HLA-mismatched Allogeneic Cellular Therapy (HMMACT) After Chemotherapy in High Risk Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Induction mortality
研究概览
简要总结
This phase I trial studies the side effects of donor stem cell transplant in treating patients with high risk acute myeloid leukemia. Giving low doses of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells when they do not exactly match the patient's blood. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect)
详细描述
PRIMARY OBJECTIVES:
I. To assess the feasibility of cytarabine based chemotherapy and human leukocyte antigen (HLA)-mismatched allogeneic cellular therapy (HMMACT) in patients with high risk acute myeloid leukemia (AML), with feasibility measured by induction mortality (IM) and complete response rate.
SECONDARY OBJECTIVES:
I. To obtain preliminary estimates of clinical outcome following cytarabine based chemotherapy and HMMACT in patients with high risk AML, as measured by event free survival (EFS) and overall survival (OS).
II. To further evaluate the safety outcomes of induction and consolidation of cytarabine and HMMACT in terms of serious infections (grade 4), time to recovery of absolute neutrophil counts and platelets and incidence of graft versus host disease (GvHD).
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have a histologically and cytological confirmed acute myeloid leukemia, high risk AML defined as:
- •Age > 60, or
- •Presence of complex cytogenetic abnormalities (with > 3 cytogenetic abnormalities), del (7q, -5, -7), t(9,22), 11q(23) or high risk mutations by FISH eg MLL, FLT-3 +
- •Secondary AML, or
- •A white blood cell count of > 50 x10^9/L
- •Patients must be medically ineligible for allogeneic stem cell transplant (alloSCTx) or not have a known fully HLA matched sibling for planned sibling transplant.
- •Patients must have measurable or evaluable disease
- •Diagnosis of AML according to World Health Organization (WHO) diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with French-American-British Cooperative group (FAB) classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration and biopsy performed within 14 days prior to administration of 1st dose of remission induction chemotherapy; if a bone marrow aspirate and biopsy were obtained within 28 days prior to the first dose of remission induction therapy then these tests may be submitted for review at University of Southern California (USC) and a repeat screening bone marrow does not need to be conducted;
- •Cohort A: newly diagnosed AML, no prior cytotoxic chemotherapy
- •Cohort B: newly diagnosed AML, failed to achieve Complete remission (CR) with single standard Induction chemo.
- •Patient has at least one medically fit family member expected to be HLA mismatched at 1-9/10; more commonly and preferred: 4-6/10 loci (parent, sibling, niece/nephew, etc but adult children preferred)
- •Absolute neutrophil count (ANC) > 1500, unless due to direct bone marrow involvement of disease
- •Platelets > 75,000, unless due to direct bone marrow involvement of disease
- •Hemoglobin > 8.0 gm/dL, transfusion allowed
- •Serum creatinine < 2.0 x the upper limits of institutional normal (ULN)
- •Total bilirubin < 1.5 x the upper limits of institutional normal
- •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT )< 2.5 x the upper limits of institutional normal (=< 5 x ULN for patients with liver involvement of leukemia)
- •Cardiac left ventricular ejection fraction (LVEF) > 45%
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •Estimated survival of at least 3 months
- •Patients must be able to understand and agree to sign an Institutional Review Board (IRB)-approved informed consent form
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study, and for two months after study participation
- •DONOR: Donor screening; all donors will meet the standard blood donor criteria established by the participating local blood center, American Association of Blood Banks (AABB)
- •DONOR: Donors will be selected from among the subject's relatives, adult children preferred
- •DONOR: Infectious disease testing will be done per Hemacare policy and AAAB guidelines
- •DONOR: Donor and intended recipient red cell type and compatibility will be determined
- •DONOR: Donors will be pre-selected on the basis of HLA haploidentity
- •DONOR: If patient is cytomegalovirus (CMV)-negative, donors who are CMV-negative will be preferred; CMV serology of the donor will be tested prior to the allogeneic cell donation; donations from CMV-positive donors to CMV-negative recipients will be given if no CMV negative donor is available, and CMV surveillance and pre-emptive treatment given
排除标准
- •Cohort A: Patients who have received prior cytotoxic chemotherapy, such as anthracyclines and cytarabine not permitted; but prior treatment with demethylating agents (azacytidine or decitabine, lenalidomide, etc) ALLOWED.
- •Cohort B: Patients who have received prior fludarabine, clorarabine or drugs known to target T cells not permitted; but prior standard induction with anthracylines and cytarabine ALLOWED including after demethylating agents.
- •Have uncontrolled systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular or respiratory systems
- •Pregnant and/or lactating
- •Patients who have had non-biopsy surgery in the last 10 days
- •Active central nervous system (CNS) disease; patients with previously treated leptomeningeal disease without evidence of remaining leukemia cells by spinal fluid will be eligible
- •Known active autoimmune disorder
- •Known to be human immunodeficiency virus (HIV)-positive or have active hepatitis B or C
- •Patients concurrently taking the following drugs are excluded: mycophenolate, cyclosporine, prednisone > 20mg/day, or immunosuppressive agents
- •DONOR: Personal or family history of severe sickle cell disease or variant (unless donor has tested negative); testing for the presence of hemoglobin S is not required
- •DONOR: Positive infectious disease test as dictated by blood collection center's standard operating procedure (SOP)
- •DONOR: Current uncontrolled hypertension
- •DONOR: Diabetes mellitus
- •DONOR: Active peptic ulcer disease
- •DONOR: Pregnant or breast-feeding
- •DONOR: Currently taking lithium therapy
- •DONOR: History of autoimmune disease
- •DONOR: History of coronary disease
研究组 & 干预措施
Treatment (chemotherapy, G-PBSC)
INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-3 and cytarabine IV on days 1-7. HMMACT: Patients receive G-PBSC on day 9.
干预措施: mitoxantrone hydrochloride (Drug)
Treatment (chemotherapy, G-PBSC)
INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-3 and cytarabine IV on days 1-7. HMMACT: Patients receive G-PBSC on day 9.
干预措施: cytarabine (Drug)
Treatment (chemotherapy, G-PBSC)
INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-3 and cytarabine IV on days 1-7. HMMACT: Patients receive G-PBSC on day 9.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (chemotherapy, G-PBSC)
INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-3 and cytarabine IV on days 1-7. HMMACT: Patients receive G-PBSC on day 9.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Induction mortality
时间窗: Up to 8 weeks
Complete remission rate (complete remission [CR] or incomplete remission [CRi])
时间窗: Up to 3 years
Exact 95% confidence intervals will be constructed.
次要结局
- Occurrence of serious infections (grade 4) assessed using National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) v4.0(Up to 3 years)
- Time to recovery of absolute neutrophil counts (ANC)(From stem cell infusion to the first of 3 consecutive days in which the ANC is more than 0.5 x 10^9/L, assessed up to 3 years)
- Time to recovery of platelets(From stem cell infusion until the first of 3 consecutive days in which the platelet count is more than 30 x 10^9/L, assessed up to 3 years)
- Incidence of GvHD(Up to 3 years)
- Estimate of clinical outcome as measured by event free survival (EFS)(From the start of induction until documentation of failure to achieve a CR or CRi during induction, initiation of a salvage therapy, disease recurrence/progression (after induction), or death due to any cause, assessed up to 2 years)
- Estimate of clinical outcome as measured by overall survival (OS)(From the start of induction until death due to any cause, assessed up to 2 years)