| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected
(R0) non-small cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected
(R0) non-small cell lung cancer (NSCLC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to compare the Disease-free survival (DFS) in the canakinumab versus placebo arms as determined by local investigator assessment. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objective:
- To compare overall survival (OS) in the canakinumab arm versus placebo arm
Other secondary objectives:
1. To compare lung cancer specific survival in the canakinumab arm versus placebo arm
2. To characterize the safety profile of canakinumab
3. To characterize the pharmacokinetics of canakinumab therapy
4. To characterize the prevalence and incidence of immunogenicity (anti-drug antibodies, ADA) of canakinumab
5. 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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub-study, CACZ885T2301A, will enroll adult subjects with NSCLC Stage IIA-IIIA, IIIB (N2 disease only) who are candidates for complete resection surgery (and therefore prospective candidates for the main study, CACZ885T2301). Biomarker samples pre- and post-surgery will be collected from these subjects.
Objectives
For all subjects participating into sub-study:
• To assess the levels of hs-CRP, other
cytokines and additional biomarker levels in blood
at pre- and post-surgery.
For subjects who will also enroll into the main
study:
• To determine whether there is an association
between pre- and post-surgery biomarker levels
with canakinumab efficacy (e.g. DFS, OS).
Endpoints:
- Summary statistics of hs-CRP and other PD biomarkers
- DFS and OS by hs_-CRP and other PD biomarkers |
|
| E.3 | Principal 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 (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 (N2 disease only) who are candidates for
complete resection surgery. |
|
| E.4 | Principal 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 neoadjuvant chemotherapy or neoadjuvant radiotherapy.
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 and 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-1β 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 receiving any biologic drugs targeting the immune system (for example, TNF blockers, anakinra, rituximab, abatacept, or tocilizumab).
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 defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
19a. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment and for up to 3 months after last dose of study drug. Basic contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal suppository
•
• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| DFS determined by local investigator assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses will be performed for DFS: 1) an interim analysis (IA) for futility when approximately 196 (50%) of the 392 DFS events have been observed (expected around 27 months from the date of first patient randomized in the study). 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), and
2) An IA for efficacy when approximately 294 (75%) of the 392 DFS events have been observed (expected around 34 months from the date of first patient randomized in the study). The study will not be assessed for futility at the second IA. |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
- OS
Other secondary endpoints:
1. Lung cancer specific survival (LCSS)
2. Frequency of AEs, ECGs and laboratory abnormalities
3. Serum concentration-time profiles of canakinumab and appropriate individual PK parameters based on population PK model
4. Serum concentrations of anti-canakinumab antibodies
5. 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 definitive deterioration in global health status/QoL, shortness of breath and pain per QLQ-C30 together with the utilities derived from EQ-5D-5L are secondary PRO variables of interest |
|
| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient reported outcomes |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 120 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Costa Rica |
| Egypt |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Lebanon |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Oman |
| Panama |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 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 (refer to protocol Section 10.7) 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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