Phase I Study of Escalating Doses of Total Marrow and Lymphoid Irradiation (TMLI) Combined With Fludarabine and Melphalan as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With High-Risk Acute Leukemia or Myelodysplastic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Incidence of toxicity
研究概览
简要总结
This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor stem cell transplant in treating participants with high-risk acute leukemia or myelodysplastic syndrome. Giving chemotherapy, such as fludarabine and melphalan, and total marrow and lymphoid irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of total marrow and lymphoid irradiation (TMLI) with fixed doses of fludarabine and melphalan (FM100) as a preparative regimen in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) and who are not eligible for standard myeloablative regimens, with either a matched donor (Arm A) or a haploidentical donor (Arm B).
II. To describe toxicities attributable to TMLI by dose level in patients treated under this regimen.
SECONDARY OBJECTIVES:
I. To evaluate the safety of the regimen, at each dose level, by assessing the following: type, frequency, severity, attribution, time course and duration of adverse events, including acute/chronic graft versus host disease (GVHD), infection and delayed engraftment.
研究设计
- 研究类型
- 干预性
- 分配方式
- 不适用
- 干预模型
- 单组
- 主要目的
- 治疗
- 盲法
- 开放（无盲法）
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- Eligible patients with a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories:
- Acute myelogenous leukemia:
- Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5, 5q-, -7, 7q-, 11q23-non t (9;11), inv (3), t (3;3),t (6;9), t (9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease
- Patients with active disease
- Patients with chemosensitive active disease
- Acute lymphocytic leukemia:
- Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (< 44 chromosomes); t (v;11q23): MLL rearranged; t (9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p
- Patients with active disease
- Patients with chemosensitive active disease
- Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories
- Acute myelogenous leukemia:
- Patients ≥ 12 years and < 55 years are also included if they are not candidates for myeloablative conditioning regimens due to comorbidities
- Karnofsky or Lansky performance status of ≥ 70
- A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute
- Patients must have a serum bilirubin ≤ 2.0 mg/dl
- Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal
- Ejection fraction measured by echocardiogram or multigated acquisition (MUGA) ≥ 50%
- Carbon monoxide diffusing capacity (DLCO) and forced expiratory volume FEV1 > 50% predicted
- PATIENT-SPECIFIC INCLUSION CRITERIA
- Patients should have discontinued all previous intensive therapy, chemotherapy or radiotherapy for 2 weeks prior to commencing therapy on this study
- NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs); FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
- All patients with prior radiation treatment to the lung, liver, and kidney will be excluded; for other scenarios of prior radiation treatment, up to 2000 cGY at 2 gray Gy per day will be allowed; inclusion of patients with previous radiation exposure will be determined based on the radiation oncologist MD evaluation and judgment
- DONOR: Arm A: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate primed blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor; DQ or DP mismatch is allowed per discretion of the principal investigator
- DONOR: Arm B: The recipient must have a related donor genotypically HLA-A, B, C and DRB1 loci haploidentical to the recipient; no HLA matched sibling or matched unrelated donor is available; DSA is allowed with desensitization done if recommended by donor selection committee (DSC) per City of Hope (COH) standard operating procedures (SOP)
- DONOR: Both arms: All donors in both arms should be evaluated and approved by DSC
排除标准
- Having any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
- Receiving any investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
- NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs), FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the regimen
- Patients with other malignancies are ineligible for this study, other than non-melanoma skin cancers
- The recipient has another medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery in which the opinion of the principal investigator would place the recipient at unacceptable risk
- Patients may not have had a prior autologous or allogeneic transplant
- Patients may not have received more than 3 prior lines of intensive chemotherapy, where the regimen intent was to induce remission
- In the opinion of the principal investigator (PI), the participant has a condition that will preclude them from complying with study treatment
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
- All subjects must have the ability to understand and the willingness to sign a written informed consent; they are to give voluntary written informed consent before performance if any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; cognitively impaired subjects will be included only if their guardian or legal representative agrees to sign the written informed consent
- DONOR: Donor selection for both arms must be approved by the donor selection committee
- DONOR: Evidence of active infection
- DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy or leukapheresis
- DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy could be harvested for bone marrow (BM) if safer for the donor and if approved by the principal investigator (PI)
- DONOR: Human immunodeficiency virus (HIV) positive
研究组 & 干预措施
Treatment (TMLI, fludarabine, melphalan)
Participants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
干预措施: Total Marrow Irradiation (Radiation)
Treatment (TMLI, fludarabine, melphalan)
Participants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (TMLI, fludarabine, melphalan)
Participants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
干预措施: Fludarabine (Drug)
Treatment (TMLI, fludarabine, melphalan)
Participants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
干预措施: Melphalan (Drug)
结局指标
主要结局
Incidence of toxicity
时间窗: Up to 2 years
Toxicity will be scored on both the Bearman scale and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5 scale. Toxicity information recorded in each patient will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity, and dose levels in each arm.
次要结局
- Event-free survival(From start of protocol therapy up to 2 years)
- Overall survival(From start of protocol therapy up to 2 years)
- Relapse/progression(From start of protocol therapy up to 2 years)
- Non-relapse mortality(Up to 2 years)
- Incidence of infection(Up to day 100 post-transplant)
- Neutrophil recovery(Up to 2 years)
- Acute graft versus host disease of grades 2-4 and 3-4(Up to 100 days post-transplant)
- Chronic graft versus host disease(Up to 2 years)
- Bone marrow (BM) residual damage(Up to 2 years)
- Immune reconstitution(Up to 2 years)
- Complete remission proportion(At day 30)
- Incidence of toxicities/adverse events (AEs)(Up to 100 days post-transplant)
- CD4+, CD8+ and CD56+16+(Up to 2 years)
研究者
研究点 (1)
标识符
- NCT 编号
- NCT03494569
- 其他研究编号
- 17505, NCI-2018-00497, 17505
日期
- 首次提交
- (8年前)
- 首次发布
- (8年前)
- 主要完成日期
- (11个月后)
- 研究完成日期
- (11个月后)
- 最近核实
- (29天前)
- 最近更新
- (前天)
监管与共享
- FDA 监管药物
- 是
- FDA 监管器械
- 否
- 是否有结果
- 否