NCT04959175

招募中

1 期

Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies

National Cancer Institute (NCI)3 个研究点分布在 1 个国家目标入组 320 人2021年9月23日

干预措施Allogeneic HSCT Mesna Cyclophosphamide Total Body Irradiation (TBI)Mycophenolate Mofetil Fludarabine Sirolimus Filgrastim

概览

阶段: 1 期
干预措施: Allogeneic HSCT
疾病 / 适应症: Hematologic Neoplasms
发起方: National Cancer Institute (NCI)
入组人数: 320
试验地点: 3
主要终点: determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60
状态: 招募中
最后更新: 4天前

概览研究者入排标准研究组 & 干预措施结局指标研究点相似试验

概览

简要总结

Background:

Certain blood cancers can be treated with blood or bone marrow transplants. Sometimes the donor cells attack the recipient's body, called graft-versus-host disease (GVHD). The chemotherapy drug cyclophosphamide helps reduce the risk and severity of GVHD. Researchers want to learn if using a lower dose of cyclophosphamide may reduce the drug's side effects while maintaining its effectiveness. Such an approach is being used in an ongoing clinical study at the NIH with promising results, but this approach has not been tested for transplants using lower doses of chemotherapy/radiation prior to the transplant.

Objective:

To learn if using a lower dose of cyclophosphamide will help people have a successful transplant and have fewer problems and side effects.

Eligibility:

Adults ages 18-85 who have a blood cancer that did not respond well to standard treatments or is at high risk for relapse without transplant, and their donors.

Design:

Participants may be screened with the following:

Medical history

Physical exam

Blood and urine tests

Heart and lung tests

Body imaging scans (they may get a contrast agent)

Spinal tap

Bone marrow biopsy

Participants will be hospitalized for 4-6 weeks. They will have a central venous catheter placed in a chest or neck vein. It will be used to give medicines, transfusions, and the donor cells, and to take blood. In the week before transplant, they will get 2 chemotherapy drugs and radiation. After the transplant, they will get the study drug for 2 days. They will take other drugs for up to 2 months.

Participants must stay near NIH for 3 months after discharge for weekly study visits. Then they will have visits every 3-12 months until 5 years after transplant.

Participants and donors will give blood, bone marrow, saliva, cheek swab, urine, and stool samples for research.

详细描述

Background: With novel therapies for hematologic malignancies, an increasing number of older and/or less fit patients are achieving remissions, but these new therapies are not curative, making consolidation approaches with curative intent such as allogeneic transplantation necessary. Frailty is a phenotype that predicts a patient s intolerance of physiologic stressors and may predict a patient s tolerance of intensive consolidative strategies. Frailty phenotype, though increasing in incidence in older patients, can occur in younger patients and may predict poor survival after allogeneic transplantation. We have yet to define the ideal allogeneic transplantation regimen for older patients or those with frailty or pre-frail phenotypes. Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-matched-related, HLA-matched-unrelated, HLA-mismatched-unrelated, and HLA-haploidentical HCT; it has become the most widely adopted change to transplantation platforms over the last decade. When clinically translated, the dose (50 mg/kg/day) of PTCy used was partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and was partly empirical. In both MHC-haploidentical and MHC-disparate murine HCT models, a dose of 25 mg/kg/day was superior to 50 mg/kg/day on days +3 and +4 in terms of GVHD severity and mortality. Lower dosing of PTCy also was associated with less broad reductions of T-cell numbers after PTCy and lower toxicity than higher dosing. In patients on an NIH study using myeloablative conditioning, a dose of 25 mg/kg/day has been associated with more rapid engraftment and potentially better immune function without an increase in severe acute GVHD. Objectives: Determine whether PTCy 25 mg/kg on days +3 and +4 can maintain adequate protection against grade III-IV acute GVHD and reduce toxicity associated with transplantation in older and/or unfit transplant recipients receiving reduced intensity conditioned allogeneic HCT. Determine the frailty measures associated with outcomes after allogeneic transplantation. Eligibility: Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation. Age 60-85 years, or age 18-60 years and unfit for myeloablative conditioning (MAC). At least one potentially suitable HLA-matched related, HLA-haploidentical donor, HLA-matched unrelated, or \>=5/10 HLA-mismatched unrelated donor. Karnofsky performance score \>=60 Adequate organ function Design: Open-label, multi-center, non-randomized, phase I/II study There will be four separate arms: HLA-matched elderly, HLA-matched young/infirm, HLA-partially matched elderly, and HLA-partially matched young/infirm All subjects will receive nonmyeloablative conditioning consisting of fludarabine, cyclophosphamide, and total body irradiation; GVHD prophylaxis with PTCy 25 mg/kg on days +3 and +4, MMF, and sirolimus; and bone marrow as the stem cell source Subjects will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicities for the Simon two-stage design. Dose escalation of PTCy will be permitted within each arm if stopping rules are met at the 25 mg/kg/day on days +3 and +4 dose. Frailty assessments will be performed prior to transplantation conditioning and serially after allogeneic transplantation.

注册库

clinicaltrials.gov

开始日期

2021年9月23日

结束日期

2027年4月30日

最后更新

4天前

研究类型

Interventional

研究设计

Sequential

性别

All

研究者

发起方

National Cancer Institute (NCI)

责任方

Sponsor

入排标准

入选标准

•INCLUSION CRITERIA - Recipient
•Subjects must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including, but not limited to, one of the following:
•Acute myeloid leukemia in morphologic complete remission (\<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
•B-cell acute lymphoblastic leukemia in first or subsequent complete remission
•T-cell acute lymphoblastic leukemia in first or subsequent complete remission
•Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)
•Primary myelofibrosis of intermediate-2 or higher risk by the DIPSS
•Chronic myelomonocytic leukemia
•Chronic myelogenous leukemia resistant to or intolerant of \>=3 tyrosine kinase inhibitors or with history of accelerated phase or blast crisis
•B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment, after autologous transplantation or has progressed through at least 2 lines of therapy

排除标准

•Recipient:
•Subjects who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 2 weeks prior to the date of beginning conditioning.
•Poorly controlled malignant indication for transplantation such as:
•Leukemia not having achieved morphologic remission (i.e. bone marrow blasts \>5% or active extramedullary disease)
•Lymphoma not having achieved at least a partial response to prior chemotherapy or radiation
•Uncontrolled intercurrent illness that in the opinion of the site PI would make it unsafe to proceed with transplantation.
•The potential for some of the study medications to be transmissible via breast milk of nursing mothers is unknown. Because there is unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding must be discontinued.
•Active malignancy of non-hematopoietic type which is: metastatic, relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment, or limited disease treated with curative intent treatment within the last 2 years. This excludes nonmelanoma skin cancers.
•INCLUSION CRITERIA - Donor:
•Related (age \>=12) and unrelated (age \>=18) donors deemed eligible (i.e., evaluated at NIH in accordance with existing institutional Standard Policies and Procedures or evaluated per the standards required by the IRB of the National Marrow Donor Program or applicable registry), and willing to donate research samples will be included.

主要结局

determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60

时间窗: 60 days

The fraction of evaluable patients who experience grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals. In addition, a cumulative incidence curve for this endpoint will be constructed.

次要结局

Grade II-IV acute GVHD at day 100 and 200(100 days/200 days)
Overall survival, progression-free survival, and disease-free survival at one year(1 year)
Rate of Fried s Frailty Phenotypes (FP)(1 year)
Chronic GVHD at one year(1 year)
Progression/relapse at one year(1 year)
Non-relapse mortality at 100 days and one year(100 days and 1 year)
Grade III-IV acute GVHD at day 100 and 200(100 days/200 days)
Estimation of platelet engraftment, neutrophil engraftment.(day 28 and day 100)