DURVALUMAB for Non-small cell lung cancer

Inclusion criteria

• {"criterion_text":"- Participant must be ≥ 18 years, at the time of screening.\n- The participant should be deemed to have adequate cardiac and lung function, according to a multidisciplinary assessment. A pre- or postbronchodilator FEV1 of 1.0 L and >40% postoperative predicted value. Use of these cut-off values to assess candidacy for resection should be guided by the results of cardiopulmonary exercise testing as outlined in the ESMO guidelines on pre-treatment risk assessment. Both an FEV1 and a DLCO test are required for assessing lung function prior to resection\n- Minimum body weight of 30 kg.\n- Male and/or female. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies\n- Negative pregnancy test (serum) for FOCBP\n- Female participants must be for 1 year or more postmenopausal, surgically sterile, or using at least one highly effective method of contraception (a highly effective method of contraception isdefined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) (a) Females < 50 years old are considered postmenopausal if they have been amenorrhoeic for 12 months or more prior to enrolment following cessation of exogenous hormonal treatment and folliclestimulating hormone (FSH) levels in the postmenopausal range. (b) Females ≥ 50 years old are considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment, or had radiation-induced menopause with last menses > 1 year ago, or had chemotherapy-induced menopause with last menses > 1 year ago. (c) Female participants of child-bearing potential must agree to use at least 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 prior to enrolment (screening), while receiving study intervention, SoC CT or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents. Cessation of birth controlafter this point should be discussed with a responsible physician. (d) Non-sterilised male partners of a female participant of child-bearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening their female partner, while their female partner is receiving study intervention, SoC CT or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents. (e) Periodic abstinence, as well as the rhythm and withdrawal methods are not acceptable methods of birth control.\n- Male participants who intend to be sexually active with a female partner of child-bearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening , while receiving study intervention, SoC CT or CRT and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period\n- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the CSP\n- Provision of signed and dated written informed consent prior to collection of samples. Participation is voluntary and if a participant declines to consent, they will not be excluded from the main study.\n- All races, gender and ethnic groups are eligible for this study.\n- Histologically or cytologically documented NSCLC\n- Deemed resectable or borderline resectable at baseline, confirmed by MDT evaluation at diagnosis\n- Previously untreated and pathologically confirmed stage IIB to select (ie, N2) stage IIIB disease (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2016).(a) Nodal status should be investigated with whole body FDG-PET, plus contrast-enhanced computed tomography, and it is required that nodal status be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. (b) Mandatory brain MRI with IV contrast or brain computed tomography with IV contrast at the time of staging\n- WHO or ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dose\n- Participants must have been confirmed as EGFR/ALK wild type via an appropriately validated local test Participants with known sensitising EGFR mutations or ALK rearrangements are excluded from the study.\n- At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography or MRI and is suitable for accurate repeated measurements\n- Adequate organ and bone marrow function as follows: − Haemoglobin ≥ 9.0 g/dL. − Absolute neutrophil count ≥ 1.5 × 109 /. − Platelet count ≥ 100×109 /L. − Serum bilirubin ≤ 1.5×the ULN or ≤ 3×ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia). − Alanine aminotransferase and AST ≤ 2.5×ULN. − Calculated CrCL > 40 mL/min as determined by Cockcroft Gault (using actual body weight).\n- Minimum life expectancy of 12 weeks"}

Exclusion criteria

• {"criterion_text":"- 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), chronic diverticulitis or previous complicated diverticulosis, or history of allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol\n- History of active primary immunodeficiency\n- Investigator judgement of one or more of the following: − Mean resting corrected QT interval > 470 ms, 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 under 40 years of age in first-degree relatives\n- Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, antiPD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.\n- 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 or as an anti-emetic (eg, computed tomography scan premedication)\n- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention\n- Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study intervention\n- Any medical contraindication to treatment with platinumbased doublet CT, as listed in the local labellin\n- Previous treatment in the present study or a previous durvalumab clinical study regardless of treatment arm assignment\n- Participation in another clinical study with a study intervention administered in the last 4 weeks prior to first dose of durvalumab or 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\n- Participants with a known hypersensitivity to durvalumab or any excipients of the product(s).\n- Unresectable NSCLC confirmed by MDT evaluation at diagnosis: − Deemed unresectable NSCLC by multidisciplinary evaluation -Any stage IIIC\n- Participants whose planned surgery at enrolment includes wedge resections\n- Participants contraindicated for surgical intervention due to comorbid conditions\n- Existence of more than one primary tumour, such as: mixed small cell and NSCLC histology; synchronous or metachronous tumours that could represent distinct primary tumours\n- 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 without evidence of disease.\n- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, 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 may be included but only after consultation with the Study Clinical Lead. − Participants with coeliac disease controlled by diet alone\n- Known active hepatitis infection, positive HCV antibody, 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.\n- Known to have tested positive for HIV (positive HIV 1 or 2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice)"}

Primary endpoints

• {"endpoint_text":"- Resection rate defined as the proportion of all participants who underwent definitive surgery. The analysis will be performed in all participants who received at least one dose of study intervention (FAS).","definition_or_measurement_approach":"Resection rate = proportion of all participants who underwent definitive surgery; analysis performed in all participants who received at least one dose of study intervention (Full Analysis Set, FAS)."}

Secondary endpoints

• {"endpoint_text":"- Resection rate as defined above. The analysis will be performed in the subset of the FAS assessed as resectable at baseline","definition_or_measurement_approach":"Same definition as primary resection rate; analysis in subset of FAS assessed as resectable at baseline."}
• {"endpoint_text":"- Resection rate as defined above. The analysis will be performed in the subset of the FAS assessed as borderline resectable at baseline.","definition_or_measurement_approach":"Same definition; analysis in subset of FAS assessed as borderline resectable at baseline."}
• {"endpoint_text":"- R0 resection rate. The analysis will be performed in a subgroup of the FAS who underwent definitive surgery. R1 resection rate. The analysis will be performed in a subgroup of the FAS who underwent definitive surgery. R2 resection rate. The analysis will be performed in a subgroup of the FAS who underwent definitive surgery","definition_or_measurement_approach":"R0/R1/R2 resection rates: proportion of surgical patients with respective margin statuses; analyses performed in subgroup of FAS who underwent definitive surgery."}
• {"endpoint_text":"- pCR defined as the proportion of participants who undergo surgery and have 0% residual viable tumour cells in resected lung and lymph nodes. The analysis will be performed in the Resectable Participants Cohort (ie, participants in the FAS who are deemed resectable after MDT re-assessment)","definition_or_measurement_approach":"Pathologic complete response (pCR) = 0% residual viable tumour cells in resected lung and lymph nodes; analysis in Resectable Participants Cohort (FAS deemed resectable after MDT re-assessment)."}
• {"endpoint_text":"- OS defined as the time from first dose of study intervention until the date of death due to any cause. Median OS, OS12, and OS24. The analysis will be performed in the FAS, Resectable Participants Cohort, and Unresectable Participants Cohort (ie, participants in the FAS who are deemed unresectable after MDT reassessment","definition_or_measurement_approach":"Overall survival = time from first dose to death from any cause; median OS and survival at 12 and 24 months; analyses in FAS and both cohorts (Resectable and Unresectable)."}
• {"endpoint_text":"- EFS defined as the time from the first dose of study intervention to any of the following events: PD that precludes surgery, progression or recurrence of disease after surgery, PD in the absence of surgery, or death due to any cause. Median EFS, EFS12, and EFS24. The analysis will be performed in the FAS and the Resectable Participants Cohort.","definition_or_measurement_approach":"Event-free survival = time from first dose to PD precluding surgery, progression/recurrence after surgery, PD without surgery, or death; median and 12/24-month estimates; analyses in FAS and Resectable Cohort."}
• {"endpoint_text":"- PFS defined as the time from the first dose of study intervention to RECIST 1.1-defined PD, as assessed by the investigator, or death due to any cause. Median PFS, PFS12, and PFS24. The analysis will be performed in the Unresectable Participants Cohort.","definition_or_measurement_approach":"Progression-free survival per RECIST 1.1 as assessed by investigator or death; median and 12/24-month; analysis in Unresectable Cohort."}
• {"endpoint_text":"- ORR defined as the proportion of participants who have unconfirmed CR or PR, pre-surgery/pre-CRT as assessed by the investigator per RECIST 1.1. The analysis will be performed in the Resectable Participants Cohort and Unresectable Participants Cohort.","definition_or_measurement_approach":"Objective response rate = proportion with unconfirmed complete or partial response prior to surgery/CRT per RECIST 1.1; analyses in both cohorts."}
• {"endpoint_text":"- ORR defined as the proportion of participants treated with definitive CRT who have unconfirmed CR or PR, at first assessment after CRT completion as assessed by the investigator per RECIST 1.1. The analysis will be performed in the Unresectable Participants Cohort.","definition_or_measurement_approach":"ORR after definitive CRT at first post-CRT assessment per RECIST 1.1; analysis in Unresectable Cohort."}
• {"endpoint_text":"- ctDNA clearance (ie, complete molecular response, cMR, defined as the proportion of participants with a change from detectable ctDNA to undetectable ctDNA). ctDNA clearance will be assessed from baseline (pre-neoC1D1) to pre-surgery/pre-CRT, and the analysis will be performed in the FAS (biomarkerevaluable participants only).","definition_or_measurement_approach":"ctDNA clearance (cMR) = change from detectable to undetectable ctDNA from baseline to pre-surgery/pre-CRT; analysis in biomarker-evaluable subset of FAS."}
• {"endpoint_text":"- Safety and tolerability will be evaluated in terms of AEs, including PRAEs, AESIs, imAEs, SAEs, surgeryrelated AEs, fatal AEs precluding surgery, deaths within 90 days after surgery, and AEs resulting in treatment interruption and discontinuation (assessment of incidence, severity, nature, seriousness, intervention/treatment, outcome, and causality), vital signs, clinical laboratory assessments, and ECGs. The analysis will be performed in the FAS (all participants who received at least","definition_or_measurement_approach":"Safety/tolerability evaluated by adverse events (including listed types), vital signs, labs, ECGs; analyses in FAS."}
• {"endpoint_text":"- Time from last neoadjuvant dose to surgery. Participants with delayed surgery, length and reason of surgical delay. Intended surgical approach at baseline. Actual surgical approach. Intended surgical procedure at baseline. Actual surgical procedure. Duration of surgical procedure. Length of post-operative hospital stay. The analysis will be performed in a subgroup of the FAS who underwent definitive surgery","definition_or_measurement_approach":"Surgical outcomes/endpoints including time from last dose to surgery, delays/reasons, planned vs actual approach and procedure, procedure duration, and post-op length of stay; analysis in surgical subgroup of FAS."}

Czechia

Earliest CTIS Part Ii Submission Date

27-10-2023

Latest Decision Or Authorization Date

24-01-2025

Processing Time Days

455

Number Of Sites

4

Number Of Participants

9

Italy

Earliest CTIS Part Ii Submission Date

01-02-2024

Latest Decision Or Authorization Date

24-01-2025

Processing Time Days

358

Number Of Sites

11

Number Of Participants

19

Sweden

Earliest CTIS Part Ii Submission Date

06-05-2024

Latest Decision Or Authorization Date

03-03-2026

Processing Time Days

666

Number Of Sites

2

Number Of Participants

6

Portugal

Earliest CTIS Part Ii Submission Date

01-02-2024

Latest Decision Or Authorization Date

10-03-2026

Processing Time Days

768

Number Of Sites

2

Number Of Participants

6

Hungary

Earliest CTIS Part Ii Submission Date

30-11-2023

Latest Decision Or Authorization Date

13-03-2026

Processing Time Days

834

Number Of Sites

3

Number Of Participants

7

Germany

Earliest CTIS Part Ii Submission Date

15-01-2024

Latest Decision Or Authorization Date

09-03-2026

Processing Time Days

784

Number Of Sites

7

Number Of Participants

28

France

Earliest CTIS Part Ii Submission Date

12-01-2024

Latest Decision Or Authorization Date

16-03-2026

Processing Time Days

794

Number Of Sites

7

Number Of Participants

20

Austria

Earliest CTIS Part Ii Submission Date

12-09-2023

Latest Decision Or Authorization Date

22-03-2026

Processing Time Days

922

Number Of Sites

1

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

16-04-2024

Latest Decision Or Authorization Date

25-02-2026

Processing Time Days

680

Number Of Sites

10

Number Of Participants

23

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Codes: 1,10,11,12,13,14,2,5,6,7,8 (as listed in sponsor thirdParties sponsorDuties)

Third parties

• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"1,10,11,12,13,14,2,5,6,7,8","organisation_type":"Pharmaceutical company"}