A Pivotal Phase III, Open-label, Randomized, Controlled Multi-center Study of the Efficacy of L19IL2/L19TNF Neoadjuvant Intratumoral Treatment Followed by Surgery Versus Surgery Alone in Clinical Stage III B/C Melanoma Patients
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 214
- 试验地点
- 21
- 主要终点
- Recurrence-free survival (RFS) rate
研究概览
简要总结
Phase III, open-label, randomized, controlled multi-center study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment in Stage III B/C melanoma patients.
详细描述
Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via automated randomization system) in a 1:1 fashion to one of two different arms:
ARM 1:
Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). The whole volume of L19IL2/L19TNF will be distributed among all injectable lesions.
Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. For the new lesions the treatment period will not be extended beyond the pre-defined 4 week- treatment period with a clock start at the time of the first intralesional L19IL2/L19TNF injection. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.
Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician.
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
- 未提供
排除标准
- •Uveal melanoma, mucosal melanoma or melanoma with unknown primary.
- •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, 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 allowed treatments listed at point 3 of Inclusion criteria) within 4 weeks before enrollment.
- •Previous in vivo exposure to monoclonal antibodies for biological therapy (except allowed treatments listed at point 3 of Inclusion criteria) in the 6 weeks before enrollment.
- •Planned administration of growth factors or immunomodulatory agents (except allowed treatments listed at point 3 of Inclusion criteria) within 7 days before enrollment.
- •Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
- •Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
- •Previous enrolment and randomization in this same study.
研究组 & 干预措施
Arm 1: neoadjuvant + surgery
Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first).
Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.
干预措施: L19IL2 + L19TNF (Drug)
Arm 1: neoadjuvant + surgery
Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first).
Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation.
干预措施: Surgery (Procedure)
Arm 2: surgery alone
Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization.
干预措施: Surgery (Procedure)
结局指标
主要结局
Recurrence-free survival (RFS) rate
时间窗: 1 year after randomization
Recurrence-free survival (RFS) in the treatment arm (L19IL2/L19TNF plus surgery; Arm 1) versus control arm (Arm 2).
次要结局
- Overall survival (OS)(1year, 2years, 3years after randomization)
- Clinically Meaningful Changes in Vital Signs and Physical Examinations(up to 36 months)
- HAFA((1) At Day 1, (2) At Day 29, (3) After 3 months from surgery: Day 119 to Day 144)
- Local recurrence-free survival (LRFS)(1year, 2years, 3years after randomization and 1year after surgery)
- Distant metastasis-free survival (DMFS) rate(1year, 2years, 3years after randomization and 1year after surgery)
- Recurrence-free survival (RFS) rate(2years, 3years after randomization)
- Percentage of Participants With On-Study Adverse Events (AEs) and Serious Adverse Events (SAEs)(up to 3 years)
- Changes in absolute counts and relative percentages of lymphocytic subpopulations over time((1) At screening, (2) At Day of surgery: from Day 1 to Day 54, (3) After 3 months from surgery: Day 91 to Day 144)
- Percentage of Participants With Worst On-Study Hematological and Chemistry Abnormalities(up to 36 months)