Clinical trial NCT03533816: Expanded/Activated Gamma Delta T-cell Infusion Following Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide
Official title: Phase I Study of Ex Vivo Expanded/Activated Gamma Delta T-cell Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-transplant Cyclophosphamide
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Chronic Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndromes
Keywords: Gamma delta T-cells
Hematopoietic Stem Cell Transplantation (HCT)
Post-transplant Cyclophosphamide (PTCy)
Expanded/Activated gamma delta (EAGD)
Graft versus host disease (GVHD)
haploidentical
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
Collaborators: name: In8bio Inc.
First posted: 2018-05-23
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This dose escalation study will be conducted in two phases. The first phase will have three cohorts with three recipient/donor pairs at different dose levels for each cohort. The second phase is an expansion cohort at the maximum tolerated dose determined in the first phase.
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Phase I - Dose-limiting toxicity (DLT)
timeFrame: Baseline to Day 30
measure: Phase I - Severe acute adverse events following infusion of EAGD T-cells
timeFrame: Baseline to Day 100
measure: Expansion phase - Rate of acute GVHD
timeFrame: Baseline to Day 100
Secondary outcomes:
measure: Expansion phase - Relapse following haploidentical HCT and PTCy with EAGD T-cell infusion
timeFrame: Baseline to 100 days
measure: Expansion phase - Non-relapse mortality following haploidentical HCT and PTCy with EAGD T-cell infusion
timeFrame: Baseline to 100 days
measure: Expansion phase - Overall survival following haploidentical HCT and PTCy with EAGD T-cell infusion
timeFrame: Baseline to 100 days
measure: Rate of one-year relapse-free survival (RFS)
timeFrame: Baseline to one year
measure: Rate of one-year non-relapse mortality (NRM)
timeFrame: Baseline to one year
measure: Rate of one-year overall survival (OS)
timeFrame: Baseline to one year
measure: Proportion of subjects with chronic GVHD at one year
timeFrame: Baseline to one year
Other outcomes:
Locations:
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
Study officials:
affiliation: University of Kansas Medical Center
name: Joseph McGuirk, M.D.
role: PRINCIPAL_INVESTIGATOR
References: