Randomized, Placebo-controlled, Double-blind Phase 1b/2 Study of U3-1287 (AMG 888) in Combination With Erlotinib in EGFR Treatment Naïve Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on at Least One Prior Chemotherapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 222
- 试验地点
- 1
- 主要终点
- Progression-Free Survival Following U3-1287 (AMG 888) in Combination With Erlotinib
研究概览
简要总结
This is a Phase 1b/2 study. In Phase 1b, subjects will know the treatment they are receiving. Subjects will receive Erlotinib + U3-1287. The Phase 1b portion will determine if adding U3-1287 to Erlotinib will be safe in subjects with advanced non-small cell lung cancer who fail prior treatment. In the Phase 2 portion, subjects will be blinded to the treatments they are receiving. Subjects will receive either Erlotinib alone or Erlotinib + U3-1287.
The Phase 2 portion will determine if adding U3-1287 to Erlotinib will be safe and improve survival in subjects with advanced non-small cell lung cancer who failed the first treatment.
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
- •≥ 18 years of age.
- •Histologically or cytologically confirmed stage IIIB not amenable to surgery or curative intent or stage IV NSCLC.
- •Disease progression or recurrence following treatment after last chemotherapy or chemoradiation regimen (completed within the previous 12 months) documented by radiographic assessment.
- •Measurable disease by Response Evaluation Criteria for Solid Tumors v1.1 (RECIST v1.1).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Adequate bone marrow, renal, and hepatic function.
- •Prothrombin time and partial thromboplastin time ≤1.5 x upper limit of normal (ULN).
- •Availability of recent (before treatment start) or archival tumor specimens (Phase 2 participants only).
- •For female participants, must be postmenopausal, surgically sterile, or must use maximally effective birth control during the period of therapy, and must be willing to use effective contraception up to 6 months after the last dose of study drug and had a negative urine or serum pregnancy test before entry into the study if female participants were of childbearing potential.
- •For male participants, must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose
- •Written informed consent.
排除标准
- •Left ventricular ejection fraction (LVEF) < 45%.
- •Prior epidermal growth factor receptor (EGFR)-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy.
- •More than 2 prior chemotherapy regimens for NSCLC (Phase 2 participants only).
- •History of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
- •History of corneal disease.
- •History of interstitial lung disease.
- •Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that were no longer symptomatic and required no treatment with steroids could be included in the study if they had recovered from the acute toxic effect of radiotherapy.
- •Uncontrolled hypertension (diastolic > 100 mmHg or systolic > 140 mmHg).
- •Clinically significant electrocardiogram changes that obscured the ability to assess the respiratory rate, pulse rate, QT, QTc, and QRS intervals.
- •Ascites or pleural effusion requiring chronic medical intervention.
- •Myocardial infarction within 1 year before enrollment, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or unstable cardiac arrhythmia requiring medication.
- •Treatment with anticancer therapy, antibody based therapy, retinoid therapy, or hormonal therapy within 4 weeks before study treatment or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment or treatment with small molecule tyrosine kinase inhibitors (TKIs) within 2 weeks before study drug treatment. Prior and concurrent use of hormone replacement therapy was permitted.
- •Therapeutic radiation or major surgery within 4 weeks before study treatment or palliative radiation therapy within 2 weeks before study drug treatment.
- •Participated in clinical drug trials within 4 weeks (2 weeks for small molecule TKIs) before study drug treatment. Current participation in other investigational procedures.
- •Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
- •History of hypersensitivity to any of the study drugs or to any excipients.
- •Concurrent use of CYP3A4 inducers or inhibitors.
- •Any known pre-existing condition including substance abuse that could interfere with participant's participation in and completion of the protocol.
研究组 & 干预措施
Part A: U3-1287 (high dose) + Erlotinib
U3-1287 (high dose) intravenously (IV) every three weeks (Q3W) + Erlotinib 150 mg/day orally (PO) until cancer gets worse, side effects become unacceptable or participant withdraws consent
干预措施: U3-1287 (Drug)
Part A: U3-1287 (high dose) + Erlotinib
U3-1287 (high dose) intravenously (IV) every three weeks (Q3W) + Erlotinib 150 mg/day orally (PO) until cancer gets worse, side effects become unacceptable or participant withdraws consent
干预措施: Erlotinib (Drug)
Part B: U3-1287 (low dose) + Erlotinib
U3-1287 (low dose) IV Q3W + Erlotinib 150 mg/day PO until cancer gets worse, side effects become unacceptable or participant withdraws consent
干预措施: U3-1287 (Drug)
Part B: U3-1287 (low dose) + Erlotinib
U3-1287 (low dose) IV Q3W + Erlotinib 150 mg/day PO until cancer gets worse, side effects become unacceptable or participant withdraws consent
干预措施: Erlotinib (Drug)
Part B: Placebo + Erlotinib
Placebo matching U3-1287 IV Q3W + Erlotinib150 mg/day PO until cancer gets worse, side effects become unacceptable or participant withdraws consent
干预措施: Erlotinib (Drug)
Part B: Placebo + Erlotinib
Placebo matching U3-1287 IV Q3W + Erlotinib150 mg/day PO until cancer gets worse, side effects become unacceptable or participant withdraws consent
干预措施: Placebo (Drug)
结局指标
主要结局
Progression-Free Survival Following U3-1287 (AMG 888) in Combination With Erlotinib
时间窗: Time from the randomization date up to the date of first objective documentation of disease progression or death due to any cause (whichever comes first), up to 3 years 2 months
Progression-free survival (PFS) was defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression or death due to any cause (as per Response Evaluation Criteria in Solid Tumors \[RECIST\] Version 1.1).
Progression-Free Survival in Participants With High Heregulin-Expressing Tumors Following U3-1287 (AMG 888) in Combination With Erlotinib
时间窗: Time from the randomization date up to the date of first objective documentation of disease progression or death due to any cause (whichever comes first), up to 3 years 2 months
Progression-free survival (PFS) was defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression or death due to any cause (as per Response Evaluation Criteria in Solid Tumors \[RECIST\] Version 1.1). Heregulin (HRG) high is defined as delta cycle threshold value \< 3.9.
Progression-Free Survival in Participants With Low Heregulin-Expressing Tumors Following U3-1287 (AMG 888) in Combination With Erlotinib
时间窗: Time from the randomization date up to the date of first objective documentation of disease progression or death due to any cause (whichever comes first), up to 3 years 2 months
Progression-free survival (PFS) was defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression or death due to any cause (as per Response Evaluation Criteria in Solid Tumors \[RECIST\] Version 1.1). Heregulin (HRG) low is defined as a delta cycle threshold value ≥ 3.9.
次要结局
- Duration of Stable Disease Following U3-1287 (AMG 888) in Combination With Erlotinib(For participants whose best response is SD as the time from date of first documentation of stable disease up to the date of first documentation of progressive disease, up to 3 years 2 months)
- Time to Objective Response Following U3-1287 (AMG 888) in Combination With Erlotinib(Time from date of randomization up to date of first documentation of objective response of either CR or PR (whichever comes first), up to 3 years 2 months)
- Treatment-Emergent Adverse Events Occurring in ≥10% of Participants Following U3-1287 (AMG 888) in Combination With Erlotinib(From the date of signing the informed consent form up to 53 days after the last dose of patritumab/placebo or up to 30 days after the last dose of erlotinib if patritumab/placebo was discontinued earlier, up to 3 years 2 months)
- Pharmacokinetic Parameter of Cycle 3 Patritumab Area Under the Concentration-time Curve Over the Dosing Interval 0 to τ (AUC) Following U3-1287 (AMG 888) in Combination With Erlotinib(Cycle 1: predose, end of infusion (EOI), 3 hour (h) postdose; Cycle 2: predose; Cycle 3: predose, EOI, 3 h, 6h, 24 h, 72 h, 168 h, 336 h; Cycle 4, Cycle 5, Cycle 7, and Cycle 9: predose (each cycle is 21 days))
- Pharmacokinetic Parameter of Cycle 3 Patritumab Concentration End of Infusion (CEOI) and Minimum (Trough) Concentration (Cmin) Following U3-1287 (AMG 888) in Combination With Erlotinib(Cycle 1: predose, end of infusion (EOI), 3 hour (h) postdose; Cycle 2: predose; Cycle 3: predose, EOI, 3 h, 6h, 24 h, 72 h, 168 h, 336 h; Cycle 4, Cycle 5, Cycle 7, and Cycle 9: predose (each cycle is 21 days))
- Erlotinib Concentrations at Cycle 3 Day 1 Following U3-1287 (AMG 888) in Combination With Erlotinib(Cycle 3, Day 1: predose, 1 h, 2 h, 3 h, 6h, 24 h postdose (each cycle is 21 days))
- Overall Survival Following U3-1287 (AMG 888) in Combination With Erlotinib(Time from the randomization date up to the date of death due to any cause, up to 3 years 2 months)
- Objective Response Following U3-1287 (AMG 888) in Combination With Erlotinib(Time from date of randomization up to date of first documentation of objective response of either CR or PR (whichever comes first), up to 3 years 2 months)
- Time to Disease Progression Following U3-1287 (AMG 888) in Combination With Erlotinib(Time from date of randomization up to the date of first objective documentation of disease progression, up to 3 years 2 months)
- Pharmacokinetic Parameter of Erlotinib Trough (Cmin) Concentrations From Participants Receiving 150 mg Erlotinib Following U3-1287 (AMG 888) in Combination With Erlotinib(Cycle 1: predose, end of infusion (EOI), 3 hour (h) postdose; Cycle 2: predose; Cycle 3: predose, EOI, 3 h, 6h, 24 h, 72 h, 168 h, 336 h; Cycle 5, Cycle 7, and Cycle 9: predose (each cycle is 21 days))