Neoadjuvant nivolumab combination treatment in resectable non-small cell lung cancer patients: Defining optimal combinations and determinants of immunological response (NEOpredict-Lung)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Essen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Dec 2019 → 27 Nov 2025

Decision date (initial)

2024-06-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bristol–Myers Squibb

External identifiers

EU CT number

2024-513074-22-00

EudraCT number

2019-002478-29

ClinicalTrials.gov

NCT04205552

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

The primary objective of this study is to determine the feasibility of four weeks of preoperative immunotherapy with nivolumab, nivolumab plus relatlimab at different dosis in patients with early stage or locally advanced non-small cell lung cancer eligible for curative resection.

Secondary objectives 8

1. Estimation of pathological tumor response rate (rate of complete pathological responses defined as absence of viable tumor cells on routine hematoxylin and eosin staining of resected tumors and lymph nodes; rate of major pathological responses defined as 10% or less viable tumor cells on routine hematoxylin and eosin staining of resected tumors)
2. Estimation of curative (R0) resection rate
3. Assessment of radiologic response on computed tomography per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
4. Assessment of disease-free survival rate at 12 months per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1
5. Assessment of overall survival rate at 12 months
6. Assessment of safety and tolerability of preoperative immunotherapy
7. Estimation of morbidity and mortality within 90 days of surgery
8. Exploratory translational analyses for investigation of immunomodulatory and anticancer activity of preoperative treatment with nivolumab and nivolumab/relatlimab combination therapy

Conditions and MedDRA coding

non-small cell lung cancer (NSCLC) of clinical stages IB, II and selected stage III A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patients with histologically (core biopsy) or cytologically (e.g. bronchoscopy-guided biopsy) confirmed non-small cell lung cancer (NSCLC) eligible for anatomic resection, with the following specifications: o Clinical stages I B, II and selected stage III A (T3 N1, T4 with satellite nodule in the same lung N0/N1, selected T1a-T2b N2 cases considered suitable for primary surgical approach by the multidisciplinary tumor board) according to UICC 8th edition
2. Males and females, ages ≥ 18 years, inclusive o Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study treatment. o Women of childbearing potential (WOCBP) must agree to follow instructions for highly effective method(s) of contraception for the duration of treatment with study medication plus 5 months after the last dose of the study drug.
3. ECOG ≤ 1
4. Exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3) by PET/CT and/or invasive mediastinal lymph node staging by EBUS-TBNA and/or staging mediastinoscopy as indicated by current guidelines.
5. Exclusion of distant metastases by standard of care imaging studies, which include but are not limited to PET/CT or PET/MRI, or CT or MRI of thorax, abdomen, pelvis, and bone scan. Asymptomatic brain metastases will be excluded by MRI or contrast-enhanced CT as indicated by current guidelines
6. Measurable target tumor prior to immunotherapy using standard imaging techniques
7. Sufficient pulmonary function to undergo curative lung cancer surgery, ppFEV1>30%, ppDLCO>30%, ppVO2max ≥ 10 ml/min/kg (if CPET was mandated per local guidelines)
8. Adequate hematological, hepatic and renal function parameters: [...]
9. Sufficient cardiac left ventricular defined as LVEF ≥ 50% documented either by echocardiography or MUGA (echocardiography preferred test, MUGA not used in German site) within 6 months before first administration of study drug
10. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

Exclusion criteria 33

1. Active or history of autoimmune disease or immune deficiency
2. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
3. Subjects who have undergone organ transplant or allogeneic stem cell transplantation
4. ppFEV1<30%, ppDLCO<30%, ppVO2max < 10 ml/min/kg (if CPET was mandated per local guidelines)
5. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: [..]
6. History of other clinically significant cardiovascular disease (i.e.[..])
7. Cardiovascular disease-related requirement for daily supplemental oxygen
8. History of two or more myocardial infarctions or two or more coronary revascularization procedures
9. Subjects with history of myocarditis, regardless of etiology
10. Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN). Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are within ULN. If TnT or TnI levels are >1 to 2 × ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the coordinating investigator or designee. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the coordinating investigator or designee
11. Patients with active neurological disease should be excluded
12. Active malignancy or a prior malignancy within the past 3 years. Patients with the following conditions are not excluded from participation:[..]
13. Known history of positive test for human immunodeficiency virus (HIV-1 and HIV-2) or known acquired immunodeficiency syndrome (AIDS). [..]
14. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen positive, or hepatitis C antibody [..]
15. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
16. Receipt of live attenuated vaccine within 30 days prior to the first dose of study medication
17. Peripheral polyneuropathy NCI CTCAE Grade ≥ 2
18. History of gastric perforation or fistulae in past 6 months
19. Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment
20. The patient has undergone major surgery within 28 days prior to enrollment except staging mediastinoscopy, diagnostic VATS or implantation of a venous port-system
21. Any other concurrent preoperative antineoplastic treatment including irradiation
22. Pregnant women
23. Breastfeeding women
24. Insufficient cardiac left ventricular function defined as LVEF<50% by echocardiography (outside Germany: or MUGA scan) within 6 months before first administration of study drug
25. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
26. Subjects with history of severe toxicity or life-threatening toxicity (grade 3 or 4) related to prior immune therapy (e.g.[..] except those that are unlikely to re-occur with standard countermeasures [..]
27. Subjects with history of severe or life-threatining (grade 3 or 4) infusion-related reactions to prior immune therapy
28. Prior treatment with LAG-3 targeting agent
29. Participation in another interventional clinical study within the last 3 months prior to inclusion or simultaneous participation in other clinical studies
30. Previous treatment with nivolumab or relatlimab
31. Previous immunotherapy for lung cancer
32. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
33. Any contraindications against nivolumab or relatlimab

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary variable is the number of patients undergoing curatively intended surgery of non-small cell lung cancer within 43 days of initiation of study therapy.

Secondary endpoints 8

1. Objective response rate (RECIST 1.1)
2. Pathological response rate per ypTNM classification and per IASLC recommendations [..]
3. R0 resection rate
4. Disease-free survival rate at 12 months per RECIST 1.1
5. Overall survival rate at 12 months
6. Safety and tolerability of preoperative immunotherapy
7. Morbidity and mortality within 90 days of curative surgery
8. Translational parameters [..]

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Essen AöR

Sponsor organisation

Universitaetsklinikum Essen AöR

Address

Hufelandstrasse 55, Holsterhausen Holsterhausen

City

Essen

Postcode

45147

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Prof. Dr. Martin Schuler

Public contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Universitätsmedizin Essen - Studienzentrum GmbH

Locations

3 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications