eoadjuvant nivolumab combination treatment in resectable non-small cell lung cancer patients: Defining optimal combinations and determinants of immunological response

Phase 2

Recruiting

• Conditions: lungcancer; Non small cell lung cancer; 10038666; 10029107; 10038737

• Registration Number: NL-OMON52539
• Lead Sponsor: niversity Hospital Essen

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 9 September 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: Not specified
• Target Recruitment: 10

Inclusion Criteria

• 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.
• 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.
• ECOG <= 1
• Exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3)
by PET/CT and/or mediastinal lymph node sampling by EBUS-TBNA and/or staging
mediastinoscopy.
• 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.
• Measurable target tumor prior to immunotherapy using standard imaging
techniques.
• 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)
• Adequate hematological, hepatic and renal function parameters:
o Leukocytes >= 2,000/mm³, platelets >= 100,000/mm³, absolute neutrophil count
(ANC) >= 1,500/µL, hemoglobin >= 9 g/dL (5.58 mmol/L),
o Anti-platelet therapy (such as but not limited to clopidogrel) should be
discontinued pre-operatively according to local standards. If this therapy
cannot be interrupted due to severe cardiovascular comorbidity, patient is
ineligible for the trial
o Adequate coagulation function as defined by International Normalized Ratio
(INR) <= 1.5, and a partial thromboplastin time (PTT) <= 5 seconds above the
upper limit of normal (ULN) (unless receiving anticoagulation therapy).
Patients receiving warfarin/phenprocoumon or direct oral anticoagulants are to
be bridged according to local standards and have achieved stable coagulation
profile prior to surgery.
o Serum creatinine <= 1.5 x upper limit of normal
o Bilirubin <= 1.5 x upper limit of normal, AST and ALT <= 3.0 x upper limit of
normal, alkaline phosphatase <= 6 x upper limit of normal
• Sufficient cardiac left ventricular defined as LVEF >= 50% documented either
by echocardiography or MUGA (echocardiography preferred test) within 6 months
before first administration of study drug
• Patient able and willing to provide written informed consent and to comply
with the study protocol and with the planned surgical procedures

Exclusion Criteria

• Active or history of autoimmune disease or immune deficiency, including, but
not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome,
Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
Patients with the following conditions are not excluded from participation:
o Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
o Patients with controlled type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
o Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
systemic immunosuppressive treatment, in particular corticosteroids are
permitted to enroll.
• 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.
Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune
disease.
• Subjects who have undergone organ transplant or allogeneic stem cell
transplantation.
• ppFEV1<30%, ppDLCO<30%, ppVO2max < 10 ml/min/kg (if CPET was mandated per
local guidelines)
• Uncontrolled or significant cardiovascular disease including, but not limited
to, any of the following:
o Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within
the 6 months prior to consent
o Uncontrolled angina within the 3 months prior to consent
o Any history of clinically significant arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or torsades de pointes)
o QTc prolongation > 480 msec
o History or clinical signs of pulmonary hypertension (sPAP >35 mmHg if
examination clinically indicated)
• History of other clinically significant cardiovascular disease (i.e.,
cardiomyopathy, congestive heart failure with New York Heart Association [NYHA]
functional classification III-IV, pericarditis, significant pericardial
effusion, significant coronary stent occlusion, deep venous thrombosis, etc )
• Cardiovascular disease-related requirement for daily supplemental oxygen
History of two or more myocardial infarctions or two or more coronary
revascularization procedures
• Subjects with history of myocarditis, regardless of etiology
• 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
• Patients with active neurological diease should be excluded.
• Active malignancy or a p

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary variable:<br /><br>Primary variable is the number of patients undergoing curatively intended<br /><br>surgery of non-small cell lung cancer within 43 days of initiation of study<br /><br>therapy.<br /><br><br /><br>Fore more information see protocol section 5.2 </p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Secondary variables:<br /><br>• Objective radiological response rate per (RECIST 1.1)<br /><br>• Pathological response rate (complete pathological responses defined as<br /><br>absence of viable tumor cells on routine hematoxylin and eosin staining of<br /><br>resected tumors and lymph nodes; rate of major pathological responses defined<br /><br>as 10% or less viable tumor cells on routine hematoxylin and eosin staining of<br /><br>resected tumors)<br /><br>• R0 resection rate<br /><br>• Disease-free survival rate at 12 months per RECIST 1.1<br /><br>• Overall survival rate at 12 months<br /><br>• Safety and tolerability of preoperative immunotherapy<br /><br>• Morbidity and mortality within 90 days of curative surgery<br /><br><br /><br>Exploratory variables:<br /><br>• Translational parameters are assessed in tumor and lymph node samples, blood<br /><br>cells, plasma, serum, and exhalate<br /><br><br /><br>Fore more information see protocol section 5.2 </p><br>