A Phase I Study of CYT107 (Recombinant Glycosylated Human IL-7) in Recipients of HLA Matched Ex Vivo T Cell Depleted Bone Marrow or Peripheral Blood Stem Cell Transplant
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Toxicity of CYT107 in post-transplant patients with AML, CML and MDS using the NCI Common Toxicity Criteria version 3.0 with the BMT specific adverse event grading system.
研究概览
简要总结
This is a phase I inter-patient dose escalation open labeled study assessing multiple doses of CYT107 in patients of at least 15 years of age, who are recipients of HLA matched ex vivo T cell depleted bone marrow or peripheral blood stem transplants.
The dose escalation design is aimed at establishing the absence of significant toxicity and to define a biologically active dose in this patient population.
At each dose level, eligible patients will receive 3 doses of CYT107 injected subcutaneously (under the skin of the arm, legs, or stomach) once a week for 3 weeks.
Groups of three patients will be entered at each dose level of CYT107. Three dose levels are planned: 10 mcg/kg/week, 20 mcg/kg/week and 30 mcg/kg/week. Three patients must complete day 42 of the study at a dose level without a dose limiting toxicity (DLT) before there is escalation to the next dose level.
详细描述
Rationale: Delayed and deficient reconstitution of T cells and their functions are a major obstacle to the success of a hematopoietic stem cell transplant (HSCT). CYT-107 may have potential clinical use after allogeneic HSCT to enhance lymphoid reconstitution which could have a number of beneficial effects including decreased morbidity and mortality from post-transplant infections. Our preliminary data with a previous generation IL-7, CYT 99 007, raise the possibility that IL-7 could have, in some cases, an anti-GVHD effect while keeping the anti-tumor effect of the allograft intact.
Primary Objective:
- To determine the safety and a recommended dose of CYT107 (r-hIL-7) in recipients of an HLA-matched related or unrelated ex vivo T-cell-depleted bone marrow (BM) or peripheral blood stem cell (PBSC) transplant after initial engraftment and hematopoietic reconstitution.
- If toxicities are encountered, to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).
Secondary Objectives:
- To define the pharmacokinetics of escalating doses of CYT107 in recipients of allogeneic transplants.
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
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to read consent form and give informed consent.
- •At least 15 years old.
- •Histologically confirmed non-lymphoid hematological malignancy.
- •Recipient of T cell depleted bone marrow (BM) or peripheral blood stem cell (PBSC) transplant from a 6/6 HLA (A, B, DR by intermediate resolution) identical related or unrelated donor after myeloablative conditioning.
- •Received TCD HCT containing < 1x105 CD3+ T cells/kg of recipient.
- •Patient included in at least one of the following categories:
- •AML in 2nd or greater complete remission.
- •High-risk AML (high-risk cytogenetics, undifferentiated leukemia, secondary AML, antecedent MDS) in 1st remission.
- •CML in 2nd or greater chronic phase, 2nd or greater accelerated phase.
- •MDS intermediate or high risk by IPSS criteria.
- •History of opportunistic infection (CMV viremia requiring anti-viral therapy, PCP pneumonia, mycobacterial infection, herpes zoster, viral respiratory infection (influenza, RSV, para-influenza), etc.
- •CD4+ T cell count < 100 at 6 months post-transplant.
- •At high risk for opportunistic infection (e.g., history of treated invasive fungal infection prior to the transplantation, positive CMV serology in patient, or positive toxoplasmosis serology in donor and patient, etc.).
- •60 - 210 days post transplant.
- •In remission at the time of initiation of CYT
- •Documented engraftment with sustained neutrophil counts of at least 1000/mcl and untransfused platelet counts > 20 000/mcl for 3 consecutive lab values (the last one tested <10 days before initiation of treatment) on 3 different days prior to treatment. Patients who have engrafted but require G-CSF for myelosuppressive antibiotics or antiviral medications are eligible if they require G-CSF no more than twice weekly and their ANC remains >1000/mcl.
- •KPS > 60%.
- •Adequate organ function:
- •Cardiac: No evidence of change in cardiac function by history, exam and/or EKG post-HCT.
- •Pulmonary: Absence of dyspnea or hypoxia (< 90% of saturation by pulse oxymetry on room air).
- •Hepatic: Bilirubin <= 1.5 X ULN, AST (SGOT) and /or ALT (SGPT) <= 2.5 X ULN. PT/PTT < 1.5 X ULN.
- •Renal: Calculated Creatinine clearance > 60 mL/min/1.73 m
- •[Note: all transplant patients had an ejection fraction of > 40% on their pre-transplant echocardiogram and a DLCO > 50% of predicted (corrected for hemoglobin)]
排除标准
- •No evidence or history of acute GVHD or of chronic GVHD.
- •No recurrent leukemia post HCT.
- •No active uncontrolled viral, bacterial or fungal infection.
- •No documented HIV-1 or -2, HBV or HCV infection at any time before or after transplant (a positive hepatitis B serology indicative of a previous immunization is not an exclusion criteria).
- •Not be receiving systemic corticosteroid, anti-mitotic agent or other immunosuppressive treatment.
- •Not receiving Growth Hormone or gonadotropin agonists/ antagonists.
- •Not receiving any cytokine support other than G-CSF post-HCT.
- •Not receiving concurrent treatment with another investigational drug and/or biological agent.
- •Not receiving anticoagulant therapy.
- •No uncontrolled hypertension.
- •No history of lymphoid malignancy (e.g. Hodgkin disease, non Hodgkin lymphoma, Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia) or acute biphenotypic leukemia.
- •No peripheral lymphadenopathy (any lymph node > 1 cm).
- •No history of EBV associated lymphoproliferation.
- •No EBV viremia equal to or greater than 500 copies EBV DNA/mL of blood by quantitative PCR.
- •No history of autoimmune disease nor a HCT donor with a history of an autoimmune disease.
- •Fertile patients must use effective birth control. Not pregnant or nursing. Negative pregnancy test within 2 weeks of study treatment.
- •QTc prolongation (QTc > 470 ms) or prior history of significant arrhythmia or ECG abnormalities.
- •No active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
- •Any past or current psychiatric illness that, in the opinion of the investigator, would interfere with adherence to study requirements or the ability and willingness to give written informed consent.
研究组 & 干预措施
I
Single arm dose escalation study. Three successive cohorts of 3 patients each. Doses to be evaluated: 10, 20, and 30 mcg/kg/dose for 3 consecutive doses.
CYT107 is a recombinant protein belonging to the class of growth factors known as cytokines.
CYT107 is a heavily glycosylated and sialylated form of recombinant human Interleukin-7.
CYT107 is supplied as a sterile colorless liquid at a concentration of 4 mg/ml.
干预措施: CYT107 - Recombinant glycosylated human interleukin 7. (Drug)
I
Single arm dose escalation study. Three successive cohorts of 3 patients each. Doses to be evaluated: 10, 20, and 30 mcg/kg/dose for 3 consecutive doses.
CYT107 is a recombinant protein belonging to the class of growth factors known as cytokines.
CYT107 is a heavily glycosylated and sialylated form of recombinant human Interleukin-7.
CYT107 is supplied as a sterile colorless liquid at a concentration of 4 mg/ml.
干预措施: rhIL-7 (CYT107) (Drug)
结局指标
主要结局
Toxicity of CYT107 in post-transplant patients with AML, CML and MDS using the NCI Common Toxicity Criteria version 3.0 with the BMT specific adverse event grading system.
时间窗: Visits: 2 week screening period; treatment visits on days 0, 7, and 14; non-treatment visits on Days 1, 21, 28, 42, 56, and 77.
次要结局
- Pharmacokinetics and Pharmacodynamics(Study days 0, 1, 7, 14, 21, 28, 42, and 77.)