An Open-Label, Multicenter, Phase 1 Study With Expansion Cohorts of Ramucirumab or Necitumumab in Combination With Osimertinib in Patients With Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer After Progression on First-Line EGFR TKI Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 29
- 试验地点
- 3
- 主要终点
- Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The main purpose of this study is to evaluate the safety of ramucirumab or necitumumab in combination with osimertinib in participants with non-small cell lung cancer (NSCLC).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •Have a diagnosis of NSCLC with at least 1 measurable lesion assessable using standard techniques by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).
- •Have T790M-positive status using a test validated and performed locally after disease progression on EGFR tyrosine kinase inhibitor (TKI) treatment.
- •Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at the time of enrollment.
- •Have serum albumin that is ≥25 grams per liter at the time of enrollment.
- •Have adequate organ function, with all screening labs performed within 7 days of treatment initiation.
- •Have a life expectancy of ≥3 months.
- •Have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
排除标准
- •Previous treatment with an EGFR monoclonal antibody (except for past treatment for squamous cell carcinoma of head and neck or metastatic colorectal cancer).
- •Previous treatment with osimertinib or third generation EGFR TKIs.
- •Participants with symptomatic or growing brain metastases less than 4 weeks prior to enrollment.
- •History of drug-induced interstitial lung disease (ILD), ILD, or radiation pneumonitis requiring treatment with steroid prior to study enrollment, or any evidence of clinically active ILD.
- •Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment. Participants with a history of gross hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 2 months prior to enrollment are excluded.
- •Have experienced any arterial thrombotic event or arterial thromboembolic event, including myocardial infarction, unstable angina (history or evidence of current clinically relevant coronary artery disease of current ≥Class III as defined by Canadian Cardiovascular Society Angina Grading Scale or congestive heart failure of current ≥Class III as defined by the New York Heart Association), cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment.
- •Have a history of deep vein thrombosis, pulmonary embolism, or any other significant venous thromboembolism (venous catheter thrombosis or superficial venous thrombosis not considered "significant") during the 3 months prior to study enrollment. Participants with venous thromboembolism occurring 3 to 6 months prior to study enrollment are allowed, if being treated with low molecular weight heparin.
- •Have a history of gastrointestinal perforation and/or fistula within 6 months prior to enrollment.
- •Have a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
- •Have uncontrolled hypertension, as defined in CTCAE Version 4.0, prior to initiating study treatment, despite antihypertensive intervention. CTCAE Version 4.0 defines uncontrolled hypertension as Grade >2 hypertension; clinically, the participant continues to experience elevated blood pressure (systolic >160 millimeters of mercury [mmHg] and/or diastolic >100 mmHg) despite medications.
- •Are receiving chronic therapy with any of the following medications within 7 days prior to enrollment:
- •nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, ibuprofen, naproxen, or similar agents).
- •other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide).
- •Have radiologically documented evidence of major blood vessel invasion or encasement by cancer.
- •Have radiographic evidence of pulmonary intratumor cavitation, regardless of tumor histology.
- •Are receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, or targeted therapy or radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks prior to enrollment.
- •Have abnormal cardiac findings.
- •Have undergone chest irradiation within 2 weeks prior to study drug administration, have not recovered from all radiation-related toxicities, or requires corticosteroids. A 2-week washout is permitted for focal palliative radiation to non-central nervous system disease.
研究组 & 干预措施
Arm A: Ramucirumab + Osimertinib
Dose Finding: Participants received Ramucirumab 10 milligrams/kilogram (mg/kg) given intravenously (IV) on day 1 every 2 weeks and osimertinib 80 milligrams (mg) given orally daily during each 14-day cycle.
干预措施: Ramucirumab (Drug)
Arm A: Ramucirumab + Osimertinib
Dose Finding: Participants received Ramucirumab 10 milligrams/kilogram (mg/kg) given intravenously (IV) on day 1 every 2 weeks and osimertinib 80 milligrams (mg) given orally daily during each 14-day cycle.
干预措施: Osimertinib (Drug)
Arm B: Necitumumab + Osimertinib
Dose Finding: Participants received Necitumumab 800 mg given IV on days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle.
干预措施: Necitumumab (Drug)
Arm B: Necitumumab + Osimertinib
Dose Finding: Participants received Necitumumab 800 mg given IV on days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle.
干预措施: Osimertinib (Drug)
Cohort A: Ramucirumab + Osimertinib
Dose Expansion: Participants received Ramucirumab 10 mg/kg given IV on day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle.
干预措施: Ramucirumab (Drug)
Cohort A: Ramucirumab + Osimertinib
Dose Expansion: Participants received Ramucirumab 10 mg/kg given IV on day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle.
干预措施: Osimertinib (Drug)
结局指标
主要结局
Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Arm A: Cycle 1 through Cycle 2 (14-day cycle); Arm B: Cycle 1 (21-day cycle)
A Dose Limiting Toxicity (DLT) was defined as one of the following Adverse Events (AE) that is likely related to the study drug or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Any nonhematologic Grade ≥3 toxicity, except for toxicities such as liver or renal function abnormality, skin rash that resolves with appropriate therapy, transient hypersensitivity and injection site reactions, myalgia, fatigue, constipation, electrolyte imbalance, nausea, vomiting, diarrhea 2. Hematologic toxicity was considered a DLT as the following: 1. Grade 4 toxicity lasting ≥7 days, or 2. Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet transfusion, or 3. Febrile neutropenia 3. Death if considered related to study treatment 4. Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting
次要结局
- Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab(Predose on Day (D) 1 of Cycle (C) 2, Predose on Day 1 of Cycle 4, Predose on Day 1 of Cycle 5, Predose on Day 1 of Cycle 7, Predose on Day 1 of Cycle 13)
- Objective Response Rate (ORR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With a Complete Response (CR) or Partial Response (PR)(Baseline to Objective Disease Progression (up to 25 months))
- Progression Free Survival (PFS) for Ramucirumab in Combination With Osimertinib(Baseline to Measured Progressive Disease or Death from Any Cause (up to 26 months))
- Overall Survival (OS) for Ramucirumab in Combination With Osimertinib(Baseline to Death from Any Cause (up to 29 months))
- Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab(Predose on Day 1 of Cycle 3, Predose on Day 1 of Cycle 5)
- Disease Control Rate (DCR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With CR, PR or Stable Disease (SD)(Baseline to Objective Disease Progression (up to 25 months))
- Duration of Response (DoR) for Ramucirumab in Combination With Osimertinib(Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (up to 25 months))