A Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Canakinumab in Combination With Docetaxel Versus Placebo in Combination With Docetaxel in Adult Subjects With Non-small Cell Lung Cancer (NSCLC) Previously Treated With PD-(L)1 Inhibitors and Platinum-based Chemotherapy (CANOPY 2)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 245
- 试验地点
- 7
- 主要终点
- Safety run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This study was designed to evaluate the role of canakinumab in combination with docetaxel in subjects with advanced non-small cell lung cancer (NSCLC) previously treated with PD-(L)1 inhibitors and platinum-based chemotherapy.
详细描述
This was a multicenter, Phase III study designed to evaluate the efficacy and safety of canakinumab in combination with docetaxel versus placebo in combination with docetaxel, as second- or third-line treatment. The study included adult subjects with advanced NSCLC whose disease had progressed after prior treatment with a PD-(L)1 inhibitor. Subjects had also been pre-treated with platinum-based chemotherapy, either given together with PD-(L)1 inhibitor or sequentially.
The study consisted of 2 parts:
- Part 1: Safety run-in. This part was conducted to confirm the Recommended Phase 3 Regimen (RP3R) of the canakinumab and docetaxel combination. Participants were treated for at least 2 complete cycles of treatment (21 days per cycle) for safety evaluation (DLT-Dose Limiting Toxicities) to define RP3R. Participants from the safety run-in part were treated until any discontinuation criteria were met. After treatment discontinuation, all participants were followed for safety evaluations during the safety follow up period (up to 130 days). Additionally, subjects who discontinued study treatment without prior documented disease progression continued efficacy assessments in the efficacy follow-up phase irrespective of the start of new antineoplastic therapy and until documented progressive disease as per protocol. After the RP3R was determined, enrollment in this part was closed and additional participants were enrolled in the randomized part (part 2) of the study. Ongoing patients from the safety run-in part continued their treatment at the assigned dose level according to the dose and schedule for the safety run-in part.
- Part 2: Randomized part. The randomized, double-blind, placebo-controlled part of the study opened after confirmation of the RP3R for the combination of canakinumab and docetaxel. Participants from the randomized part were treated until any discontinuation criteria were met as per protocol. After treatment discontinuation, all participants were followed for safety evaluations during the safety follow up period (up to 130 days). Additionally, subjects who discontinued study treatment without prior documented disease progression continued efficacy assessments in the efficacy follow-up phase irrespective of the start of new antineoplastic therapy and until documented progressive disease as per protocol.
Based on the lack of efficacy observed in the primary analysis, Novartis decided to halt canakinumab/placebo treatment. Subjects continued to receive docetaxel if they were deriving clinical benefit as per investigator assessment until discontinuation
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed advanced (stage IIIB) or metastatic NSCLC.
- •Subject had received one prior platinum-based chemotherapy and one prior PD-(L)1 inhibitor therapy for locally advanced or metastatic disease.
- •Subject with ECOG performance status (PS) of 0 or
- •Subject with at least 1 evaluable (measurable or non-measurable) lesion by RECIST 1.1 in solid tumors criteria.
排除标准
- •Subject who previously received docetaxel, canakinumab (or another IL-1β inhibitor), or any systemic therapy for their locally advanced or metastatic NSCLC other than one platinum-based chemotherapy and one prior PD-(L)1 inhibitor.
- •Subject with EGFRor ALK positive tumor.
- •History of severe hypersensitivity reaction to monoclonal antibodies, taxanes or excipients of docetaxel or canakinumab.
研究组 & 干预措施
Safety run-in part: Canakinumab+docetaxel
Participants were treated with full doses of docetaxel 75mg/m^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1). Subjects were assessed for at least 2 complete cycles of treatment (21 days per cycle; a total of 42 days) for safety evaluation (DLT) to define RP3R. De-escalation to canakinumab 200 mg subcutaneous every 6 weeks + docetaxel 75 mg/m^2, every 3 weeks could also be considered.
干预措施: Canakinumab (Drug)
Safety run-in part: Canakinumab+docetaxel
Participants were treated with full doses of docetaxel 75mg/m^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1). Subjects were assessed for at least 2 complete cycles of treatment (21 days per cycle; a total of 42 days) for safety evaluation (DLT) to define RP3R. De-escalation to canakinumab 200 mg subcutaneous every 6 weeks + docetaxel 75 mg/m^2, every 3 weeks could also be considered.
干预措施: Docetaxel (Drug)
Randomized part: Canakinumab + docetaxel
Participants were treated with canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m^2 every 3 weeks
干预措施: Canakinumab (Drug)
Randomized part: Canakinumab + docetaxel
Participants were treated with canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m^2 every 3 weeks
干预措施: Docetaxel (Drug)
Randomized part: Placebo + docetaxel
Participants were treated with placebo subcutaneous at RP3R and docetaxel at 75 mg/m^2 every 3 weeks
干预措施: Docetaxel (Drug)
Randomized part: Placebo + docetaxel
Participants were treated with placebo subcutaneous at RP3R and docetaxel at 75 mg/m^2 every 3 weeks
干预措施: Placebo (Other)
结局指标
主要结局
Safety run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs)
时间窗: During the first 42 days of dosing
Percentage of participants with DLTs. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 42 days of docetaxel and canakinumab treatment.
Randomized Part: Overall Survival (OS)
时间窗: From randomization until death or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approximately (approx.) 18 months)
OS is defined as the time from randomization to date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. If a subject was not known to have died, then OS was censored at the latest date the subject was known to be alive (on or before the cut-off date).
次要结局
- Randomized Part: Progression-Free Survival (PFS)(From randomization until disease progression, death or final analysis data cutoff date (08-Jan-2021) whichever comes first (assessed up to approx. 18 months))
- Randomized Part: Time to Definitive 10-point Deterioration (TTD) Symptom Scores of Chest Pain, Cough and Dyspnea Per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) Lung Cancer (LC13) Questionnaire(From baseline through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 18 months))
- Overall Response Rate (ORR)(Through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 10 months for the safety run-in part and 18 months for the randomized part))
- Duration of Response (DOR)(From first documented response of CR or PR to date of first documented progression, death or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approx. 10 months for the safety run-in and 18 months for the randomized))
- Disease Control Rate (DCR)(Through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 10 months for the safety run-in part and 18 months for the randomized part))
- Randomized Part: Time to Response (TTR)(From randomization until first documented response or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approx. 18 months))
- Randomized Part: Change From Baseline in GHS/QoL, Shortness of Breath and Pain Scores as Per the EORTC QLQ C30 Questionnaire(Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment until progression (post-treatment efficacy visits), 7 and 28 days post progression through final analysis cutoff date of 08Jan2021 (up to approx. 18 months))
- Randomized Part: Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Health State Scores(Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment until progression (post-treatment efficacy visits), 7 and 28 days post progression through final analysis cutoff date of 08Jan2021 (up to approx. 18 months))
- Safety run-in Part: Time of Maximum Plasma Concentration (Tmax) of Canakinumab(Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days)
- Safety run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Canakinumab(Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days)
- Safety run-in Part: AUClast of Docetaxel(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days)
- Randomized Part: Cmax of Docetaxel(Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days)
- Randomized Part: Canakinumab Antidrug Antibodies (ADA) at Baseline(Baseline)
- Randomized Part: Time to Definitive 10-point Deterioration in Global Health Status (GHS)/Quality of Life (QoL), Shortness of Breath and Pain Per EORTC QLQ-C30 Questionnaire(From baseline through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 18 months))
- Safety run-in Part: Cmax of Docetaxel(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days)
- Randomized Part: Canakinumab ADA Incidence On-treatment(Pre-dose at Cycle 1 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1 , end of treatment, and 130 days after end of treatment through final analysis data cutoff date of 08-Jan-2021 (assessed up to 18 months). Each cycle is 21 days)
- Randomized Part: Change From Baseline in Chest Pain, Cough and Dyspnea Scores as Per the EORTC-QLQ LC13 Questionnaire(Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment until progression (post-treatment efficacy visits), 7 and 28 days post progression through final analysis cutoff date of 08Jan2021 (up to approx. 18 months))
- Randomized Part: Pre-dose Plasma Trough Concentration (CTrough) of Canakinumab(Pre-dose on Cycle 1 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1 and Cycle 18 Day 1. Each cycle is 21 days.)
- Safety run-in Part: Maximum Plasma Concentration (Cmax) of Canakinumab(Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days)
- Randomized Part: AUClast of Docetaxel(Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days)
- Safety run-in Part: Tmax of Docetaxel(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days)
- Randomized Part: Tmax of Docetaxel(Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days)