Study of efficacy and safety of canakinumab as adjuvant therapy in adult subjects with stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected non-small cell lung cancer

• Register: EUCTR
• Last refreshed on: 16 May 2022
• Main ID: EUCTR2017-004011-39-AT
• Date of registration: 16/03/2018
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma AG
• Public title: Study of efficacy and safety of canakinumab as adjuvant therapy in adult subjects with stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected non-small cell lung cancer
• Scientific title: A phase III, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected (R0) non-small cell lung cancer (NSCLC)
• Date of first enrolment: 27/04/2018
• Target sample size: 1382
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004011-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Costa Rica, Czech Republic, Egypt, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Jordan, Korea, Democratic People's Republic of, Lebanon, Malaysia, Mexico, Netherlands, New Zealand, Norway, Oman, Panama, Peru, Poland, Portugal, Romania, Russian Federation, Singapore, Slovakia, Slovenia, Spain, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Drug Regulatory Affairs
• Affiliation: Novartis Pharma GmbH

• Name: Drug Regulatory Affairs
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects eligible for inclusion in this study have to meet all of the following criteria at the time of screening:

1.1.Written informed consent must be obtained prior to any screening procedures.
2.Age = 18 years
3a. Completely resected (R0) NSCLC AJCC/UICC v. 8 stage IIA-IIIA and IIIB ( T>5 cm, N2 disease only).
The maximum number of days allowed from surgery to randomization is:
• 70 days if subjects were treated with surgery, but did not receive chemotherapy or radiation.
• 182 days if subjects were treated with surgery and chemotherapy, but no radiation.
• 259 days if subjects were treated with surgery, chemotherapy and radiation
7a. Subjects must have recovered from all toxicities related to prior systemic therapy to grade = 1 (CTCAE v 5.0). Exception to this criterion:
subjects with any grade of alopecia, neuropathy (grade =2), and subjects meeting the laboratory specifications described in inclusion 8.
8. Subjects must have adequate organ function including the following laboratory values at the screening visit:
• Absolute neutrophil count (ANC) = 1.5 x 109/L
• Platelets = 100 x 109/L
• Hemoglobin (Hgb) > 9 g/dL
• Creatinine clearance greater than 45 ml/min using Cockcroft-Gault formula
• Total bilirubin = 1.5 x ULN
• Aspartate transaminase (AST) = 3 x ULN
• Alanine transaminase (ALT) = 3 x ULN
9. ECOG performance status (PS) of 0 or 1.
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Inclusion criteria applicable for sub-study (CACZ885T2301A)
1. Written informed consent to sub-study must be obtained prior to any collections.
2. Age = 18 years
3. Subjects with NSCLC Stage IIA-IIIA, IIIB ( T>5cm,N2 disease only) who are candidates for complete resection surgery.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 834
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 548

Exclusion criteria:
1. Subjects with unresectable or metastatic disease, positive microscopic margins on the pathology report, and/or gross disease remaining at the time of surgery.
2. Subjects who received any neoadjuvant treatment.
3a. Presence or history of a malignant disease, other than the resected NSCLC, that has been diagnosed and/or required therapy within the past 3 years.
4a. History of clinically significant interstitial lung disease (= grade 2).
5a. History or current diagnosis of cardiac disease, including any of the following:
• recent myocardial infarction or coronary artery bypass graft (CABG) surgery within last 6 months,
• uncontrolled congestive heart failure,
• unstable angina (within last 6 months),
• clinically significant (symptomatic) cardiac arrhythmias
6a.Thoracic radiotherapy to lung fields = 4 weeks prior to starting cycle 1 day 1 or subjects who have not recovered from radiotherapy-related toxicities.
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to randomization or who have not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and subjects can be enrolled in the study =1 week after the procedure.
8. Uncontrolled diabetes as defined by the investigator.
9. Known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C (positive or indeterminate central laboratory results).
10a. Subjects must be evaluated for tuberculosis as per local treatment guidelines or clinical practice. Subjects with active tuberculosis are not eligible. In subjects without active tuberculosis, if the results of the
evaluation require treatment per local guidelines, then the treatment should be initiated before randomization (unless otherwise required by Health Authorities or IRB in which case curative treatment must be completed prior to screening).
11a. Subjects with suspected or proven immunocompromised state or infections, including:
a. Known history of testing positive for Human Immunodeficiency Virus (HIV) infections.
b. Those with any other medical condition such as active infection, treated or untreated, which in the opinion of the investigator places the subject at an unacceptable risk for participation in immunomodulatory therapy.
c. Allogeneic bone marrow or solid organ transplant
d. Those requiring systemic or local treatment with any immune modulating agent in doses with systemic effects e.g.:
i. Prednisone >20 mg (or equivalent) oral or intravenous daily for >14 days;
ii. Prednisone > 5 mg and = 20 mg (or equivalent) daily for > 30 days;
iii. Equivalent dose of methotrexate >15 mg weekly.
12a. Live or attenuated vaccination within 3 months prior to first dose of study drug (e.g. MMR, Yellow Fever, Rotavirus, Smallpox, etc.).
13. Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1ß inhibitor).
14. History of hypersensitivity to canakinumab or drugs of a similar class.
15. Subjects who have received an investigational drug or device within 30 days prior to first dose of study drug or those who are expected to participate in any other investigational drug or device during the conduct
of the study.
16. Subjects who received any biologic drugs targeting the immune system at any time.
17. Any medical condition resulting in a life expectancy of less than 5 years, other than the risk for recurrent lung cancer.
18. Pregnant or nursing women, where pregnancy is d

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected (R0) non-small cell lung cancer (NSCLC)
MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: canakinumab
Product Code: ACZ885
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: CANAKINUMAB
CAS Number: 914613-48-2
Current Sponsor code: ACZ885
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Product Name: canakinumab
Product Code: ACZ885
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: CANAKINUMAB
CAS Number: 914613-48-2
Current Sponsor code: ACZ885
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: The primary objective is to compare the Disease-free survival (DFS) in the canakinumab versus placebo arms as determined by local investigator assessment.

Timepoint(s) of evaluation of this end point: One interim analysis (IA) will be performed for DFS for futility when
approximately 196 (50%) of the 392 DFS events have been observed.
The primary intent of this IA is to determine whether there is a need to
stop the study early for lack of efficacy (futility, there is no plan to stop
the study for efficacy at this IA).

Secondary Objective: Key secondary objective:
- To compare overall survival (OS) in the canakinumab arm versus placebo arm

Other secondary objectives:
1. To compare DFS by local investigator assessment and OS in the
canakinumab versus placebo arms in subgroups defined respectively by
PD-L1 and CD8 expression levels
2. To compare lung cancer specific survival in the canakinumab arm versus placebo arm
3. To characterize the safety profile of canakinumab
4. To characterize the pharmacokinetics of canakinumab therapy
5. To characterize the prevalence and incidence of immunogenicity (anti-drug antibodies, ADA) of canakinumab
6. To assess the effect of canakinumab versus placebo on PROs (EORTC QLQ-C30 with QLQ-LC13 incorporated and EQ-5D) including functioning and health-related quality of life

Primary end point(s): DFS determined by local investigator assessment

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: The study will end once the final OS analysis is performed when approximately 504 deaths are observed or when statistical significance is reached for OS analysis and the final analysis of study data is conducted. All available data from all subjects up to this cutoff date will be analyzed. If the primary analysis of DFS does not demonstrate treatment benefit, the follow-up for OS will end.

Secondary end point(s): Key secondary endpoint:
- OS

Other secondary endpoints:
1. DFS by local investigator assessment and OS in PD-L1 and CD8
subgroups
2. Lung cancer specific survival (LCSS)
3. Frequency of AEs, ECGs and laboratory abnormalities
4. Serum concentration-time profiles of canakinumab and appropriate individual PK parameters based on population PK model
4. Serum concentrations of anti-canakinumab antibodies
5. Anti-drug antibodies (ADA) prevalence at baseline and ADA incidence
on-treatment of canakinumab
6. Time to definitive 10 point deterioration symptom scores of pain, cough and dyspnea per QLQ-LC13 questionnaire are primary PRO variables of interest. Time to 10 point definitive deterioration in global health status/QoL, shortness of breath and pain per QLQ-C30 questionnaire, time to first deterioration for symptom scores of pain,
cough, dyspnea per QLQ-LC13 questionnaire, time to first 10 point
deterioration for global health status/QoL, shortness of breath and pain
per QLQ-C30 questionnaire together with the utilities derived from EQ-5D-5L are secondary PRO variables of interest

Secondary ID(s)

CACZ885T2301

2017-004011-39-DE

Source(s) of Monetary Support

Novartis Pharma AG

Ethics review

Status: Approved
Approval date: 10/04/2018
Contact: