An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination With Gemcitabine and Cisplatin in the First-Line Treatment of Patients With Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 192
- 试验地点
- 1
- 主要终点
- Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The purpose of the Phase 1b portion of the study is to investigate how the body tolerates necitumumab, in combination with gemcitabine and cisplatin chemotherapy as first line treatment in participants with Stage IV squamous NSCLC and to determine the recommended dose for the subsequent Phase 2 portion of the study.
The purpose of the Phase 2 portion of the study is to evaluate the efficacy of necitumumab in combination with gemcitabine and cisplatin chemotherapy in participants with Stage IV squamous NSCLC in a first-line setting.
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
- None
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Squamous Non-Small Cell Lung Cancer Disease (NSCLC)
- •Clinical Stage IV NSCLC
- •Measurable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
- •No prior systematic chemotherapy, targeted therapy, surgery and chest radiotherapy
- •Ha resolution to Grade less than or equal to (≤) 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, of all clinically significant toxic effects of prior therapy for other than NSCLC
- •Adequate-organ function defined as:
- •Total bilirubin ≤1.5 x the upper limit of normal value (ULN)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
- •Serum creatinine ≤ 1.2 x ULN or calculated creatinine clearance (CrCL)>50 milliliter per minute (mL/min) (per the Cockcroft Gault formula or equivalent and/or 24-hour urine collection)
- •Absolute neutrophil count (ANC) greater than or equal to ≥1.5 x 10^3/μL(microliter)
- •Hemoglobin ≥10.0 g/dL(gram per deciliter)
- •Platelets ≥100 x 10^3/μL
- •At least 20 years of age
- •Estimated life expectancy of at least 12 weeks
- •A formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 5 unstained slides of tumor sample prior to randomization for the evaluation of epidermal growth factor receptor (EGFR) protein expression (IHC).
- •If women: surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method (failure rate <1%) during and for 6 months after the treatment period (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method). If men: surgically sterile or compliant with a highly effective contraceptive regimen during and for 6 months after the treatment period.
- •Has provided signed informed consent
排除标准
- •Has enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device
- •Participant has undergone major surgery within 28 days prior to enrollment or have planned major surgery, subcutaneous venous access device placement within 7 days prior to enrollment Phase 1b) or randomization (Phase 2).
- •Has undergone any prior radiation therapy, except for Gamma Knife radiation and palliative radiation treatment at least 14 days have elapsed from last radiation treatment prior to enrollment (Phase 1b) or randomization (Phase 2)
- •Has brain metastases that are symptomatic or require surgery, medication and radiotherapy except for stereotactic irradiation
- •Has superior vena cava syndrome
- •Has clinically relevant coronary artery disease or uncontrolled congestive - heart failure
- •Participant has uncontrolled hypertension defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg despite standard medical management.
- •Has diabetes requiring insulin
- •Has an angina or has experienced myocardial infarction within 6 months prior to enrollment (Phase 1b) or randomization (Phase 2)
- •Has an Acquired Immunodeficiency Syndrome (AIDS)-related illness or have evidence of or test positive test results for human immunodeficiency virus (HIV)
- •Has evidence of or test positive test results for hepatitis B, or hepatitis C virus antibodies
- •Has a known allergy and history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab, or any other contraindication to one of the administered treatments
- •Has significant third-space fluid retention requiring drainage
- •Has history of interstitial pneumonitis
- •Has an ongoing or active infection
- •Has a history of significant neurological or psychiatric disorders
- •Has a Grade 2 peripheral neuropathy
- •Pregnant (confirmed within 7 days prior to enrollment [Phase 1b] or randomization [Phase 2]), or breastfeeding
- •Has known history of drug abuse
- •Assessed as inadequate for the study by the investigator or sub investigator
研究组 & 干预措施
Necitumumab + Gem and Cis
Phase 1b Dose Escalation: Necitumumab 800 milligram (mg) on Days 1 and 8 of every 21 day cycle, administered as an intravenous (IV) infusion. Gemcitabine (Gem) dose escalation of 1000 or 1250 milligram per square meter (mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin (Cis) 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.
Phase 2 Randomized: Necitumumab 800 mg on Days 1 and 8 of every 21 day cycle, administered as an IV infusion. Gemcitabine at fixed dose determined in Phase 1b (1000 or 1250 mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.
干预措施: Necitumumab (Drug)
Necitumumab + Gem and Cis
Phase 1b Dose Escalation: Necitumumab 800 milligram (mg) on Days 1 and 8 of every 21 day cycle, administered as an intravenous (IV) infusion. Gemcitabine (Gem) dose escalation of 1000 or 1250 milligram per square meter (mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin (Cis) 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.
Phase 2 Randomized: Necitumumab 800 mg on Days 1 and 8 of every 21 day cycle, administered as an IV infusion. Gemcitabine at fixed dose determined in Phase 1b (1000 or 1250 mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.
干预措施: Gemcitabine (Drug)
Necitumumab + Gem and Cis
Phase 1b Dose Escalation: Necitumumab 800 milligram (mg) on Days 1 and 8 of every 21 day cycle, administered as an intravenous (IV) infusion. Gemcitabine (Gem) dose escalation of 1000 or 1250 milligram per square meter (mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin (Cis) 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.
Phase 2 Randomized: Necitumumab 800 mg on Days 1 and 8 of every 21 day cycle, administered as an IV infusion. Gemcitabine at fixed dose determined in Phase 1b (1000 or 1250 mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles.
干预措施: Cisplatin (Drug)
Gemcitabine + Cisplatin
Phase 2 Randomized: Gemcitabine at fixed dose determined in Phase 1b (1000 to 1250 mg/m^2) on Day 1 and Day 8 of every 21 day cycle,administered as an IV infusion over approximately 30 minutes for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 120 minutes for a maximum of 4 cycles .
干预措施: Gemcitabine (Drug)
Gemcitabine + Cisplatin
Phase 2 Randomized: Gemcitabine at fixed dose determined in Phase 1b (1000 to 1250 mg/m^2) on Day 1 and Day 8 of every 21 day cycle,administered as an IV infusion over approximately 30 minutes for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 120 minutes for a maximum of 4 cycles .
干预措施: Cisplatin (Drug)
结局指标
主要结局
Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Day 1 to Day 21 in Cycle 1 (Up To 21 days)
DLT was defined as any of the following events graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, when the event occurred within 21 days from Day 1 in Cycle 1 and was considered to be definitely or probably related to necitumumab and/or gemcitabine-cisplatin chemotherapy: Grade 4 neutropenia ≥ 7 days, Grade ≥ 3 febrile neutropenia except for transient febrile neutropenia (Grade 3 neutropenia with fever ≥ 38.5 degrees Celsius (°C) for ≤ 24 hours), Grade 3 thrombocytopenia requiring platelet substitution, Grade 4 thrombocytopenia, ≥Grade 3 nonhematologic toxicity (excluding nausea, vomiting, arthralgia, myalgia, asthenia, fatigue, diarrhea, constipation, anorexia), any toxicity leading to the omission of necitumumab on Day 8 or 15 (for participants for whom necitumumab was delayed from Days 8 to 15) during the Cycle 1.
Phase 2: Overall Survival (OS)
时间窗: From Date of Randomization until Death Due to Any Cause (Up To 39 Months)
OS defined as the time from the date of randomization to the date of death due to any cause. Participants who are alive at the time of study completion or are lost to follow-up will be censored at the time they were last known to be alive.
次要结局
- Phase 2: Time to Treatment Failure (TTF)(From Date of Randomization to Measured Progressive Disease, Death Due to Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up To 39 Months))
- Phase 2: Change From Baseline in Lung Cancer Symptom Scale (LCSS)(Baseline, Cycle 4 (Cycle = 3 weeks))
- Phase 1b: Pharmacokinetics (PK): Maximum Concentration (Cmax) of Necitumumab(Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion)
- Phase 1b: PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Gemcitabine and Cisplatin(Gemcitabine: C1D1: Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion)
- Phase 1b: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR])(Baseline to Measured Progressive Disease (Up To 39 Months))
- Phase 2: Progression Free Survival (PFS)(From Date of Randomization to Measured Progressive Disease or Death Due to Any Cause (Up To 39 Months))
- Phase 2: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR])(Baseline to Measured Progressive Disease (Up To 39 Months))
- Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Index Score(Baseline, Cycle 4 (Cycle = 3 weeks))
- Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Visual Analog Scale (VAS)(Baseline, Cycle 4 (Cycle = 3 weeks))
- Phase 1b: PK: Cmax of Gemcitabine and Cisplatin(Gemcitabine: Cycle 1(C1) Day1(D1): Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1 D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion)
- Phase 2: PK: Minimum Concentration (Ctrough) of Necitumumab(Predose Day 1 of Cycle 1, 2, 3, 4, and every 2 cycles after Cycle 5)
- Phase 1b: PK: Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Necitumumab(Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion)
- Phase 2: Number of Participants With Serum Anti-Necitumumab Antibody Assessment (Immunogenicity)(Baseline up to 30 Days Post Last Infusion (estimated up to 39 months))