Expanded/Activated Gamma Delta T-cell Infusion Following Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide

Официальное название

Phase I Study of Ex Vivo Expanded/Activated Gamma Delta T-cell Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide

Обзор

Gamma delta T-cells are part of the innate immune system with the ability to recognize malignant cells and kill them. This study uses gamma delta T-cells to maximize the anti-tumor response and minimize graft versus host disease (GVHD) in leukemic and myelodysplastic patients who have had a partially mismatched bone marrow transplant (haploidentical).

Подробное описание

Many patients with hematological malignancies require a bone marrow transplant for curative treatment. A matched sibling donor is optimal but may not be available. Therefore, a partially matched family member (haploidentical) may be a viable alternative. The incidence of graft vs. host disease, however, can become more of a significant, even fatal, factor with partial matches.

T-cells have been shown to be the key player in the post-transplant immune phenomena. The majority of T-cells are composed of alpha beta T-cells with a small minority of gamma delta T-cells, which are known to have the unique ability to kill malignant cells without antigen recognition.

This study proposes to extract, concentrate, and activate gamma delta T-cells from the peripheral blood to provide innate anti-tumor effect with minimal risk of GVHD. Safety and impact and/or the rate of GVHD will be evaluated.

Вмешательства

• Препарат EAGD T-cell infusion (Phase I)
  The Alpha Beta (α/β) T-Cell Depletion System utilizes the CliniMACS instrument to yield a gamma delta (γδ) enriched cell therapy product.
• Препарат EAGD T-cell infusion (Expansion)
  The Alpha Beta (α/β) T-Cell Depletion System utilizes the CliniMACS instrument to yield a gamma delta (γδ) enriched cell therapy product.

Первичные конечные точки

• Phase I - Dose-limiting toxicity (DLT) [Срок оценки: Baseline to Day 30]
• Phase I - Severe acute adverse events following infusion of EAGD T-cells [Срок оценки: Baseline to Day 100]
• Expansion phase - Rate of acute GVHD [Срок оценки: Baseline to Day 100]

Вторичные конечные точки (7)

• Expansion phase - Relapse following haploidentical HCT and PTCy with EAGD T-cell infusion [Срок оценки: Baseline to 100 days]
• Expansion phase - Non-relapse mortality following haploidentical HCT and PTCy with EAGD T-cell infusion [Срок оценки: Baseline to 100 days]
• Expansion phase - Overall survival following haploidentical HCT and PTCy with EAGD T-cell infusion [Срок оценки: Baseline to 100 days]
• Rate of one-year relapse-free survival (RFS) [Срок оценки: Baseline to one year]
• Rate of one-year non-relapse mortality (NRM) [Срок оценки: Baseline to one year]
• Rate of one-year overall survival (OS) [Срок оценки: Baseline to one year]
• Proportion of subjects with chronic GVHD at one year [Срок оценки: Baseline to one year]

Критерии участия

Критерии включения

The following criteria are used to enroll patients in the study before transplant.

• Patients with neoplastic hematological disorders with indication of allogeneic transplant according to the National Comprehensive Cancer Network (NCCN) or other standard guidelines as follows:

• Acute myeloid leukemia \[AML\] in morphologic complete remission with intermediate/high-risk features (per NCCN criteria) or relapsed disease
• Chronic myeloid leukemia \[CML\] in any chronic phase.
• Myelodysplastic syndrome \[MDS\] with intermediate/high risk features or refractory disease (with bone marrow blast count <10%).
• Acute lymphoblastic leukemia \[ALL\] in morphologic complete remission with high-risk features or relapsed disease.
• Negative test for donor-specific antibody within 28 days of starting conditioning regimen.
• Age Criteria: 19-65 years.
• Organ Function Criteria: The following organ function testing should be done within 35 days before study registration.

• Cardiac: Normal left ventricular ejection fraction (LVEF) (50% or above) as measured by MUGA or Echocardiogram.
• Pulmonary: FVC, FEV1 and DLCO (corrected) should be 50% or above of expected.
• Renal: serum creatinine level to be <2 mg/dl AND estimated (Cockcroft-Gault formula) or measured (takes priority if done) creatinine clearance (CrCl) must be equal or greater than 70 mL/min/1.73 m2.
• Hepatic: serum bilirubin 1.5 upper limit of normal (ULN), Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 ULN, and alkaline phosphatase 2.5 ULN.
• Performance status: Karnofsky performance score (KPS) or Lansky score: ≥80.
• Hematopoietic cell transplant comorbidity index (HCT-CI) <3. Exception may be made on individual cases after discussion with the primary investigator.
• Consent: All patients must be informed of the investigational nature of this study and given written informed consent in accordance with institutional and federal guidelines.

The following criteria are required within 48 hours prior to infusion of the EAGD T cell product.

• Absence of uncontrolled infection with sepsis syndrome (e.g persistent positive blood culture).
• NO hemodynamic instability (due to sepsis or organ dysfunction) or circulatory volume overload.
• NO clinically significant organ toxicity that are defined as follows:

• Heart failure with subnormal LVEF or clinical fluid overload.
• Elevated serum creatinine or subnormal creatinine clearance (either estimated or measured).
• Elevated total bilirubin ≥1.5 upper normal level (unless indirect hyperbilirubinemia attributed to non-hepatic pathology), or elevated liver enzymes (ALT, AST, ALP) >5 x ULN.
• Hypoxemia requiring oxygen therapy
• NO acute graft versus host disease (any grade).
• Neutrophil engraftment.

Критерии исключения

• Non-compliant patients.
• No appropriate caregivers identified.
• Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician).
• Active central nervous system (CNS) neoplastic involvement.
• Morbid obesity with body mass index >35 (borderline cases may be considered on case-by-case basis after discussion with the primary investigator).
• Patients with known allergy to DMSO.
• HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive.
• Pregnant or breastfeeding women.

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 · 2 центра

• University of Kansas Cancer Center — Westwood
• Ohio State University Medical Center — Columbus

Идентификаторы

NCT: NCT03533816 · IIT-2018-Gamma-DeltaTcell

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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