhavesh Poladia
Thangam Hospital and Thangam Cancer Centre
Dept. of Medical Oncology
54, Dr. Sankaran Road,Namakkal-637001
Namakkal TAMIL NADU
9819151554
bhaveshpoladia@gmail.com
Dr Kaushal Kalra
Vardhman Mahavir Medical College & Safdarjung Hospital
Department of Medical Oncology,
New Delhi,110029
New Delhi DELHI
9968663394
kaushalkalra@yahoo.com
Dr Mithun Shah
Zydus Cancer Centre
Dept. of Medical Oncology
C/O Zydus Hospitals & Healthcare Research Pvt Ltd,
Zydus Hospital Road, S.G. Highway, Near Sola Bridge,
Thaltej, PIN-380054
Ahmadabad GUJARAT
(1) ICD-10 Condition: C349||Malignant neoplasm of unspecifiedpart of bronchus or lung,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Arm A: Durvalumab plus Domvanalimab
Arm A: Durvalumab on Day 1 of each cycle plus Domvanalimab on Day 1 of each cycle for up to 12 months.
Comparator Agent
Arm B: Durvalumab plus placebo
Arm B: Durvalumab plus placebo on Day 1 of each cycle for up to 12 months.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
90.00 Year(s)
Gender
Both
Details
Part I Screening
1 Participant must be ≥ 18 years at the time of screening.
2 Participants must have histologically or cytologically documented NSCLC and have been treated with concurrent CRT for locally advanced (Stage III), unresectable disease .
3 Tumour sample requirements as follows: Provision of a tumour tissue sample (obtained ≤ 3 months prior to screening Part 1 is preferred; ≤ 6 months old is acceptable if no sample of ≤ 3 months is available). An FFPE block sufficient for sectioning 20 slides (5 micron thickness) is preferred. If FFPE blocks cannot be submitted, then a set of newly-cut, unstained slides to enable the necessary testing may be provided.
4 Tumour PD L1 status ≥ 1% as determined using the Ventana SP263 PD L1 IHC assay by a central laboratory.
5 Documented EGFR and ALK wild-type status.
6 Tumours harbouring mutations in any of the following genes, if known, as determined by existing local test results: ROS1, RET, MET, BRAF, NTRK1, NTRK2, and ERBB2 are excluded.
7 Capable of giving signed informed consent for tumour sample collection that includes compliance with the requirements and restrictions listed in the pre-screening informed consent form (Part I screening ICF), which includes compliance with the requirements and restrictions listed in the ICF and this protocol.
Part II Screening
Participants are eligible to be randomised to the study only if all of the following Part II inclusion criteria and none of the exclusion criteria apply:
8 Participants must have not progressed following definitive, platinum based, concurrent chemoradiation therapy. Screening imaging should include brain imaging (MRI is the preferred modality however high-quality CT with IV contrast is acceptable).
9 Participants must have received at least 2 cycles of platinum- based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 28 days prior to the first dose of study intervention in the study (1 cycle is defined as 21 or 28 days). For participants who are recovering from toxicities associated with prior treatment, the first dose of study intervention may be delayed by up to 28 days from the end of chemoradiation therapy. Sites are strongly encouraged to complete screening within the first 14 days of the 28 day screening period.
10 The platinum-based chemotherapy regimen must have contained cisplatin or carboplatin and one of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care regimens. Gemcitabine is not permitted.
11 The last dose of chemotherapy must be administered prior to, or concurrently with, the final dose of radiation. Consolidation chemotherapy after radiation is not permitted but administration of 1 2 induction cycles of chemotherapy prior to cCRT is acceptable. Where possible, chemotherapy regimens should be given according to National Comprehensive Cancer Network (NCCN) Guidelines or European Society for Medical Oncology (ESMO) Guidelines.
12 A total dose of radiation of 60 Gy ± 10% (54 Gy to 66 Gy) as part of the chemoradiation therapy is required to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or a 3D conforming technique.
13 World Health Organization (WHO) Performance Status of 0 or 1 at randomisation.
14 Adequate organ and marrow function
15 Minimum life expectancy of 12 weeks at randomisation
16 Body weight > 30 kg at enrolment and randomisation
17 Male or female.
Reproduction: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
18 Negative pregnancy test (serum) for WOCBP:
19 Female participants must be 1 year post menopausal, surgically sterile, or using 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). WOCBP must agree to use one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to 115 days after the last dose. Non sterilised male partners of a WOCBP must use a male condom and spermicide throughout this period.
20 Male participants who intend to be sexually active with a WOCBP must be surgically sterile or using an acceptable method of contraception from the time of screening throughout the total duration of the study, and for drugs that are potentially genotoxic the drug washout period (115 days after the last dose of study intervention) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period.
Informed Consent
21 Capable of giving signed informed consent.
For Optional Genomic initiative participation only: Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative. If a participant declines to participate in the genetics research, there will be no penalty or loss of benefit to the participant. A participant who declines genetics research participation will not be excluded from any other aspect of the main study.
ExclusionCriteria
Details
Participants are excluded from the study if any of the following criteria apply:
1 As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations); or a history of allogeneic organ transplant, which, in the investigator s opinion, makes it undesirable for the participant to participate in the study, or that would jeopardize compliance with the protocol
2 History of another primary malignancy, except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy or adequately treated carcinoma in situ or Ta tumours without evidence of disease
3 Prior allogeneic bone marrow transplantation or stem cell/solid organ transplantation
4 Active or prior documented autoimmune or inflammatory disorders (with exception)
5 Severe infection within 4 weeks prior to initiation of study treatment
6 History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis, ILD, pleural effusion, or pulmonary fibrosis .
7 History of leptomeningeal carcinomatosis
8 History of primary immunodeficiency
9 Active hepatitis infection, positive HCV antibody, HBV surface antigen (HbsAg) or HBV core antibody (anti HBc) at screening. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HbsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
10 Positive test for HIV (positive HIV 1/2 antibodies) or known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice)
11 Active EBV infection, or known or suspected chronic active EBV infection at screening
12 Mixed small cell and NSCLC cancer histology
13 Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced, unresectable NSCLC
14 Participants with locally advanced, unresectable NSCLC who have progressed during definitive platinum- based cCRT
15 Participants who have had disease considered for surgical treatment as part of their care plan, such as Pancoast or superior sulcus tumours
16 Participants with T4 lesions that invade major vascular structures such as pulmonary artery or cardiac tissues are ineligible.
17 Investigator judgement of 1 or more of the following:
ï€ Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening
ï€ History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause TdP
ï€ Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden cardiac death < 40 years of age in first degree relatives
18 History of symptomatic congestive heart failure; unstable angina pectoris; uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment; or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the clinical study lead.
19 Subjects with a history of myocardial infarction, transient ischemic attack, pulmonary embolism, or stroke diagnosed in the past 6 months, or venous thrombosis diagnosed in the past 3 months
20 Known allergy or hypersensitivity to any of the study interventions.
21 Receipt of prior or current cancer treatment for NSCLC, including but not limited to, radiation therapy, investigational agents, chemotherapy, and mAbs. Prior surgical resection of metachronus NSCLC (ie, Stage I or II) is permitted.
22 Prior exposure to immune mediated therapy including, but not limited to, anti-TIGIT, anti–CTLA 4, anti-PD 1, anti-PD-L1, anti-PD L2 antibodies, excluding therapeutic anticancer vaccines. Live attenuated vaccines within 30 days prior to the first dose of the study intervention are not permitted.
23 Participants who are expected to require any other form of antineoplastic therapy while participating in the trial are excluded.
24 Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab plus domvanalimab (with exceptions)
25 Major surgical procedure (as defined by the investigator) within 4 weeks prior to the first dose of study intervention. Prior surgical resection of metachronous NSCLC (i.e., Stage I or II) is permitted.
26 Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy (excluding alopecia).
27 Participants with CTCAE ≥ Grade 2 pneumonitis from prior chemoradiation therapy
28 Any prior Grade ≥ 3 immune related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
29 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer related conditions (eg, hormone replacement therapy) is allowed.
30 Previous treatment in the present study
31 Concurrent participation in another clinical study, unless it is an observational (non interventional) clinical study, or the follow up period of an interventional study
32 Participation in another clinical study with a study intervention during the last 3 months prior to randomisation or concurrent enrolment in another clinical study, unless it is an observational, noninterventional clinical study during the follow up period of an interventional study
33 Prior randomisation or treatment in a previous durvalumab or domvanalimab clinical study regardless of treatment arm assignment
34 Receipt of any immunotherapy, or investigational drug within 4 weeks prior to the first dose of study drug; and in the case of monoclonal antibodies 6 weeks prior to the first dose of study drug
35 Participants with a known sensitivity to durvalumab or domvanalimab, any anti-TIGIT, or any excipients of the products
36 Judgement by the investigator that the participant is unsuitable to participate in the study and the participant is unlikely to comply with study procedures, restrictions, and requirements
37 Female participants who are pregnant or breastfeeding, or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 115 days after the last dose of study treatment.
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
To demonstrate superiority of durvalumab plus domvanalimab relative to durvalumab plus placebo in participants with locally advanced, unresectable NSCLC who have not progressed on prior platinum based cCRT, with:
1 PD-L1 TC ≥ 50%
2 assessment by PFS as assessed by BICR
PFS measured by HR
up to approximately 77 months
Secondary Outcome
Outcome
TimePoints
As primary, with:
1 PD-L1 TC ≥ 1%
2 assessment by PFS as assessed by BICR
PFS measured by HR
up to approximately 77 months
As primary, with:
PD-L1 TC ≥ 50%, or
PD-L1 TC ≥ 1%
assessment by OS
OS measured by HR
up to approximately 92 months
As primary, with:
PD-L1 TC ≥ 50%, or
PD-L1 TC ≥ 1%
assessment by:
ORR
DoR
PFS2
TTDM
TFST
PFS6, PFS12, PFS18, PFS24
OS24
PFS as assessed by investigator
ORR as measured by odds ratio
DoR as measured by median
PFS2 as measured by HR
TTDM as measured by HR
TFST as measured by HR
PFS6, PFS12, PFS18 and PFS24 as measured by the proportion of participants still alive and progression-free
OS24 measured by the Kaplan-Meier estimate of OS at 24 months
PFS as assessed by investigator, measured by HR
up to approximately 92 months
To test the above objectives using an alternative PD-L1 IHC assay, PD-L1 IHC 22C3 pharmDx, who have not progressed on prior platinum based cCRT, with:
PD-L1 TPS ≥ 50%, or
PD-L1 TPS ≥ 1%
All endpoints as given for the VENTANA PD-L1 (SP263) IHC assay will also be assessed for the alternate PD-L1 IHC 22C3 pharmDx assay
up to approximately 92 months
To assess the PK of durvalumab when given in combination with domvanalimab, in participants with locally advanced, unresectable NSCLC, with PD-L1 TC ≥ 1% as measured by the VENTANA PD-L1 (SP263) IHC assay, who have not progressed on prior platinum based cCRT
Concentration of durvalumab in serum and PK parameters
up to approximately 77 months
To assess the PK of domvanalimab when given in combination with durvalumab, in participants with locally advanced, unresectable NSCLC, with PD-L1 TC ≥ 1% as measured by the VENTANA PD-L1 (SP263) IHC assay, who have not progressed on prior platinum based cCRT
Concentration of domvanalimab in serum and PK parameters
up to approximately 77 months
To investigate the immunogenicity of durvalumab, in participants with locally advanced, unresectable NSCLC with PD-L1 TC ≥ 1% as measured by the VENTANA PD-L1 (SP263) IHC assay, who have not progressed on prior platinum-based cCRT
Presence of ADAs for durvalumab as measured by rates of occurrence of ADAs and titres
up to approximately 77 months
To investigate the immunogenicity of domvanalimab in participants with locally advanced, unresectable NSCLC with PD-L1 TC ≥ 1% as measured by the VENTANA PD-L1 (SP263) IHC assay, who have not progressed on prior platinum-based cCRT
Presence of ADAs for domvanalimab as measured by rates of occurrence of ADAs and titres
up to approximately 77 months
To assess time to deterioration in pulmonary symptoms
cough, dyspnoea, chest pain
TTFCD as measured by HR
up to approximately 77 months
Safety objective
To assess the safety and tolerability of durvalumab plus domvanalimab as compared to durvalumab plus placebo in participants with locally advanced, unresectable NSCLC who have not progressed on prior platinum based cCRT
Endpoint/variable
Safety and tolerability will be evaluated in terms of AEs, physical examinations, vital signs including systolic and diastolic blood pressure and pulse, ECGs, and laboratory findings including clinical chemistry, haematology and urinalysis
up to approximately 77 months
Target Sample Size
Total Sample Size="860" Sample Size from India="40" 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,
randomised, double blind, placebo controlled, multicentre, international study
assessing the efficacy and safety of durvalumab and domvanalimab compared with
durvalumab plus placebo in adults with locally advanced (Stage III),
unresectable NSCLC whose disease has not progressed following definitive
platinum based cCRT. It is estimated that approximately 860 participants with
PD-L1 TC ≥ 1% will be randomised at approximately 200 sites in approximately 20
countries. Participants will be randomised in a 1:1 ratio to one of the
following intervention arms. Participants in the durvalumab plus domvanalimab
arm will assigned treatement for up to a maximum of 12 months (maximum 13
cycles with the last administration by Week 48), or until clinical progression,
confirmed RECIST 1.1 defined radiological progression, unacceptable toxicity,
withdrawal of consent, or an intervention discontinuation criterion is met,
whichever is earlier. After study intervention discontinuation, all
participants will be followed up for safety assessments 90 days after their
last dose of study intervention (ie, the safety follow up visit). All
participants randomised in the study should be followed up for survival.