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A phase III, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult patients with stages AJCC/UICC v8 II-IIIA and IIIB (T.>cm N2) completely resected (R0) non-small cell lung cancer (NSCLC)

PHRR190130-002038

CACZ885T2301

2018-CT0468

A phase III, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult patients with stages AJCC/UICC v8 II-IIIA and IIIB (T.>cm N2) completely resected (R0) non-small cell lung cancer (NSCLC)

This phase III, multicenter, randomized, double blind study will evaluate the 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 (R0) non-small cell lung cancer (NSCLC) Subjects may be screened after undergoing complete surgical resection of their NSCLC and having R0 status confirmed (negative margins on pathologic review), after completing adjuvant cisplatin-based doublet chemotherapy if applicable, (and, if applicable, radiation therapy for stage IIIA N2 or IIIB N2 disease) and after all entry criteria are met. Subjects must not have had preoperative neo-adjuvant chemotherapy or radiotherapy to achieve the R0 status. Approximately 1500 subjects will be randomized 1:1 to canakinumab, 200 mg subcutaneously (s.c.) every 3 weeks or matching placebo, s.c., every 3 weeks (Figure 4-1). Randomization will be stratified by AJCC/UICC v. 8 stage: IIA versus IIB versus I IIA versus IIIB with T>5cm, N2 disease; Histology: squamous versus non-squamous; and
Region: Western Europe and North America vs. eastern Asia vs. Rest of
the world (RoW).

Start Date Duration in Months Target Completion Date Actual Completion Date
2019-08-22 77 2026-01-22 0000-00-00

Ongoing

Institution Classification Region LTO #
Novartis Healthcare Philippines, Inc. Private Business NCR 3000006283930
Institution Region
Novartis Healthcare Philippines, Inc. NCR
Name E-Mail Institution and Institution Address
Anna Liza Calingasin anna_liza.calingasin@novartis.com Novartis Healthcare Philippines, Inc. 5/F Ayala North Exchange Tower 1 Salcedo corner Amorsolo Streets Legaspi Village, Makati City 1229 Philippines
Name E-Mail Institution and Institution Address
Jerome Gonzaga jerome.gonzaga@novartis.com Novartis Healthcare Philippines, Inc. 5/F Ayala North Exchange Tower 1 Salcedo corner Amorsolo Streets Legaspi Village, Makati City 1229 Philippines
Name Expertise Affiliation
Christina G. Galvez, MD Oncology St Luke Medical Center - Global City
Felycette Gay Martinez-Lapus, MD Oncology Davao Doctors Hospital
Guia Elena Imelda R. Ladrera, MD Oncology Lung Center of the Philippines
Maria Belen E. Tamayo, MD Oncology Makati Medical Center
Priscilla B. Caguioa, MD Oncology St. Luke's Medcal Center Quezon City
Project Location Institutional Ethics Review Board
St Luke Medical Center - Global City N/A
Davao Doctors Hospital Davao Doctors Hospital Ethics Review Committee
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
Makati Medical Center Makati Medical Center Institutional Review Board
St. Luke's Medcal Center Quezon City N/A

stages AJCC/UICC v8 II-IIIA and IIIB (T.>cm N2) completely resected (R0) non-small cell lung cancer (NSCLC)

The primary efficacy variable of the study is disease free survival (DFS), defined as the time from the date of randomization to the date of the first documented disease recurrence as assessed by local investigator radiologically or death due to any cause. In case of non -conclusive radiological evidence, a biopsy performed to confirm recurrence will be used as DFS event. DFS events will be assessed locally.

The key secondary objective is to determine whether treatment with canakinumab prolongs overall survival (OS) compared with placebo arm.
OS is defined as the time from the date of randomization to the date of death due to any cause. If a subject is not known to have died, then OS will be censored at the latest date the subject was known to be alive (on or before the cut-off date).

Recruiting

  • Argentina
  • Australia
  • Austria
  • Belgium
  • Brazil
  • Bulgaria
  • Canada
  • Chile
  • China
  • Colombia
  • Costa Rica
  • Czech Republic
  • Egypt
  • France
  • Germany
  • Greece
  • Guatemala
  • Hong Kong
  • Hungary
  • India
  • Italy
  • Japan
  • Jordan
  • Lebanon
  • Malaysia
  • Mexico
  • Netherlands
  • Norway
  • Oman
  • Panama
  • Peru
  • Philippines
  • Poland
  • Portugal
  • Romania
  • Russia
  • Singapore
  • Slovakia
  • South Africa
  • South Korea
  • Switzerland
  • Taiwan
  • Thailand
  • Turkey
  • United Arab Emirates
  • United Kingdom
  • United States
  • Vietnam

Clinical Trial

CACZ885T2301

20181012103237

2019-01-07

0000-00-00

11

2

Unspecified

22 Aug 2019

INCLUSION CRITERIA
1. Written informed consent must be obtained prior to any screening procedures.
2. Age ≥ 18 years
3. Completely resected (R0) AJCC/UICC v. 8 stage IIA with T>4-5 cm and N0 (no nodal
involvement), if no adjuvant chemotherapy is given, must be randomized within 70 days post complete surgical resection of their NSCLC.
4. Subjects with completely resected (R0) AJCC/UICC v. 8 stages IIA, IIB, IIIA or IIIB (T>5 cm N2) disease NSCLC, who received chemotherapy and no radiation therapy must be randomized within 182 days post complete surgical resection of their NSCLC.
5. Subjects with completely resected (R0) AJCC/UICC v. 8 stage IIIA N2 (T ≤5 cm only) or
stage IIIB (T> 5cm N2) disease who receive radiation therapy along with chemotherapy
detailed in inclusion criterion 6, must be randomized within 259 days of complete surgical
resection.
6. Adjuvant chemotherapy is mandatory with stage AJCC/UICC v. 8 stage II-IIIA and stage
IIIB (T>5cm N2) disease for 4 cycles (21 or 28 day cycles) as per local/national guidelines (except if not tolerated, in which case at least 2 cycles of adjuvant chemotherapy are required).
 Adjuvant chemotherapy is mandatory (at least 2 cycles) for all subjects except those who have stage IIA disease with T>4-5 cm.
 Chemotherapy must be cisplatin based. Combination partners may include
vinorelbine, etoposide, docetaxel or gemcitabine for any histology. For nonsquamous
carcinomas only, the combination partner may be pemetrexed.
7. Subjects must have recovered from all toxicities related to prior systemic therapy to grade
≤ 1 (CTCAE v 4.03). Exception to this criterion: subjects with any grade of alopecia and
grade 2 or less neuropathy are allowed to enter the study.
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.
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.
3. 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. Exceptions to this exclusion
include the following: completely resected basal cell and squamous cell skin cancers, and
completely resected carcinoma in situ of any type.
4. History of interstitial lung disease.
5. 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 (e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker).
6. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting cycle 1 day 1 or subjects
who have not recovered from radiotherapy-related toxicities. Radiation therapy is
suggested, but not required to be given to subjects with completely resected (R0)
AJCC/UICC v. 8 stage IIIA or IIIB with T>5cm N2 disease, (mediastinal radiation).
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).
10. Subjects with a history of tuberculosis (TB) infection, active or latent, or one of the
following risk factors:
a. History of any of the following: residence in a congregate setting: jail or prison, homeless shelter or chronic care facility, substance abuse (injected or non-injected); health care workers with unprotected exposure to subjects who are at high risk of TB or subjects with TB disease before identification and correct airborne precautions of the infected subject.
b. Close contact (i.e. sharing the same air space in a household or other enclosed environment for prolonged period (days or weeks, not hours or minutes) with a person with active TB disease within the past 12 months.
c. Evidence of TB infection, active or latent, at screening as determined by purified protein derivative (PPD) skin test and /or QuantiFERON®-TB Gold (QFT-g) assay as defined by country guidelines (refer to Determination of TB status to be further defined in full protocol).
i. If presence of TB, active or latent, is established then treatment for TB (according to country guidelines for TB treatment or TB treatment must be completed before treatment with
immunomodulating drugs) must have been completed prior to screening as per country guidelines.
ii. In the absence of country TB (active or latent) guidelines, the following has been demonstrated: TB has been adequately treated with antibiotics, cure can be demonstrated, and risk factors resulting in TB exposure and contracting TB have been removed (e.g. subject no longer lives in high-risk TB exposure setting).
11. Subjects with suspected or proven immunocompromised state, including:
a. Human Immunodeficiency Virus (HIV) infections including those receiving ant-viral therapy.
b. Those with any other medical condition, which in the opinion of the investigator places the subject at an unacceptable risk for participation in immunomodulatory therapy
c. Those requiring systemic or local treatment with any immune modulating agent in doses with systemic effects e.g. high dose oral or intravenous steroids (>20 mg prednisone orally daily for >14 days, > 5 mg prednisone orally daily or the equivalent dose of intravenous steroid or methotrexate >15 mg weekly.
d. Important clarification: Topical, inhaled or local steroid use in doses that are not considered to cause systemic effects are permitted.
12. Live vaccination within 3 months prior to first dose of study drug.
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.

Interventional

canakinumab

Canakinumab is a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody that
belongs to the IgG1/κ isotype subclass. The relative molecular mass of canakinumab based on
the amino acid sequence without post-translational modification (e.g., glycosylation), but
including N-terminal pyroglutamate formation and the C-terminal lysine residues at the heavy
chains, is MW = 145157 Da. Canakinumab is manufactured in a murine SP2/0 cell line.

Date Amendment Classification Reason
2019-04-15 Amendments related to the protocol Informed consent
2020-04-22 Amendments related to the protocol Informed consent

Randomized

Double Blind

This is a double blind study. In particular, subjects, investigators, study team, or anyone involved in the study conduct will remain blinded to the identity of the treatment from the time of randomization until unblinding of the study. Randomization data are kept strictly confidential until the time of unblinding, and will not be accessible to anyone involved in the conduct of the study, with the exception of the external independent statistical group, which needs to prepare safety and efficacy interim DFS analysis reports for the DMC, the PK bioanalyst, modeler and modeling programmer. These personnel will not be involved in any other trial activities and treatment allocation information will be kept confidential until clinical database lock. The study bioanalyst will receive a copy of the randomization schedule to facilitate analysis of the samples. The identity of the treatments will be concealed by the use of investigational drugs (canakinumab or placebo) that are identical in packaging, labeling, schedule of administration and in appearance. Confidentiality of randomization data is required to limit the occurrence of potential bias arising from the influence that the knowledge of treatment may have on the recruitment and allocation of subjects. Unblinding will only occur in the case of subject emergencies (see Section 8.3), following the Data Monitoring Committee (DMC)  recommendations (e.g. after the interim analyses) (see Section 10.7), for regulatory reporting purposes and at the end of the study.

Parallel

The purpose of this prospective, multicenter, randomized, double blind, placebo-controlled
phase III study is to evaluate the efficacy and safety of canakinumab as adjuvant therapy,
following standard of care for completely resected (R0) AJCC/UICC v. 8 stages II-IIIA and
stage IIIB (T>5cm N2) NSCLC subjects.

Phase III

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