This study has been transitioned to CTIS with ID 2024-513074-22-00 check the CTIS register for the current data. Primary Objective:The primary objective of this study is to determine the feasibility of four weeks of preoperative immunotherapy with…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
- Respiratory tract therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary variable:
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.
Fore more information see protocol section 5.2
Secondary outcome
Secondary variables:
• Objective radiological response rate per (RECIST 1.1)
• Pathological response rate (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)
• R0 resection rate
• Disease-free survival rate at 12 months per RECIST 1.1
• Overall survival rate at 12 months
• Safety and tolerability of preoperative immunotherapy
• Morbidity and mortality within 90 days of curative surgery
Exploratory variables:
• Translational parameters are assessed in tumor and lymph node samples, blood
cells, plasma, serum, and exhalate
Fore more information see protocol section 5.2
Background summary
Lung cancer develops from malignantly altered cells that multiply aggressively,
invade neighbouring tissue and are able to form tumours there. In addition,
tumour cells can also invade lymph nodes, then spread to more remote organs
through the blood stream (metastases).
In its early stages, when the tumour is still clearly separated off from
healthy organ tissue and if the patient's state of health allows this, the
disease can be cured by surgically removing the tumour. However, an operation
can often also be performed in cases where the tumour has already advanced
locally. In these cases, prior treatment (so-called neoadjuvant therapy) is
often applied before the operation. Should the tumour respond to this
pre-treatment, not only does it make the operation possible, it often also
allows for a complete removal of the tumour and possibly a more gentle surgical
method, and mitigates postoperative complications. In addition, successful
pre-treatment prevents recurrences (relapses) from occurring.
By now, we know a great deal about our immune system and its signalling
pathways and about how cancer cells take away their natural defences even
though they should actually be recognised as "foreign". Immunotherapy is used
in the study presented here; to be specific, the investigational drug
Nivolumab/Opdivo and Relatlimab are not targeted against the cancer cell
directly, but intervene as antibodies at key checkpoints of the immune system.
Antibodies are proteins, like those our immune system produces itself.
The effect of Nivolumab/Opdivo is based on the fact that it binds to a molecule
called PD-1 and in that way blocks it. PD-1 is found on different cells in the
immune system and controls parts of it by shutting them down. These natural
"brakes" protect against such things as immune reactions to the body's own
cells (so-called autoimmune responses), but they also come in useful for tumour
cells. The immune response is again set into motion through the
Nivolumab/Opdivo-mediated blockade of PD-1. Nivolumab/Opdivo has already been
tested and approved in Germany and many other countries for treating various
cancers including advanced NSCLC, but not for the neoadjuvant treatment of
NSCLC.
The effect of Relatlimab is based on the fact that it binds to a molecule
called LAG-3 which is found on specific cells and in that way potentially
stimulates the natural immune response, which can lead to the death of tumour
cells. Relatlimab is currently undergoing clinical testing, in other words it
has not yet been approved by authorities for treatment. As of 26 June 2019,
1,348 study participants received Relatlimab, sometimes in combination with
Nivolumab/Opdivo, which is expected to have a positive enhancing effect on
immunotherapy.
The primary goal of the study being presented here is to find out whether
patients with early or locally advanced NSCLC will profit from a 4-week
treatment with Nivolumab/Opdivo, alone or in combination with Relatlimab before
the planned surgery. In accordance with standard treatment at this stage, all
patients shall have potentially curative surgery no later than 6 weeks
following the start of immunotherapy.
*
For more information see protocol Section 2
Study objective
This study has been transitioned to CTIS with ID 2024-513074-22-00 check the CTIS register for the current data.
Primary Objective:
The primary objective of this study is to determine the feasibility of four
weeks of preoperative immunotherapy with Arm A nivolumab (240 mg q2w), Arm B
nivolumab (240 mg q2w) plus relatlimab (80 mg q2w), and arm C nivolumab (240 mg
q2w) plus relatlimab (240 mg q2w) in patients with early stage or locally
advanced non-small cell lung cancer eligible for curative resection.
Based on the results of a pilot study it is expected that at least 26 of 30
patients treated in each study arm will undergo curatively intended surgery
within 6 weeks of initiation of study treatment (first given on day 1). A study
arm will be declared non-feasible if 5 or more patients experience a delay of
curatively intended surgery beyond day 43, either due to toxicities or disease
progression. Continuous monitoring of prespecified stopping boundaries
facilitates early termination of non-feasible study arm to reduce patient risks.
Secondary and other Objectives:
- 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)
- Estimation of complete (R0) resection rate
- Assessment of radiologic response on computed tomography per Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Assessment of disease-free survival rate at 12 months per RECIST version 1.1
- Assessment of overall survival rate at 12 months
- Assessment of safety and tolerability of preoperative immunotherapy
- Estimation of morbidity and mortality within 90 days of surgery
- Exploratory translational analyses for investigation of immunomodulatory and
anticancer activity of preoperative treatment with nivolumab and
nivolumab/relatlimab combination therapy
Study design
This is an international, multicenter, open-label, randomized, three-armed,
modular phase II study. Patients with histologically confirmed non-small cell
lung cancer (NSCLC) of 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), who are eligible for anatomic resection will be included.
The study will involve a total of 3 participating sites in Germany, Netherlands
and Belgium. Patients will be randomized between Arm A or Arm B to include in
total up to 60 evaluable subjects. Arm C will open subsequently to complete
enrolment of Arms A and B. Consecutive patients will be enrolled in Arm C to
include up to 30 evaluable patients.
Subjects in all arms will receive 2 preoperative treatment cycles with a cycle
duration of 14 days. Study treatment consists of nivolumab q2w in Arm A, and
nivolumab q2w plus relatlimab q2w in Arms B and C.
Following neoadjuvant study treatment all patients will proceed to standard of
care surgery, which is followed by standard of care adjuvant therapy if
clinically indicated. Surgery and adjuvant therapy are not part of the
NEOpredict-Lung study treatment.
Subjects will have 6 follow-up visits until after 12 months of study treatment.
After 12 months, standard of care follow-up will be provided at the study
centers as recommended by the applicable guidelines.For each subject, the total
duration of the study will be approximately 14 months including follow-up.
For the study as a whole, the primary outcome will be continuously evaluated
for each treatment arm. Clinical outcomes will be evaluated when the last
patient will have completed the follow-up period. Early termination of a study
arm will occur once prespecified stopping boundaries are crossed.
For more information see protocol section 5
Intervention
Subjects randomized to the nivolumab arm (Arm A) will receive 2 cycli nivolumab
240 mg administered IV over 30 minutes (q2w).
Subjects randomized to the nivolumab/relatlimab arm (Arm B) will receive 2
cycli nivolumab 240 mg administered IV over 30 minutes followed by relatlimab
80 mg administered IV over 30 minutes (q2w).
Another 30 evaluable patients will be enrolled in Arm C (nivolumab 240 mg plus
relatlimab 240 mg q2w) once arms A and B are fully enrolled.
Following the neoadjuvant study treatment all patients will proceed to the
standard of care surgery, which is folled by standard of care adjuvant therapy
if clinically indicated. the standard of care surgery and adjuvant therapy are
not part of interventions for this study
Laboratory evaluations are also part of standard of care, the information of
the SOC laboratory evaluations will be used in the study.
Tumor assessments are planned at screening, before operation and every 3 months
after surgery are also part of the standard of care assessments for this
patient population.
For more information see protocol section 7 and 8
Study burden and risks
Immune Checkpoint Inhibitors (ICIs) are a new class of therapeutics with proven
clinical activity over a broad range of cancer entities. The clinical efficacy
of ICI combination therapy with nivolumab and ipilimumab was demonstrated in a
subgroup of NSCLC patients characterized by high tumor mutational burden, and
the ICI combination showed superior overall survival as compared to standard
platinum-based first-line chemotherapy.
Overall, ICI therapy was safe and had a favorable toxicity profile in patients
with localized and metastatic NSCLC.
Today, ICI therapy is well established in thoracic oncology. Physicians
treating NSCLC patients are experienced with this modality. They are well aware
of its toxicities and potential hazards. A pattern of immune-related AEs has
been defined across all cancer entities treated with ICIs, for which
well-accepted management algorithms have been developed. Most high-grade events
were manageable with the use of corticosteroids or hormone replacement therapy
(endocrinopathies) as instructed in these management algorithms. This scenario
applies to all arms of the NEOpredict-Lung study, as they are exploring
treatments which act indirectly by reinvigoration of immune responses. It is
not expected that the addition of relatlimab to nivolumab in Arms B and C will
significantly alter the spectrum of potential treatment-associated toxicities.
Importantly, data of a randomized study in patients with malignant melanoma has
provided definitive evidence of increased clinical efficacy and acceptable
safety of the nivolumab/relatlimab combination as compared to nivolumab
monotherapy. The risk evaluation of NEOpredict-Lung is based on current
clinical experience with relatlimab as single agent or combined with nivolumab
from ongoing and completed studies. Importantly, the mode of action of this
antibody combination is similar.
The study NEOpredict-Lung will assess investigational (relatlimab) and marketed
(nivolumab) drugs whose effects on pregnancy are not yet known or fully
defined. Contraception is therefore required for participants who are WOCBP or
male, and for female partners of male participants who are WOCBP
Throughout the NEOpredict-Lung study the rate of patients who do not proceed to
curative surgery within the predefined time frame is continuously monitored for
each study arm. This allows early closure of unfeasible treatment arms based on
prespecified criteria. To ensure an ongoing favorable risk/benefit assessment
for subjects enrolled in NEOpredict-Lung, an independent Data Safety Monitoring
Board (DSMB) has been established to monitor the safety and clinical activity
of the treatments throughout the conduct of the trial. A recent analysis based
on data from close to 5,000 patients with early stage NSCLC demonstrated a
median time from diagnosis to surgery of 38 days. At multivariate analysis,
patients who had surgery later than 38 days after diagnosis had numerically
inferior OS at 5 years. However, the threshold time associated with
statistically significant worse survival was not reached before 90 days. The
addition of the maximum screening (28 days) and preoperative treatment periods
(42 days) of the NEOpredict-Lung study amounts 70 days. This still is
considerably shorter than the threshold time of 90 days for a delay in surgery
of NSCLC which was associated with worse survival. This supports the time lines
foreseen in this study, which puts highest priority on patient safety.
For more information see protocol section 2.3
Hufelandstrasse 55
Essen 45147
DE
Hufelandstrasse 55
Essen 45147
DE
Listed location countries
Age
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 prior malignancy within the past 3 years.
Patients with the following conditions are not excluded from participation:
o Patients with completely resected basal cell carcinoma, cutaneous squamous
cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ,
non-invasive intestinal polyps, and patients with isolated elevation in
prostate-specific antigen or low risk prostate cancer managed with active
surveillance or watchful waiting in the absence of radiographic evidence of
metastatic prostate cancer.
• Known history of positive test for human immunodeficiency virus (HIV-1 and
HIV-2) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for
HIV-1 and HIV-2 must be performed at screening.
• Any positive test result for hepatitis B virus or hepatitis C virus
indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg,
Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive
(except if HCV RNA negative).
• 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
• Receipt of live attenuated vaccine within 30 days prior to the first dose of
study medication.
• Peripheral polyneuropathy NCI CTCAE Grade >= 2
• History of gastric perforation or fistulae in past 6 months
• Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to
enrollment.
• The patient has undergone major surgery within 28 days prior to enrollment
except staging mediastinoscopy, diagnostic VATS or implantation of a venous
port-system.
• Any other concurrent preoperative antineoplastic treatment including
irradiation
• Pregnant women
• Breastfeeding women
• Insufficient cardiac left ventricular function defined as LVEF<50% by
echocardiography or MUGA within 6 months before first administration of study
drug
• A confirmed history of encephalitis, meningitis, or uncontrolled seizures in
the year prior to informed consent.
• Subjects with history of severe or life-threatening toxicity (grade 3 or 4)
related to prior immune therapy (e.g. anti-CTLA-4 or anti-PD-1/PD-L1 treatment
or any other antibody or drug specifically targeting T-cell co-stimulation or
immune checkpoint pathways) except those that are unlikely to re-occur with
standard countermeasures (e.g., hormone replacement after endocrinopathy.
• Subjects with history severe or life-threatening (grade 3 or 4)
infusion-related reactions to prior immune therapy
• Prior treatment with LAG-3 targeted agent.
Other
• Participation in another interventional clinical study within the last 3
months prior to inclusion or simultaneous participation in other clinical
studies
• Previous treatment with nivolumab or relatlimab
• Previous immunotherapy for lung cancer
• 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
• Any contraindications against nivolumab or relatlimab
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-513074-22-00 |
| EudraCT | EUCTR2019-002478-29-NL |
| ClinicalTrials.gov | NCT04205552 |
| CCMO | NL72532.031.21 |