A Phase I/II Dose Escalation Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Dacarbazine for Patients With Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 96
- 试验地点
- 2
- 主要终点
- Phase II: best objective response rate (BORR)
研究概览
简要总结
A prospective, open-label, multi-center, Phase I/II study of L19IL2 in combination with Dacarbazine in patients with metastatic melanoma.
详细描述
A prospective, open-label, multi-center, Phase I/II dose escalation study in which cohorts of 3-6 patients with metastatic melanoma will be assigned to receive escalating doses of L19-IL2 in combination with a fixed dose of Dacarbazine.
After definition of MTD and RD during the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio to receive open label the combination treatment at the RD (Arm 1) or DTIC monotherapy (Arm 2).
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
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18-70 years of age, inclusive
- •Must have histologically or cytologically confirmed cutaneous metastatic melanoma (Stage IV). For the Phase II part only patients with Stage IV M1a or M1b will be enrolled.
- •Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as identified by CT or MRI scan within 28 days before the first study drug administration.
- •Baseline LDH within normal range
- •Maximal 1 line of previous systemic treatment for metastatic disease (prior adjuvant melanoma therapy, e.g., IFN, is permitted.
- •For women of childbearing potential, a negative pregnancy test within 72 hours prior to the first dose of study treatment.
- •Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
- •Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
- •Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
- •Life expectancy of at least three months
- •Adequate organ function: serum creatinine ≤ 1.5 x ULN, total bilirubin ≤ 30 mM/L (or mg/dL, ≤ 2.0 mg/dL), hepatic transaminases ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN.
- •ANC count ≥ 1.5 x 10^9/L, platelet count ≥ 100 x 10^9/L, hemoglobin > 9 g/dL
- •Normal 12-lead ECG and normal bidimensional echocardiogram or MUGA
- •All toxic effects of prior therapy must have resolved to grade ≤1 unless otherwise specified above
- •Willing and able to give written informed consent.
排除标准
- •Pregnant or breastfeeding female
- •Primary ocular melanoma
- •Primary mucosal melanoma
- •Use of any investigational or other anti-cancer drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of DTIC and L19-IL2
- •Prior radiation to a target lesion, unless there has been clear progression of the lesion since radiotherapy
- •A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
- •History or clinical evidence of brain metastases or leptomeningeal disease
- •Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix
- •Treatment with DTIC within 6 months before start of study
- •Treatment with Ipilimumab within 6 months before start of study
- •Hypersensitivity to DTIC
- •Concomitant use of drugs known to alter cardiac conduction
- •Chronic use of corticosteroids used in the management of cancer or non-cancer-related illness
- •Unstable or serious concurrent uncontrolled medical conditions
- •Inadequately controlled cardiac arrhythmias including atrial fibrillation
- •History of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris
- •Heart insufficiency > grade II NYHA criteria
- •Uncontrolled hypertension
- •Ischemic peripheral vascular disease
- •Active infection or incomplete wound healing.
- •History or evidence of active autoimmune disease.
- •Known history of allergy to intravenously administered proteins/peptides/antibodies
- •History of organ allograft.or allogeneic peripheral blood progenitor cell or bone marrow transplantation
- •Major trauma including surgery within 4 weeks prior to entering the study.
- •Any underlying medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results (e.g. AE).
- •Melanoma patients with BRAF 600 E mutation who are amenable to receive approved treatments able to extend overall survival.
研究组 & 干预措施
Ph I: L19IL2 + DTIC
Cohorts of 3-6 patients will receive escalating doses of L19-IL2 until MTD is reached.
L19-IL2 will be administered on days 1, 8 & 15 of each 21-day-cycle. Dacarbazine will be given at a fixed dose on day 1 of each 21-day cycle, 30 minutes after the end of the L19-IL2 infusion.
干预措施: L19IL2 - Ph I (Drug)
Ph I: L19IL2 + DTIC
Cohorts of 3-6 patients will receive escalating doses of L19-IL2 until MTD is reached.
L19-IL2 will be administered on days 1, 8 & 15 of each 21-day-cycle. Dacarbazine will be given at a fixed dose on day 1 of each 21-day cycle, 30 minutes after the end of the L19-IL2 infusion.
干预措施: DTIC (Drug)
Ph II - ARM 1: L19IL2 at RD + DTIC
During the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio: 30 patients assigned to Arm 1 will receive L19IL2 at the RD + DTIC at a fixed dose.
干预措施: L19IL2 at RD - Ph II (Drug)
Ph II - ARM 1: L19IL2 at RD + DTIC
During the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio: 30 patients assigned to Arm 1 will receive L19IL2 at the RD + DTIC at a fixed dose.
干预措施: DTIC (Drug)
Ph II - ARM 2: DTIC monotherapy
During the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio: 30 patients assigned to Arm 2 will receive DTIC at a fixed dose as monotherapy.
干预措施: DTIC (Drug)
结局指标
主要结局
Phase II: best objective response rate (BORR)
时间窗: Up to 1 year
Evaluation of antitumor activity
Phase I: maximum tolerated dose (MTD) and recommended dose (RD) of L19IL2
时间窗: From day 1 to day 21 of Cycle 1 (each cycle is 21-days)
Establish the MTD and the RD of L19IL2 (in combination with dacarbazine) to be used for phase II study
次要结局
- Phase I: disease control rate(At 6 months)
- Phase II: safety and tolerability of L19-IL2 in combination with DTIC vs DTIC alone.(Up to 1 year)
- Phase I: median progression free survival (mPFS)(Up to 1 year)
- Phase I: median overall survival and overall survival rate(Up to 1 year)
- Phase II: disease control rate(At 6 months)
- Phase II: median progression free survival (mPFS)(Up to 1 year)
- Phase II: median overall survival and overall survival rate(Up to 1 year)
- Phase I: best objective response rate (BORR)(Up to 1 year)
- Phase I: duration of objective response(From week 6 up to 1 year)
- Phase II: duration of objective response(Up to 1 year)