A Phase 1 Study of MONALIZUMAB (IPH2201), a Humanized Anti CD94/NKG2A Monoclonal Antibody (Mab) Initiated 2 Months After an HLA Matched Allogenic Stem Cell Transplantation (SCT) Prepared With a Reduced Intensity Conditioning
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Occurence ratio of dose-limiting toxicity (DLT)
研究概览
简要总结
This study will determine the Maximal Tolerated Dose if any and the recommended dose for phase 2 of monalizumab, a monoclonal antibody directed against the CD94/NKG2A receptor, after allogenic stem cell transplantation. All patients will receive one single intravenous administration of one of the four doses of monalizumab.
详细描述
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative option for most of hematological malignancies, though the graft-versus-tumor (GVT) effect mediated by immune cells from the donor. However, the use of Allo-HSCT is limited by its toxicity, notably the graft-versus-host disease (GVHD) that is a major cause of non-relapse mortality (NRM). Conditioning regimens dramatically improved during the last fifteen years, with a decrease of both GVHD and NRM rates. Now, disease recurrence after Allo-HSCT is the first cause of treatment failure and remains a concern for approximately 30% of the patients.
Based on a safety immunologic platform (ATG based reduced toxicity conditioning regimens), it is needed to develop post Allo-HSCT strategies to decrease the incidence of relapse. In this context, the modulation of immune cell activity could play a role to prevent relapse. NK cells have a unique capacity to exert potent GVT effects without inducing GVHD. Moreover, NK cells recovery occurs early after Allo-HSCT and NK cells function are not severely impaired by the use of ciclosporin A, that is given for few months after Allo-HSCT as GVHD prophylaxis. Thus, NK cell modulation appears as a viable option for early immune intervention after Allo-HSCT.
Monalizumab (IPH2201), a monoclonal antibody has a non-depleting and purely blocking activity directed with high affinity and specificity against the CD94/NKG2A receptor expressed by subsets of NK cells, activated αβ CD8+ T cells, γδ-T cells and NK T cells. By suppressing the inhibitory signal transduced by NKG2A, IPH2201 enhances the anti-tumor functions, including cytolytic activity of these immune effector cells.The aim of the study is to determine the safety of IPH2201 after allogenic stem cell transplantation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patients presenting a hematological malignancy (acute myeloid leukemia, acute lymphoblastic leukemia, High risk R-IPSS myelodysplastic syndromes, multiple myeloma, chronic lymphoid leukemia, chronic myeloid leukemia, myeloproliferative neoplasm, Hodgkin lymphoma or Non-Hodgkin lymphoma) treated by allogeneic HSCT according to the following parameters :
- •Donor : HLA matched related or unrelated (10/10) donor
- •Graft : peripheral blood stem cells
- •Conditioning : All types of conditioning reduced toxicity conditioning regimens ATG as in-vivo T-cell depletion
- •GVHD prophylaxis by cyclosporine, still ongoing at full dose at the time of the inclusion
- •Patient being in one of the following post-graft situation at the time of inclusion:
- •Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) patients: in morphological complete remission (CR) with less than 5% bone marrow blast count.
- •High risk R-IPSS myelodysplastic syndromes patients: with at least marrow CR with less than 5% marrow blast count.
- •Multiple myeloma patients: in at least very good partial response.
- •Chronic Lymphoid Leukemia patients: in CR.
- •Chronic Myeloid Leukemia patients: in hematological CR.
- •Myeloproliferative neoplasm patients: no criteria for disease in acceleration phase.
- •Hodgkin lymphoma or Non-Hodgkin lymphoma patients: in CR.
- •Age ≥ 18 and ≤ 70 years
- •ECOG = 0-1 or Karnofsky index ≥ 70%
- •Clinical laboratory values at screening
- •Calculated creatinine clearance (according to MDRD) > 50 ml/min/1.73 m2
- •Independence of red blood cell transfusion
- •Platelet count > 75 x 109/l
- •ANC > 1 x 109/l
- •Bilirubin < 1.5 ULN
- •ALT and AST < 3 ULN
- •Patients (male or female) who accept and are able to use contraceptive methods recognized as highly effective throughout the study and up to 5 months after the drug administration
- •Signed informed consent of the current clinical study, prior to any protocol-specific procedure
- •Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen
- •Non inclusion Criteria:
- •Previous history of grade ≥ II acute GVHD (Glucksberg classification)
- •Current active disease or positive serology for HIV before grafting, and/or HCV with detectable viremia and/ or HBV with positive Hbs Antigen.
- •Abnormal cardiac status with any of the following :
- •Ejection fraction (measured by ultrasound or radionuclide imaging) < 50%
- •Unstable angina
- •Myocardial infarction within the last 6 months
- •Presence or persistence of documented congestive heart failure (New York Heart Association functional classification III-IV)
- •Arrhythmia requiring treatment and which is not stabilized by the treatment.
- •QTc ≥ 450 ms (M) or 470 ms (F) (Bazett formula)
- •Previous other allogeneic hematopoietic transplantation or solid organ transplantation
- •Any other serious concurrent uncontrolled medical disorder within 4 weeks prior to IPH2201 administration
- •Use of systemic corticosteroids ongoing or within the last 1 week prior IPH2201 admin-istration
- •Use of any investigational agent within 3 months prior to first dosing (except procedure of conditioning regimen including registered drugs combinations, i.e. Busulfan and Fludarabine or Busulfan and Endoxan)
- •History of another malignancy (except, basal cell carcinoma of the skin, or in situ cervix carcinoma, or any other malignancy in complete remission for more than 3 years since the completion of the treatment). However in the case of leukemia or MDS a previous malignancy accountable for the present disease will not be an exclusion criteria if in complete remission for more than 2 years
- •Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
- •Pregnant or lactating women
排除标准
- 未提供
研究组 & 干预措施
Monalizumab
Monalizumab treatment will be initiated 75 to 100 days after hematopoietic stem cells transplantation. Patients will receive a single dose of monalizumab by intravenous route over 1 hour.
干预措施: Monalizumab (Drug)
结局指标
主要结局
Occurence ratio of dose-limiting toxicity (DLT)
时间窗: 4 weeks
The occurrence of any of these 3 events will lead to the reporting of a Dose Limiting Toxicity: * Any Grade ≥ 3 toxicity according to CTCAE attributable to IPH2201 administration, occurring within 4 weeks of IPH2201 administration and considered as relevant by the investigator * Any grade ≥ II acute GVHD requiring a treatment by systemic corticosteroids and occurring within 4 weeks of IPH2201 administration. * Any grade ≥ moderate chronic GVHD occurring within 4 weeks of IPH2201 administration.
次要结局
- Incidence of acute GVHD of each grade or chronic GVHD of each degree of severity(from D0 to Week 26 after administration of IPH2201 and at 1 year after transplantation)
- Probabilities of non-relapse mortality (NRM)(1 year after the administration of IPH2201)
- Cumulative incidence of relapse (CIR)(1 year after administration of IPH2201.)
- Probability of Disease Free Survival (DFS)(1 year after the administration of IPH2201)
- Probability of Overall survival (OS)(1 year after the administration of IPH2201)