Phase I/II Study Using Prophylactic Donor Lymphocyte Infusion Early Post-Transplant After Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide for High-Risk Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 430
- 试验地点
- 1
- 主要终点
- determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT
研究概览
简要总结
Background:
People with blood cancers often receive blood or bone marrow transplants. But even with these treatments, the risk of relapse is high. Researchers want to see if giving the transplant recipient an infusion of lymphocytes (a type of white blood cell) from their transplant donor early after the transplant can reduce that risk.
Objective:
To learn if giving donor lymphocytes early after a transplant will help reduce the risk of relapse for people with certain blood cancers.
Eligibility:
Adults aged 18-65 with high-risk leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma that does not respond well to standard treatments and/or has a high risk of relapse. Healthy potential bone marrow and lymphocyte donor relatives aged 12 and older are also needed.
Design:
Participants will be screened with:
Physical exam
Blood and urine tests
Spinal tap
Eye exam
Dental exam
Heart and lung tests
Imaging scans. A radioactive substance may be injected in their arm if a PET scan is needed.
Bone marrow aspiration and biopsy
Some screening tests will be repeated during the study.
Participants will stay at the NIH hospital for about 4 weeks. They will receive a central venous catheter. They will get chemotherapy and other drugs starting 6 days before transplant. Then they will have their transplant. They will receive donor white blood cells 7 days later. They will give blood, bone marrow, urine, and stool samples for research. They must stay near NIH for at least 100 days after transplant.
Participants will have periodic follow-up visits for 5 years.
Healthy donors will have 2-3 visits. They will give blood, bone marrow, white blood cells, and stool samples for research.
Participation will last for 5 years....
详细描述
Background:
- High-risk hematologic malignancies generally are incurable without an allogeneic hematopoietic cell transplant (HCT), but even HCT is associated with high risk of relapse and very poor overall survival.
- Prophylactic donor lymphocyte infusions (DLI) have been used to prevent relapse in high-risk diseases; preemptive DLIs have been used for MRD positivity or decreasing donor chimerism post-transplant; and, therapeutic DLIs have been used to treat overt morphologic relapse post-transplant.
- Prophylactic, preemptive, and therapeutic DLIs can cause significant graft-versus-host disease (GVHD), both acute and chronic, based on the dose of lymphocytes, timing of the infusion, and use of preparative chemotherapy, although these same factors also may impact on the therapeutic efficacy (graft-versus-tumor immunity of the DLI).
- Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) and the immunosuppressive burden after HCT.
- In pre-clinical HCT models, very large DLI doses can be given after PTCy, even as early as 24 hours after PTCy treatment, and significant GVHD is not induced, different from that seen for DLI infusions in mice treated with T-cell-depleted HCT, in which fatal GVHD is rapidly induced. This effect in PTCy-treated mice is dependent on Foxp3+ regulatory T cells.
- In patients treated at the NIH Clinical Center, DLI has been given for clinical reasons as early as 1 month post-transplant in PTCy-treated patients for infection, falling chimerism, or relapse and did not cause GVHD in these settings when additional conditioning was not given and T-cell-depleting antibodies were not used, both of which may disrupt the regulatory mechanisms induced after PTCy that are needed to control GVHD.
- The early integration of immunotherapeutic strategies, such as DLIs, after PTCy has the potential to prevent relapse in patients with high-risk hematologic malignancies, which may result in improved survival in such patients.
Objectives:
-To determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 120 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •INCLUSION CRITERIA:
- •Inclusion Criteria - Recipient:
- •Histologically or cytologically confirmed hematologic malignancy classified as high or very high disease risk by the Refined Disease Risk Index for HCT including one of the following:
- •Acute myeloid leukemia (AML) with favorable cytogenetics (t(8;21), inv(16), t(15,17)) with induction failure (persistent disease without first achieving remission of any type) or active relapse
- •AML with intermediate cytogenetics (not classified as favorable or adverse) with induction failure or active relapse (AML with intermediate cytogenetics in morphologic complete remission [CR] with minimal residual disease detectable by any modality also will be eligible)
- •AML with adverse cytogenetics (complex karyotype with >= 4 abnormalities) regardless of remission status
- •Low risk myelodysplastic syndrome (MDS) (<= 5% blasts, including chronic myelomonocytic leukemia) with adverse cytogenetics (abnormal chromosome 7 or >= 4 abnormalities) with induction failure or active relapse
- •High risk MDS (RAEB-1 or RAEB-2) with intermediate-risk cytogenetics (no abnormal chromosome 7 or < 4 abnormalities) with induction failure or active relapse
- •High risk MDS (RAEB-1 or RAEB-2) with adverse cytogenetics (abnormal chromosome 7 or < 4 abnormalities) regardless of remission status
- •Acute lymphoblastic leukemia (ALL) in CR >= 2 or with induction failure or active relapse (ALL in CR1 with minimal residual disease detected also will be eligible)
- •Chronic myelocytic leukemia (CML) in blast crisis phase
- •Hodgkin lymphoma with stable or progressive disease
- •Mantle cell lymphoma with stable or progressive disease
- •Relapsed Burkitt lymphoma in CR or partial remission (PR)
- •Aggressive B-cell Non-Hodgkin Lymphoma (NHL) (e.g., diffuse large B-cell lymphoma, transformed indolent B-cell lymphoma) with stable or progressive disease
- •T-cell NHL with stable or progressive disease
- •Multiple myeloma (MM) with induction failure as defined by failure to achieve minimal response (CR, Very Good Partial Response [VGPR], or PR) or the development of progressive disease on primary therapy, or MM with active relapse as defined by previously treated myeloma that achieved a molecular response or better that then progressed
- •Age 18-65 years.
- •At least one potentially suitable HLA-haploidentical or HLA-matched donor
- •Karnofsky performance score >60%, see Appendix A
- •Recipient participants must have adequate organ function as defined below:
- •Cardiac ejection fraction >=45% by 2D ECHO;
- •Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of >=50% predicted;
- •Estimated serum creatinine clearance of >=60 ml/minute/1.73m^2 calculated using eGFR in the clinical lab;
- •Total bilirubin <=2X the upper limit of normal;
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3X the upper limit of normal.
- •Myeloablative conditioning is toxic to the developing human fetus and is teratogenic. For this reason, the following measures apply:
- •-Women of child-bearing potential (WOCBP) and men must agree to use effective contraception (hormonal, surgical, IUD or barrier method of birth control; abstinence) from the start of conditioning regimen through at least one-year posttransplant. For the HLA haploidentical cohort the requirements are the same, however while taking sirolimus and for 12 weeks after the last dose, the birth control must be highly effective (hormonal, surgical, IUD, abstinence).
- •WOCBP must have a negative serum or urine pregnancy test within 7 days prior to enrollment.
- •Inclusion Criteria - Donor:
- •Related donor (age >=12) deemed suitable, eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, bone marrow, and stool for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation.
排除标准
- •Exclusion Criteria - Recipient:
- •Subjects who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 3 weeks prior to the date of beginning conditioning.
- •Prior myeloablative conditioning for autologous or allogeneic HCT.
- •Active breastfeeding.
- •Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is metastatic, relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment. This excludes non-melanoma skin cancers.
- •Uncontrolled intercurrent illness (e.g. severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance, active hepatitis, uncontrolled dental infection) that in the opinion of the PI would make it unsafe to proceed with transplantation.
- •Exclusion Criteria - Donor:
研究组 & 干预措施
Phase I Dose Escalation, Cohort 1 (matched)
DLI at escalating doses (1 x 10^6 CD3+ cells/kg, 3 x 10^6 CD3+ cells/kg, and 1 x 10^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Fludarabine (Drug)
Phase II Efficacy, Cohort 1 (matched)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Fludarabine (Drug)
Phase II Efficacy, Cohort 2 (haploidentical)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Busulfan (Drug)
Phase I Dose Escalation, Cohort 2 (haploidentical)
DLI at escalating doses (1 x 10^5 CD3+ cells/kg, 3 x 10^5 CD3+ cells/kg, and 1 x 10^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Fludarabine (Drug)
Donor Arm
Donors for Recipients in Arms 1-4
Phase I Dose Escalation, Cohort 1 (matched)
DLI at escalating doses (1 x 10^6 CD3+ cells/kg, 3 x 10^6 CD3+ cells/kg, and 1 x 10^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Sirolimus (Drug)
Phase I Dose Escalation, Cohort 2 (haploidentical)
DLI at escalating doses (1 x 10^5 CD3+ cells/kg, 3 x 10^5 CD3+ cells/kg, and 1 x 10^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Cyclophosphamide (Drug)
Phase I Dose Escalation, Cohort 2 (haploidentical)
DLI at escalating doses (1 x 10^5 CD3+ cells/kg, 3 x 10^5 CD3+ cells/kg, and 1 x 10^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Busulfan (Drug)
Phase I Dose Escalation, Cohort 2 (haploidentical)
DLI at escalating doses (1 x 10^5 CD3+ cells/kg, 3 x 10^5 CD3+ cells/kg, and 1 x 10^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Mycophenolate mofetil (Drug)
Phase II Efficacy, Cohort 1 (matched)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Cyclophosphamide (Drug)
Phase I Dose Escalation, Cohort 1 (matched)
DLI at escalating doses (1 x 10^6 CD3+ cells/kg, 3 x 10^6 CD3+ cells/kg, and 1 x 10^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Busulfan (Drug)
Phase I Dose Escalation, Cohort 1 (matched)
DLI at escalating doses (1 x 10^6 CD3+ cells/kg, 3 x 10^6 CD3+ cells/kg, and 1 x 10^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: donor lymphocyte infusion (Procedure)
Phase I Dose Escalation, Cohort 2 (haploidentical)
DLI at escalating doses (1 x 10^5 CD3+ cells/kg, 3 x 10^5 CD3+ cells/kg, and 1 x 10^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: donor lymphocyte infusion (Procedure)
Phase II Efficacy, Cohort 1 (matched)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: donor lymphocyte infusion (Procedure)
Phase I Dose Escalation, Cohort 1 (matched)
DLI at escalating doses (1 x 10^6 CD3+ cells/kg, 3 x 10^6 CD3+ cells/kg, and 1 x 10^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Cyclophosphamide (Drug)
Phase I Dose Escalation, Cohort 2 (haploidentical)
DLI at escalating doses (1 x 10^5 CD3+ cells/kg, 3 x 10^5 CD3+ cells/kg, and 1 x 10^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Sirolimus (Drug)
Phase II Efficacy, Cohort 1 (matched)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Busulfan (Drug)
Phase II Efficacy, Cohort 1 (matched)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Mycophenolate mofetil (Drug)
Phase II Efficacy, Cohort 1 (matched)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Sirolimus (Drug)
Phase II Efficacy, Cohort 2 (haploidentical)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Cyclophosphamide (Drug)
Phase II Efficacy, Cohort 2 (haploidentical)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Fludarabine (Drug)
Phase II Efficacy, Cohort 2 (haploidentical)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Mycophenolate mofetil (Drug)
Phase II Efficacy, Cohort 2 (haploidentical)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: Sirolimus (Drug)
Phase II Efficacy, Cohort 2 (haploidentical)
DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)
干预措施: donor lymphocyte infusion (Procedure)
Phase I Dose Escalation, Cohort 1 (matched)
DLI at escalating doses (1 x 10^6 CD3+ cells/kg, 3 x 10^6 CD3+ cells/kg, and 1 x 10^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)
干预措施: Mycophenolate mofetil (Drug)
结局指标
主要结局
determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT
时间窗: 60 days
fraction of evaluable patients who experience steroid-refractory grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals.
次要结局
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of chronic GVHD at 1 year for HLA-matched-related and HLA-haploidentical(1 year)
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of non-relapse mortality at 100 days and 1 year for HLA-matched-related and HLA-haploidentical(Day 100 and 1 year)
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of Steroid-refractory Grades II-IV and Grades III-IV aGVHD at days +100 and +200 for HLA-matched-related and HLA-haploidentical(Day 100 and 200)
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of overall survival (OS) and disease-free survival (DFS) at 1 year for HLA-matched-related and HLA-haploidentical(1 year)
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of Grades II-IV and Grades III-IV aGVHD at days +100 and +200 for HLA-matched-related and HLA-haploidentical(Day 100 and 200)
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of relapse at 1 year for HLA-matched-related and HLA-haploidentical(1 year)
- determine, at the maximally tolerated dose in the phase II portion of the study, the cumulative incidences of primary engraftment (including time to neutrophil and platelet engraftment) for HLA-matched-related and HLA-haploidentical(Day 28 and 100)