Phase 1 Dose Escalation of Early Infusion of Zoledronic Acid in Combination With Increasing Low-dose of Interleukin-2 in Order to Expand Vγ9Vδ2 T Cells After T-replete Haplo-identical Allogeneic Stem Cell Transplantation (SCT)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- determine the maximum tolerated dose (MTD) of early administration of increasing doses of low-dose IL-2 in combination with a fixed dose of Zoledronic acid after haplo-SCT
研究概览
简要总结
Patients receiving haplo-SCT are at high-risk of relapse. Vγ9Vδ2 T cells exhibit is a well-known population able to exert cytotoxicity toward a large range of tumor in vitro or in vivo. Activating and expanding Vγ9Vδ2 T cells early after haplo-SCT by using a combination of Zoledronic acid and low-dose interleukine (IL) -2 may be of benefit for patients by reducing incidence of relapse. The optimal dose of IL-2 to use remains to be determined.
This will be a Phase 1 3+3 escalation study. Three to 15 patients are planned. It will be proposed to Patients who refuse to participate to have samples collected until day +70 to study immune and gamma/delta T cells reconstitutions after haplo-transplant.
详细描述
Zoledronic acid will be administered as a single dose according to marketing and regulatory authorization at the dose of 4 mg over 15 min intravenously at day+15 post-transplant. Zoledronic acid infusion must be stopped in case of grade 3/4 adverse events during infusion.
IL-2 will be administered at a unique low-dose level 5 days per week for 4 consecutive weeks from Monday to Friday subcutaneously . IL-2 has already marketing authorization for various indications.
Three IL2 levels will be tested:
Level 1: 2 millions UI/Infusion Level 2: 4 millions UI/Infusion Level 3: 6 millions UI/Infusion Zoledronic acid and IL2 have to start at day+15 if it is a Monday or the first Monday following day+15 in order to avoid administration on week-end.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 18-70 years old
- •Patients with a hematological disease eligible for a haplo-SCT using the Baltimore regimen as conditioning regimen (Luznik, BBMT, 2008) (See 5.1.2)
- •Patients with no HLA matched sibling or unrelated donors
- •ECOG <=2
- •Signed informed consent
- •Patient affiliated to or beneficiary of the National Health Service
- •Patients previously transplanted are eligible to the study
排除标准
- •Patients with a HLA matched sibling or unrelated donor
- •Active uncontrolled infections
- •HIV positive, active Hepatitis B or C
- •Childbearing or child-breastfeading women
- •Women or men without effective contraceptive barrier if needed
- •Left ventricular ejection fraction < 50% with no previous severe cardiopathy
- •Respiratory insufficiency defined as DLCO <40% of the corrected value
- •Creatinine clearance <50 ml/min
- •Serum bilirubin >2.5 or transaminases >5 fold of normal value except if due to the hematological disease
- •Previous or concurrent second malignancy except for adequately treated basal cell carcinoma of the skin, curatively treated in situ carcinoma of the cervix, curatively treated solid cancer, with no evidence of disease for at least 2 years
- •Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- •Participation at the same time in another study in which investigational drugs are used
- •Absence of written informed consent
- •Contra-indication to Zoledronic acid: known hypersensitivity to Zoledronic acid or other bisphosphonate or Zoledronic acid formulation (excipients)
- •Recent or programmed dental care
- •Contra-indication to IL-2: known hypersensitivity to IL-2 or IL-2 formulation (excipients)
- •No previous ou current use of zoledronic acid
研究组 & 干预措施
control group
no experimental treatment
experimental group
Zoledronic acid and IL-2 Zoledronic acid: 4 mg
Three IL2 levels will be tested:
Level 1: 2 millions UI/Infusion Level 2: 4 millions UI/Infusion Level 3: 6 millions UI/Infusion
干预措施: IL2 (Drug)
experimental group
Zoledronic acid and IL-2 Zoledronic acid: 4 mg
Three IL2 levels will be tested:
Level 1: 2 millions UI/Infusion Level 2: 4 millions UI/Infusion Level 3: 6 millions UI/Infusion
干预措施: Zoledronic Acid (Drug)
结局指标
主要结局
determine the maximum tolerated dose (MTD) of early administration of increasing doses of low-dose IL-2 in combination with a fixed dose of Zoledronic acid after haplo-SCT
时间窗: 28 days after the last injection of IL2
A dose-limiting toxicity (DLT) will be defined as: * non-hematological toxicity of grade 4, including grade 4 acute GVHD 4. * non-hematological toxicity of grade 3 non-reversible for \> 7 days or reappearance of the same grade 3 after reintroduction of IL2 in case of return to at least one grade 1. * an acute GVHD grade 2-3 for \> 7 days or reappearance of GVHD grade 2-3 acute GVHD after reintroduction of IL2 if at least grade 1 acute GVHD is restored. * a reappearance of a grade 3/4 IL2 allergic reaction after reintroduction of IL2 in the event of a return to at least grade 1 after the occurrence of an allergic reaction of grade 3/4 IL2 when of the administration. * grade 4 pancytopenia with hypocellular bone marrow (no disease detection) for \> 4 weeks after the last administration of IL2.
次要结局
- Chimerism (mixed, full or uncompleted)(day 30, 60,90/100, 6 months and 1 year post-transplant)
- overall survival(last patient follow up : 36 months)
- relapse rate(last patient follow up : 36 months)
- Complete remission (CR) rate for lymphoma patients(day 100 post transplant)
- Engraftment(day 30, 60,90/100, 6 months and 1 year post-transplant)
- disease-free survival(last patient follow up : 36 months)
- Perturbation of ionic metabolism(before the graft and at days 15, 22, 29, 36, 45, 70)
- g/d T cells detection after haplo-SCT(before the graft and at days 15, 22, 29, 36, 45, 70)
- Detection of dysthyroid disease(before the graft and at day 70)
- Non relapse mortality(day 100 post transplant and one year post-transplant)
- Incidence of acute GVHD(day 100 post transplant one year post-transplant)
- Hematologic and immune reconstitutions post-transplant(before the graft and at days 15, 22, 29, 36, 45, 70)
- Incidence of acute and chronic GVHD(one year post-transplant)