Phase 1/2: CD45RA Depleted Stem Cell Addback to Prevent Viral or Fungal Infections Post TCRab/CD19 Depleted HSCT

Официальное название

Phase 1/2 Study: CD45RA Depleted Peripheral Stem Cell Addback to Prevent Viral and Fungal Infections Following Alternative Donor TCRab/CD19 Depleted Hematopoietic Stem Cell Transplant

Обзор

The major morbidities of allogeneic hematopoietic stem cell transplant (HSCT) using donors that are not human leukocyte antigen (HLA) matched siblings are graft vs host disease (GVHD) and life- threatening infections. T cell receptor alpha beta (TCRαβ) T lymphocyte depletion and CD19+ B lymphocyte depletion of alternative donor hematopoietic stem cell (HSC) grafts is effective in preventing GVHD, but immune reconstitution may be delayed, increasing the risk of infections. The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral stem cell product depleted of CD45RA naïve T lymphocytes, will accelerate immune reconstitution and help decrease the risk of infections in TCRab/CD19 depleted PSCT.

Подробное описание

The risk of severe graft versus host disease (GVHD) is increased with the use of unrelated and partially matched related donors. T cell depletion reduces the risk of severe GVHD, but immune reconstitution is delayed. Important memory T cells that may protect patients from fungal and viral infections are also removed in the T depletion process. CD45RA depletion has been studied both as a single step to reduce the risk of GVHD, and also, in conjunction with αβTCR depleted hematopoietic stem cell grafts to accelerate immune reconstitution. This single institutional trial builds on data from our protocol #18-015286, NCT03810196, "CD45RA Depleted Peripheral Stem Cell Addback for Patients at Risk for Viral or Fungal Infections Post-TCRαβ/CD19 Depleted Hematopoietic Stem Cell Transplant". This prior protocol was limited to patients with hematologic malignancies using only unrelated donors as the stem cell source.

This new study will broaden the eligible diagnoses to include non-malignant transplant indications and participants with greater than or equal to 5/10 HLA matched related donors (also known as haploidentical).

This will be a phase 1 and phase 2 study depending on the donor type. Phase 1 will include patients receiving cells from mismatched/haploidentical related donors. This will be a dose escalation study to determine the maximum tolerated cell dose of the CD45RA depleted addback. Once that dose is determined, patients with this donor type will be treated as part of phase 2.

Patients receiving their cells from unrelated donors ( 9/10 or 10/10 HLA matched) will be treated as part of phase 2 with the CD45RA depleted addback cell dose that was used on our prior study. Phase 1 and phase 2 will run concurrently.

Вмешательства

• Устройство Phase 1 Dose Level 1
  Patients in the first dose level for the CD45RA depleted addback will receive 1 X 10\^6 CD45RO+ T cells/kg. Once all patients in this dose group have been evaluated for acute GVHD at day 100, then we will advance to the next dose level if indicated by safety analysis.
• Устройство Phase 1 Dose Level 2
  Patients in the second dose level for the CD45RA depleted addback will receive 2 X 10\^6 CD45RO+ T cells/kg. Once all patients in this dose group have been evaluated for acute GVHD at day 100, then we will advance to the next dose level if indicated by safety analysis.
• Устройство Phase 1 Dose Level 3
  Patients in the third and final dose level for the CD45RA depleted addback will receive 5 X 10\^6 CD45RO+ T cells/kg. All patients in this dose group will be evaluated for acute GVHD at day 100. Based on these findings, the maximum tolerated dose (MTD) will be determined. Once MTD for the addback cell dose has been determined in Phase 1, subjects with mismatched related donors will then enroll in Phase 2.
• Устройство Phase 2 Maximum Tolerated Dose determined in Phase 1
  Patients with mismatched related donors will receive the CD45RA depleted addback at the maximum tolerated dose determined in the Phase 1 portion of the study.
• Устройство Phase 2 Established Dose from prior study, NCT03810196
  Patients with unrelated donors will receive the CD45RA depleted addback at the dose 5 X 10\^6 CD45RO+ T cells.

Первичные конечные точки

• Evaluate number of patients with acute graft vs host disease (aGVHD) [Срок оценки: Up to 100 days post-transplantation]
• Evaluate number of patients with chronic graft vs host disease (cGVHD) [Срок оценки: Up to 2 years post-transplantation]

Вторичные конечные точки (2)

• Evaluate time to immune reconstitution [Срок оценки: 2 years]
• Evaluate number of patients with viral reactivation [Срок оценки: 2 years]

Критерии участия

Критерии включения

• Disease for which allogeneic HSCT may be curative.
• Remission status of hematologic malignancies and additional disease-specific eligibility determinations will be according to standards of practice within the CHOP Cellular Immunotherapy and Transplant Program (CTTS).
• Patients must be 25 years of age and less
• Evaluation for organ and infectious status as per our CTTS standard operating procedure.
• Signed consent by parent/guardian or able to give consent if 18 years of age and older.
• Participants of childbearing potential must have a negative pregnancy test as per institutional SOP.

Критерии исключения

• Patients who have performance score less than 60.
• No suitable donor available for mobilized peripheral stem cells.
• Patients with Hodgkin lymphoma or non-Burkitt, non-lymphoblastic lymphoma.
• Planned receipt of alemtuzumab during conditioning.
• Patients with an available 10/10 HLA matched sibling donor.
• Patients who do not meet institutional disease, organ or infectious criteria.

Donor selection and eligibility:

• Unrelated donor meets National Marrow Donor Program criteria for donation.
• Related donor (at least haploidentical) willing and able to donate mobilized peripheral stem cells.
• HLA testing/matching

• HLA testing to be done by molecular methods for A, B, C, DRB1, DQB1
• Related donor: Must be ≥ 5/10 match
• Unrelated donor: 10/10 or 9/10 match
• KIR typing for haploidentical donor for hematologic malignancies
• Donor specific HLA antibodies (DSA) should be assessed for all subjects receiving an HLA mismatched graft (≤ 9/10).
• Donor must be willing to undergo granulocyte colony stimulating factor (GCSF) mobilization and peripheral blood stem cell collection
• Donors must be willing to sign consent to participate in this study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Children's Hospital of Philadelphia — Philadelphia

Публикации

• Zvyagin IV, Mamedov IZ, Tatarinova OV, Komech EA, Kurnikova EE, Boyakova EV, Brilliantova V, Shelikhova LN, Balashov DN, Shugay M, Sycheva AL, Kasatskaya SA, Lebedev YB, Maschan AA, Maschan MA, Chudakov DM. Tracking T-cell immune reconstitution after TCRalphabeta/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017 May;31(5):1145-1153. doi: 10.1038/leu.2016.321. Epub 2016 PMID 27811849
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• Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H, Jain D, McNiff J, Shlomchik WD. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood. 2008 Feb 15;111(4):2476-84. doi: 10.1182/blood-2007-08-109678. Epub 2007 Nov 28. PMID 18045967
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• Bleakley M, Heimfeld S, Jones LA, Turtle C, Krause D, Riddell SR, Shlomchik W. Engineering human peripheral blood stem cell grafts that are depleted of naive T cells and retain functional pathogen-specific memory T cells. Biol Blood Marrow Transplant. 2014 May;20(5):705-16. doi: 10.1016/j.bbmt.2014.01.032. Epub 2014 Feb 11. PMID 24525279
• Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8. PMID 26053664
• Touzot F, Neven B, Dal-Cortivo L, Gabrion A, Moshous D, Cros G, Chomton M, Luby JM, Terniaux B, Magalon J, Picard C, Blanche S, Fischer A, Cavazzana M. CD45RA depletion in HLA-mismatched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study. J Allergy Clin Immunol. 2015 May;135(5):1303-9.e1-3. doi: 10.1016/j.jaci.2014.08.019. Epub 2014 Oct 3. PMID 25282016
• Triplett BM, Shook DR, Eldridge P, Li Y, Kang G, Dallas M, Hartford C, Srinivasan A, Chan WK, Suwannasaen D, Inaba H, Merchant TE, Pui CH, Leung W. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transplant. 2015 Jul;50(7):968-77. doi: 10.1038/bmt.2014.324. Epub 2015 Feb 9. PMID 25665048

Идентификаторы

NCT: NCT06839456 · 24-022264

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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