A Global Study to Assess the Effects of Durvalumab +Domvanalimab Following Concurrent Chemoradiation in Patients with Stage III Unresectable Non-Small Cell LungCancer (PACIFIC 8)
A Phase III, Randomised, Double-blind, Placebo-controlled, Multicentre, International Study of Durvalumab plus Domvanalimab(AB154)in Participantswith Locally Advanced(Stage III), Unresectable Non-small Cell Lung Cancer Whose Disease has not Progressed Following DefinitivePlatinum-basedConcurrent Chemoradiation Therapy
This is a Phase III, parallel, randomised, double-blind, placebo-controlled,2-arm,multicentre, international study assessing the efficacy and safety of durvalumab plus domvanalimabin participants with locally advanced(Stage III), unresectable NSCLC whose disease has not progressed following definitive platinum-based cCRT. Approximately 860participants will be randomised in a 1:1 ratio to one of the following intervention arms. Randomisation will be stratified by disease stage prior to cCRT(IIIA versus IIIB/IIIC), histology (squamous versus non-squamous), and PD‑L1 status (TC ≥50% vs. TC 1-49%),as assessed by a central reference laboratory using the VENTANA PD-L1(SP263)IHC assay. Arm A: Experimental arm: durvalumab plus domvanalimabq4w for 12months.Arm B: Control arm: durvalumab plus placeboq4w for 12months
Administration of study drug (ie, durvalumab, domvanalimab or placebo) will commence on Day 1(within 3 days from randomisation) following randomisation after confirmation of eligibility and will continue on a q4w schedule for a maximum duration of 12 months. The final administration of study drug will be at the Week 48visit. 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). In addition, all participants will be followed up for survival after intervention discontinuation from the date off first dose until death, withdrawal of consent, or the end of the study (ie, progression/survival follow-up), as per the SoA.
The primary objective of this study is to assess the efficacy of durvalumab plus domvanalimab compared with durvalumab plus placebo, in participants with PD-L1status TC ≥ 50% (as assessed by a central reference laboratory using the VENTANA PD-L1[SP263] IHC assay) in terms of PFS according to RECIST 1.1 as assessed by BICR. Key secondary objectives will be PFS in participants with PD-L1 TC ≥1%, OS in participants with PD-L1 TC ≥50% or PD-L1 TC ≥1%.The primary analysis of PFS will be performed when approximately 244 BICR PFS events (66% maturity) in participants with PD-L1status TC≥50% have occurred. The superiority of durvalumab plus domvanalimab compared with durvalumab plus placebo will be assessed using a stratified log-rank test adjusting for stage (IIIA versus IIIB/IIIC), and histology (squamous versus non-squamous) for generation of the p-value. The HR and its CI will be estimated from a stratified Cox proportional hazards model and the CI will be calculated using a profile likelihood approach. The stratification factor covariates in the statistical modelling will be based on the values entered into the IRT web response system at randomisation, even if it is subsequently discovered that these values were incorrect.
|Start Date||Duration in Months||Target Completion Date||Actual Completion Date|
Pending IRB approval and contract execution
|AstraZeneca Pharmaceuticals (Philippines) Inc.||Private Business||NCR||LTO-3000002234602|
|Name||Institution and Institution Address|
|Samia Necesitofirstname.lastname@example.org||16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, Metro Manila|
|Name||Institution and Institution Address|
|Samia Necesitoemail@example.com||16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, Metro Manila|
|Marcelo Severino B. Imasa, MD||Oncology||Lung Center of the Philippines|
|Priscilla B. Caguioa, MD||Oncology||St. Luke's Medcal Center Quezon City|
|Project Location||Institutional Ethics Review Board|
|Lung Center of the Philippines||Lung Center of the Philippines Ethics Review Committee|
|St. Luke's Medcal Center Quezon City||N/A|
Locally advanced (Stage III), unresectable Non-small cell lung cancer
PFS is defined as time from randomisation until progression per RECIST1.1 as assessed by BICR, or death due to any cause
•PFS measured by HR
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 (according to Version 8 of the International Staging Manual for the Study of Lung Cancer Staging Manual in Thoracic Oncology [Goldstrawetal2016]). Initial staging procedures performed prior to initiation of any component of definitive treatment should include:
−Positron Emission Tomography –Computed Tomography (PET-CT) scan. Full body scan preferred, but scan from at least the base of skull to mid-thigh permissible. The scan must be performed up to42 days prior to the first dose of concurrent chemoradiotherapy, or induction chemotherapy cycles if utilised.
−Brain imaging with MRI or high-quality CT with IV contrast is encouraged during initial staging.
−Except for cT4 disease, biopsy strongly preferred to prove nodal status N2 or N3 via endobronchial ultrasound, mediastinoscopy, or thoracoscopy.
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)
4. Tumour PD-L1 status ≥1% as determined using the Ventana SP263 PD-L1 IHC assay by a central laboratory. PD-L1 status must be known to enable randomisation. Participants with unknown PD-L1 status are not eligible for the study.
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,andERBB2 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)
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 28days prior to the first dose of study interventionin the study (1 cycle is defined as 21 or 28days).
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 1-2induction 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. Sites are also encouraged to adhere to the following organ dosimetric specifications:
−Mean lung dose must be
−Mean oesophagus dose must be
−Heart V45 <35% or V30 <50%
13 World Health Organization(WHO)Performance Status of 0 or 1 at randomisation
14 Adequate organ and marrow function as defined below:
−Absolute neutrophil count >1.5 ×109/L (1500 per mm3)
−Platelet count >100 ×109/L (100,000 per mm3)
−Haemoglobin ≥9.0 g/dL (5.59 mmol/L)
−CrCL >40mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) using actual body weight.
−Serum bilirubin ≤ 1.5 ×ULN. This will not apply to participants with confirmed Gilbert’s syndrome (ie, persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of haemolysisor hepatic pathology) who will be allowed in consultation with their physician. In the presence of documented Gilbert’s syndrome, serum bilirubin < 3×ULN is accepted.
−AST and ALT ≤ 2.5×ULN.
15 Minimum life expectancy of 12 weeks at randomisation
16 Body weight >30kgat 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 1highlyeffective 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 3months before entering the study to 115daysafter the last dose (see Appendix G for a complete list of highly effective birth control methods). Non-sterilised male partners of a WOCBP must use a male condom and spermicide (condom alone in countries where spermicides are not approved) 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 (see Appendix G) from the time of screening throughout the total duration of the study, and for drugs that are potentially genotoxic the drug washout period (115daysafter 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 as described in Appendix A, which includes compliance with the requirements and restrictions listed in the IFC and this protocol.
22For 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.
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 ahistory 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 (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, rheumatoid arthritis, hypophysitis, uveitis, etc.]), autoimmune pneumonitis and autoimmune myocarditis. The following are exceptions to this criterion:
−Participants with vitiligo or alopecia
−Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
−Any chronic skin condition that does not require systemic therapy
−Participants without active disease in the last 5 years at randomisation may be included but only after consultation with the study physician
−Participants with celiac disease controlled by diet alone
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 HIV1/2antibodies) 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 Investigatorjudgementof 1 or more of the following:
−Mean resting corrected QT interval >470ms, obtained from triplicate ECGs performed at screening
−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
−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 priortothe first dose of the study intervention are not permitted.
23 Participantswho 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. The following are exceptions to this criterion:−Intranasal, inhaled, topical steroids or local steroid injections (eg, intraarticular injection).−Systemic corticosteroids at physiologic doses not to exceed 10mg/day of prednisone or its equivalent.−Steroids as premedication for hypersensitivity reactions or as an antiemetic (eg, CT scan premedication).
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). Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study drug may be included (eg, hearing loss) after consultation with the Clinical Study Lead. Participantswith peripheral neuropathy after consultation with the Clinical Study Lead.
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 >Grade1.
29 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (eg, hormone replacement therapy) is allowed.
Prior/Concurrent Clinical Study Experience
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
36Judgementby 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 115days after the last dose of study treatment.
Durvalumab plus Domvanalimab
Durvalumab is a human mAb of the IgG1 kappa subclass that blocks the interaction of PD-L1(but not PD-L2) with PD-1 on T cells and with CD80 (B7.1) on immune cells. It is being developed by the sponsor (AstraZenecaAB)for use in the treatment of cancer. The proposed mechanism of action for durvalumab is interference in the interaction of PD-L1with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumour elimination. Durvalumab has been approved to treat locally advanced(Stage III), unresectable NSCLC, and extensive-stage small cell lung cancer (administered in combination with chemotherapy).
Domvanalimab is a humanized IgG1 mAb that blocks the interaction of TIGIT and CD112 and CD155 whichare expressed on tumour cells and antigen presenting cells.Domvanalimabis being developed by ARCUSBiosciencesas a potential anticancer therapy for patients with solid tumours.The proposed mechanism of action for domvanalimab is interference in the interaction of TIGIT with CD112 and CD155. Blockade of TIGIT/CD112and TIGIT/CD155interactions releases the inhibition of immune responses, including those that may result in tumour elimination.Domvanalimab has been engineered to reduce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
Tumours evade immune-mediated recognition through multiple mechanisms of immune escape. On chronic tumour antigen exposure, T cells become dysfunctional/exhausted and upregulate various checkpoint inhibitory receptors that limit T cell survival and function. During the last decade, immunotherapies targeting immune checkpoints such as programmed cell death receptor 1 (PD-1) and anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have provided ample evidence of clinical benefits in many solid tumours.
TIGIT, similar to PD-1,is an inhibitory receptor and is expressed on NK cells, CD8+ T cells, CD4+ Tcells and regulatory T cells. Dual PD-1/TIGIT blockade has been demonstrated to potently increase tumour antigen-specific CD8+ T cell expansion and function in vitro and to promote tumour rejection in mouse tumour models. In a murine colon cancer model, the combination of an anti-PD-L1with anti-TIGIT and radiotherapy led to superior survival outcomes compared to anti-TIGIT with radiotherapy alone (Grapinetal2019).
There is also increasing evidence that CRT-induced cell death enhances the ability of the immune system to recognize and respond to the tumour through enhanced antigen release and presentation that, in turn, aids in the priming of immune cells to recognize and eliminate tumour cells. Besides inducing increased immune-mediated antitumouractivity, CRT also induces increased immune-suppressive activity within the tumour. Therefore, triggering or augmenting an antigenic antitumour response with CRT prior to treatment with anti-PD-L1 and anti-TIGIT therapy, such as durvalumab and domvanalimab, which preserve ongoing local immune responses by blocking local immunosuppressive signals, may result in enhanced antitumour activity by improving local control and decreasing systemic spread (Johnstonetal2014).
Clinical and nonclinical data suggest there is synergy betweenPD-L1inhibitionand TIGIT inhibition. Therefore administering durvalumab plus domvanalimab following cCRT could potentially overcome residual resistance in this setting and demonstrate further improvements on the outcomes seen with durvalumab alone.