NCT03567889招募中3 期
An Open-Label, Randomized, Controlled Multi-Center Study of The Efficacy of Daromun (L19IL2 + L19TNF) Neoadjuvant Intratumoral Treatment Followed by Surgery and Adjuvant Therapy Versus Surgery and Adjuvant Therapy in Clinical Stage IIIB/C/D Melanoma Patients
Philogen S.p.A.37 个研究点 分布在 3 个国家目标入组 186 人开始时间: 2018年9月20日最近更新:
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 186
- 试验地点
- 37
- 主要终点
- Recurrence Free Survival (RFS)
研究概览
简要总结
The trial aims to evaluate the efficacy of Daromun neoadjuvant treatment followed by surgery and adjuvant therapy to improve in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C/D melanoma patients with respect to the standard of care (surgery and adjuvant therapy).
详细描述
The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of Daromun neoadjuvant intratumoral treatment followed by surgery and adjuvant therapy versus surgery and adjuvant therapy in clinical stage III B/C/D melanoma patients. 186 patients will be randomized in a 1:1 ratio to receive Daromun treatment followed by surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2).
In both arms, follow-up for assessing recurrence-free survival will be performed up to five years after randomization. Survival information will also be collected in the following year (up to six years in total after randomization).
This is an open-label study, so there is no blinding.
Patients who successfully complete the screening evaluations and are eligible for participation in the study will be enrolled and randomly assigned (1:1) to two parallel treatment arms: Daromun plus surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2).
To ensure a balance across treatment groups, stratified randomization with permuted block will be used and separate randomization list for each subgroup (stratum) will be produced. Patients will be stratified on the basis of the following prognostic factors:
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed diagnosis of clinical stage IIIB, IIIC, and IIID (AJCC 8th edition) locoregional melanoma that is eligible for complete surgical resection of all metastases (surgically resectable).
- •Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
- •Prior anti-tumor treatment for the primary melanoma lesion, including surgery and approved adjuvant treatments (e.g., radiotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitors, etc.) is allowed. Before enrollment in the study, a wash-out period of 6 weeks is required and toxicities from prior treatments should be resumed to Grade ≤
- •Males or females, age ≥ 18 years.
- •ECOG Performance Status/WHO Performance Status ≤
- •Life expectancy of > 24 months.
- •Absolute neutrophil count > 1.5 x 109/L.
- •Hemoglobin > 9.0 g/dL.
- •Platelets > 100 x 109/L.
- •Total bilirubin ≤ 30 μmol/L (or ≤ 2.0 mg/dl).
- •ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
- •Serum creatinine < 1.5 x ULN.
- •LDH serum level ≤ 1.5 x ULN.
- •Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (i.e. positive anti-HBsAg with not vaccination and/or positive anti-HBcAg Ab), negative serum HBV-DNA is also required.
- •All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above.
- •All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients in Arm 1).
- •Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
- •Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
- •Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
- •Exclusion Criteria
- •Uveal melanoma or mucosal melanoma
- •Evidence of distant metastases at screening.
- •Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except: cervical carcinoma in situ, curatively treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry.
- •Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
- •History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
- •Inadequately controlled cardiac arrhythmias including atrial fibrillation.
- •Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
- •LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
- •Uncontrolled hypertension.
- •Ischemic peripheral vascular disease (Grade IIb-IV).
- •Severe diabetic retinopathy.
- •Active autoimmune disease.
- •History of organ allograft or stem cell transplantation.
- •Recovery from major trauma including surgery within 4 weeks prior to enrollment.
- •Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
- •Breast feeding female.
- •Anti-tumor therapy (except small surgery) within 4 weeks before enrollment.
- •Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment.
- •Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment.
- •Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis will be evaluated case by case with the Sponsor for inclusion/exclusion in the study. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criteria.
- •Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
- •Previous enrolment and randomization in the same study.
排除标准
- 未提供
研究组 & 干预措施
Daromun plus Surgery and Adjuvant therapy
Experimental
Arm-1 patients will follow these steps:
- screening period,
- 4-week open-label treatment period,
- surgery within a maximum of 4 weeks,
- adjuvant therapy.
干预措施: Daromun (Drug)
Daromun plus Surgery and Adjuvant therapy
Experimental
Arm-1 patients will follow these steps:
- screening period,
- 4-week open-label treatment period,
- surgery within a maximum of 4 weeks,
- adjuvant therapy.
干预措施: Surgery (Procedure)
Daromun plus Surgery and Adjuvant therapy
Experimental
Arm-1 patients will follow these steps:
- screening period,
- 4-week open-label treatment period,
- surgery within a maximum of 4 weeks,
- adjuvant therapy.
干预措施: Adjuvant therapy (Drug)
Surgery and adjuvant therapy
Active Comparator
Arm-2 patients will follow these steps:
- Screening period,
- direct surgery within 4 weeks from randomization,
- adjuvant therapy.
干预措施: Surgery (Procedure)
Surgery and adjuvant therapy
Active Comparator
Arm-2 patients will follow these steps:
- Screening period,
- direct surgery within 4 weeks from randomization,
- adjuvant therapy.
干预措施: Adjuvant therapy (Drug)
结局指标
主要结局
Recurrence Free Survival (RFS)
时间窗: From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months.
Recurrence Free Survival (RFS) in a time-to-event analysis in the Daromun plus surgery and adjuvant therapy treatment group (Arm 1) versus the surgery and adjuvant therapy control group (Arm 2). Analysis will be performed for the "Intention To Treat" population.
次要结局
- Adverse Events (AE)(From the inclusion in the study (signature of the informed consent form - ICF) until the first follow-up visit (up to approximately 5 months).)
- Immune-related Adverse Events (irAEs)(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).)
- Drug-Induced Liver Injury (DILI)(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).)
- Adverse Events of Special Interest (AESI)(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).)
- Haematological/chemical Laboratory Abnormalities(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).)
- Overall survival (OS)(From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first, assessed up to 72 months.)
- Recurrence free survival (RFS) as determined by the local investigator(From date of randomization until the date of the first recurrence or date of death from any cause, whichever occurs first assessed up to 60 months.)
- Event-free survival (EFS)(From date of randomization until the date of the first event as described above, assessed up to 60 months)
- Electrocardiogram (ECG) and echocardiogram (ECHO) abnormalities(1) day 0-14 (screening) for both arm; 2) at week 5 (Safety assessment) only for arm 1.)
- Physical examination(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months))
- Concomitant medication(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months))
- Human anti-fusion protein antibodies (HAFA)(1) day 0-14 (screening) for arm 1; 2) at week 5 (Safety assessment) for Arm 1; 3) at week 12 (only first follow-up) for Arm 1.)
- Vital signs (blood pressure)(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months).)
- Vital signals (heart rate)(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months))
- Vital signals (body temperature)(From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 60 months))
- Pathological responses(Assessed at the time of surgical resection of the tumor lesions.)
研究者
研究点 (37)
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