This Study Will Evaluate the Effect of Canakinumab or Pembrolizumab Given as Monotherapy or in Combination as Neo-adjuvant Treatment for Subjects With Early Stages NSCLC.
- Conditions
- Non-small Cell Lung Cancer
- Interventions
- Registration Number
- NCT03968419
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study was to evaluate the major pathological response (MPR) rate of canakinumab given as a neoadjuvant treatment, either as single agent or in combination with pembrolizumab, in addition to evaluate the MPR of pembrolizumab as a single agent and the dynamic of the tumor microenvironment changes on treatment.
- Detailed Description
This was a randomized, phase II, open-label study evaluating canakinumab, an anti-IL-1β monoclonal antibody, or pembrolizumab, a monoclonal antibody designed to block the PD-1 receptor, as monotherapy or in combination as neoadjuvant therapy. The study population included adult subjects with resectable non-small cell lung cancer (NSCLC) planned for surgery in approximately 4-6 weeks. Subjects were treated for a maximum duration of 6 weeks (2 cycles) until surgery, progression, unacceptable toxicity or discontinuation from the study treatment for any other reason.
Subjects were randomized in a 2:2:1 ratio to one of the 3 treatment arms (canakinumab alone or canakinumab in combination with pembrolizumab or pembrolizumab alone). Surgery was performed between 4 to 6 weeks after the first dose of study treatment.
All randomized subjects were followed for safety for up to 130 days following the last dose of study treatment (safety follow-up period).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 88
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Canakinumab monotherapy Canakinumab Participants received 200 mg of canakinumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery Canakinumab + pembrolizumab Pembrolizumab Participants received 200 mg of canakinumab in combination with 200 mg of pembrolizumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery Canakinumab + pembrolizumab Canakinumab Participants received 200 mg of canakinumab in combination with 200 mg of pembrolizumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery Pembrolizumab monotherapy Pembrolizumab Participants received 200 mg of pembrolizumab every 3 weeks for a maximum duration of 6 weeks prior to surgery
- Primary Outcome Measures
Name Time Method Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Canakinumab Monotherapy and in Combination With Pembrolizumab Based on Central Review At time of surgery (up to 6 weeks after first dose of study treatment) MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder.
MPR was assessed at the time of surgery in all subjects randomized to canakinumab monotherapy and in combination with pembrolizumab based on central review.
- Secondary Outcome Measures
Name Time Method Surgical Feasibility Rate Up to 6 weeks after first dose Surgical feasibility rate was defined as the percentage of subjects who underwent surgery following study treatment.
Canakinumab Antidrug Antibodies (ADA) Prevalence Predose (0 hour) on Day 1 of Cycle 1 (Cycle=21 days) Canakinumab ADA prevalence at baseline was calculated as the percentage of participants who had a canakinumab ADA positive result at baseline
Pembrolizumab ADA Prevalence Predose (0 hour) on Day 1 of Cycle 1 (Cycle = 21 days) Pembrolizumab ADA prevalence at baseline was calculated as the percentage of participants who had a pembrolizumab ADA positive result at baseline
Canakinumab ADA Incidence From baseline (Predose on Day 1 of Cycle 1) up to 130 days after last dose of study treatment (assessed up to 24.6 weeks). Cycle = 21 days Canakinumab ADA incidence on treatment was calculated as the percentage of participants who were canakinumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and canakinumab treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Serum Canakinumab Concentration Predose (0 hour) on Day 1 of Cycles 1 and 2 (Cycle =21 days) Canakinumab serum concentrations were determined at the specified time points.
Serum Pembrolizumab Concentration Predose (0 hour) and 0.5 hours post dose on Day 1 of Cycle 1 and predose on Cycle 2 (Cycle =21 days) Pembrolizumab serum concentrations were determined at the specified time points.
Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers From date of randomization up to 6 weeks after first dose MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder.
MPR rate was analyzed by the biomarker subgroups at baseline. Biomarkers included PD-L1, CD8, hs-CRP and hs-IL-6.Pembrolizumab ADA Incidence From baseline (Predose on Day 1 of Cycle 1) up to 26 days after last dose of study treatment (assessed up to 10.7 weeks). Cycle = 21 days Pembrolizumab ADA incidence on treatment was calculated as the percentage of participants who were pembrolizumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and pembrolizumab treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1 From date of randomization to date of surgery, assessed up to 6 weeks ORR is defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per local investigator's assessment by RECIST 1.1.
CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.
PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diametersMajor Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Pembrolizumab Monotherapy Based on Central Review At time of surgery (up to 6 weeks after first dose) MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder.
MPR was assessed at the time of surgery in all subjects randomized to pembrolizumab monotherapy arm based on central review.Difference in Major Pathological Response (MPR) Rate Between the Canakinumab Plus Pembrolizumab Arm and the Pembrolizumab Arm Based on Central Review At time of surgery (up to 6 weeks after first dose of study treatment) MPR was defined as the percentage of participants with ≤10% residual viable tumor cells on surgical samples. MPR was assessed at the time of surgery based on central review. The difference in MPR rate between the canakinumab plus pembrolizumab arm and the pembrolizumab arm based on central review along with the Chang and Zhang confidence interval was assessed.
Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review At time of surgery (up to 6 weeks after first dose) MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder.
MPR was assessed at the time of surgery in all subjects based on local review.
Trial Locations
- Locations (5)
University of Kansas Medical Center Neurology Dept.
🇺🇸Kansas City, Kansas, United States
Methodist Hospital / Methodist Cancer Center
🇺🇸Houston, Texas, United States
UCLA Oncology Hematology
🇺🇸La Jolla, California, United States
SUNY - Upstate Medical University
🇺🇸Syracuse, New York, United States
Novartis Investigative Site
🇹🇷Sihhiye / Ankara, Turkey