高リスク血液悪性腫瘍に対する同種造血細胞移植後のドナーリンパ球注入
高リスク血液悪性腫瘍に対する移植後シクロホスファミドを使用した同種造血細胞移植後の移植後早期の予防的ドナーリンパ球注入を使用した第I/II相研究
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....
調査の概要
状態
条件
詳細な説明
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:
-Recipient Participant:
- Histologically or cytologically confirmed hematologic malignancy classified as high or very high disease risk by the Refined Disease Risk Index for HCT
- Age 18-65
- At least one potentially suitable human leukocyte antigen (HLA)-matched related or HLA-haploidentical donor.
- Karnofsky performance score >=60
- Adequate organ function
Design:
- Open-label, single-center, non-randomized, phase I/II study
- All recipient participants will receive myeloablative conditioning, HLA-matched-related or HLA-haploidentical bone marrow HCT, GVHD prophylaxis including post- transplantation cyclophosphamide, and prophylactic donor lymphocyte infusion
- There will be 2 cohorts of recipient participants: one with HLA-matched-related donors and one with HLA-haploidentical donors
- For HLA-matched HCT, the study will proceed to a small, three-level [1) DLI: 1 x 10^6 CD3+ cells/kg on day +7, 2) DLI: 3 x 10^6 CD3+ cells/kg on day +7, 3) DLI: 1 x 10^7 CD3+ cells/kg on day +7] phase I dose escalation study based on the standard 3+3 approach
- For HLA-haploidentical HCT, the study will proceed to a small, three-level [1) DLI: 1 x 10^5 CD3+ cells/kg on day +7, 2) DLI: 3 x 10^5 CD3+ cells/kg on day +7, 3) DLI: 1 x 10^6 CD3+ cells/kg on day +7] phase I dose escalation study based on the standard 3+3 approach
- Recipient participants will be evaluated for development of steroid-refractory grade III- IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity.
- Phase II will proceed with DLI at the dose level (separately determined for each HLA cohort) which is associated with 0-1 of 6 recipient participants with steroid refractory grade III-IV aGVHD at day +60 and the least amount of toxicity.
- Simon optimal two-stage phase II trial design, to rule out excess steroid refractory grade III-IV aGVHD with the addition of prophylactic DLI, will be used in the phase II portion of the study which will enroll an additional 14 evaluable subjects in each cohort.
研究の種類
入学 (推定)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究連絡先
- 名前：Christopher G Kanakry, M.D.
- 電話番号：(240) 760-6171
- メール：christopher.kanakry@nih.gov
研究連絡先のバックアップ
- 名前：Amy H Chai
- 電話番号：(240) 858-3755
- メール：amy.chai@nih.gov
研究場所
-
-
Maryland
-
Bethesda、Maryland、アメリカ、20892
- 募集
- National Institutes of Health Clinical Center
-
コンタクト：
- For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
- 電話番号：888-624-1937
-
-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
- 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.
EXCLUSION CRITERIA:
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:
None.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：順次割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
介入なし：Donor Arm
Donors for Recipients in Arms 1-4 |
|
|
実験的：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) |
The DLI will be given on Day +7 (Day +21 for dose level -1). If a recipient participant is deemed too critically ill/unstable to receive DLI on the protocol specified day, the DLI will be delayed up to 4 days at the discretion of the PI and given within this time frame once the recipient participant s clinical status has stabilized or improved. If the DLI cannot be given during this time frame, the recipient participant will be taken off study and not considered evaluable for DLT, outcomes, or adverse events since the experimental intervention will not have been given. HLA-matched: 50 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. HLA haploidentical: 25 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. AUC targeted dose based on busulfan test dose, with a default dose of 130 mg/m2/day, given as IV infusion over 3 hours each day for 4 days Transplant days -6 through day -3 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. 40 mg/m2 IV infusion over 30-60 minutes once daily for 4 days Transplant days -6 through -3 Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, maximum initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +70 with no taper. Doses should be modified as appropriate for drug interactions. |
|
実験的：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) |
The DLI will be given on Day +7 (Day +21 for dose level -1). If a recipient participant is deemed too critically ill/unstable to receive DLI on the protocol specified day, the DLI will be delayed up to 4 days at the discretion of the PI and given within this time frame once the recipient participant s clinical status has stabilized or improved. If the DLI cannot be given during this time frame, the recipient participant will be taken off study and not considered evaluable for DLT, outcomes, or adverse events since the experimental intervention will not have been given. HLA-matched: 50 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. HLA haploidentical: 25 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. AUC targeted dose based on busulfan test dose, with a default dose of 130 mg/m2/day, given as IV infusion over 3 hours each day for 4 days Transplant days -6 through day -3 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. 40 mg/m2 IV infusion over 30-60 minutes once daily for 4 days Transplant days -6 through -3 Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, maximum initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +70 with no taper. Doses should be modified as appropriate for drug interactions. |
|
実験的：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) |
The DLI will be given on Day +7 (Day +21 for dose level -1). If a recipient participant is deemed too critically ill/unstable to receive DLI on the protocol specified day, the DLI will be delayed up to 4 days at the discretion of the PI and given within this time frame once the recipient participant s clinical status has stabilized or improved. If the DLI cannot be given during this time frame, the recipient participant will be taken off study and not considered evaluable for DLT, outcomes, or adverse events since the experimental intervention will not have been given. HLA-matched: 50 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. HLA haploidentical: 25 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. AUC targeted dose based on busulfan test dose, with a default dose of 130 mg/m2/day, given as IV infusion over 3 hours each day for 4 days Transplant days -6 through day -3 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. 40 mg/m2 IV infusion over 30-60 minutes once daily for 4 days Transplant days -6 through -3 Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, maximum initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +70 with no taper. Doses should be modified as appropriate for drug interactions. |
|
実験的：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) |
The DLI will be given on Day +7 (Day +21 for dose level -1). If a recipient participant is deemed too critically ill/unstable to receive DLI on the protocol specified day, the DLI will be delayed up to 4 days at the discretion of the PI and given within this time frame once the recipient participant s clinical status has stabilized or improved. If the DLI cannot be given during this time frame, the recipient participant will be taken off study and not considered evaluable for DLT, outcomes, or adverse events since the experimental intervention will not have been given. HLA-matched: 50 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. HLA haploidentical: 25 mg/kg IV once daily over 2 hours on days +3 and +4a Cyclophosphamide will be dosed according to ideal body weight. AUC targeted dose based on busulfan test dose, with a default dose of 130 mg/m2/day, given as IV infusion over 3 hours each day for 4 days Transplant days -6 through day -3 15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight. 40 mg/m2 IV infusion over 30-60 minutes once daily for 4 days Transplant days -6 through -3 Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, maximum initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +70 with no taper. Doses should be modified as appropriate for drug interactions. |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
determine the maximally tolerated dose of DLI that can be safely administered after HLA-matched-related HCT and after HLA-haploidentical HCT
時間枠：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. |
60 days
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
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
時間枠：Day 100 and 200
|
To evaluate steroid-refractory grade II-IV and grade III-IV acute GVHD at day 100 and 200. |
Day 100 and 200
|
|
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
時間枠：1 year
|
To evaluate chronic GVHD |
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
時間枠：Day 100 and 200
|
To evaluate grade II-IV and grade III-IV acute GVHD at day 100 and 200. |
Day 100 and 200
|
|
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
時間枠：Day 100 and 1 year
|
To evaluate non-relapse mortality |
Day 100 and 1 year
|
|
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
時間枠：1 year
|
To evaluate relapse |
1 year
|
|
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
時間枠：1 year
|
To evaluate survival |
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
時間枠：Day 28 and 100
|
Rate and timing of neutrophil and platelet engraftment reported as median engraftment times for each and cumulative incidences of each at days +28 and +100 |
Day 28 and 100
|
協力者と研究者
捜査官
- 主任研究者：Christopher G Kanakry, M.D.、National Cancer Institute (NCI)
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
- 肺炎の組織化
- 部位別新生物
- 新生物
- 免疫系疾患
- 気道疾患
- 肺疾患
- 気管支疾患
- 肺疾患、閉塞性
- 血液疾患
- 閉塞性細気管支炎
- 細気管支炎
- 気管支炎
- 移植片対宿主病
- ヘミックおよびリンパ疾患
- 閉塞性細気管支炎症候群
- 血液腫瘍
- 硫黄化合物
- 有機化学物質
- 脂肪酸
- 脂質
- 炭化水素、非環式
- 炭化水素
- 酸、非環式
- カルボン酸
- アルカン
- アルコール
- ブチレングリコール
- グリコール
- メシル酸塩
- アルカンスルホン酸塩
- アルカンスルホン酸
- スルホン酸
- 硫酸
- マクロライド
- ラクトン
- ホスホルアミドマスタード
- 窒素マスタード化合物
- マスタード化合物
- 炭化水素、ハロゲン化
- ホスホラミド
- 有機リン化合物
- カプロート
- シロリムス
- シクロホスファミド
- ミコフェノール酸
- ブスルファン
- フルダラビン
その他の研究ID番号
- 10000489
- 000489-C
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP
IPD 共有時間枠
Clinical data available during the study and indefinitely.@@@@@@@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
IPD 共有アクセス基準
Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.
IPD 共有サポート情報タイプ
- STUDY_PROTOCOL
- SAP
- ICF
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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