Clinical trial NCT02199041: Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen
Official title: Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hematological Malignancies
Keywords: Cord Blood
Haploidentical
Reduced Intensity Regimen
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
First posted: 2014-07-24
Enrollment: 24
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin receptors (KIR) ligand mismatched haploidentical donor identified, will receive a combined T cell depleted (TCD) haploidentical peripheral blood stem cell (PBSC) and unrelated umbilical cord blood transplantation (UCBT) using a total lymphoid irradiation (TLI) based preparative regimen.

Primary objective:

* To estimate the incidence of donor derived neutrophil engraftment by day +42 post-transplant for participants with high-risk hematologic malignancies undergoing a total lymphoid irradiation (TLI)-based hematopoietic cell transplantation (HCT) using a T cell depleted (TCI) haploidentical donor peripheral blood stem cell (PBSC) donor combined with an unrelated umbilical cord blood (UCB) donor.

Secondary objectives:

* Estimate the incidence of malignant relapse, event-free survival (EFS), and overall survival (OS) at one-year post-transplantation.
* Estimate the incidence and severity of acute and chronic graft versus host disease (GVHD) in the first 100 days after transplantation.
* Estimate the incidence of secondary graft failure transplant related mortality (TRM) and transplant related morbidity in the first 100 days after HCT.

Detailed description: Prior to stem cell infusion, participants will receive a preparative regimen of total lymphoid irradiation (TLI), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare their bone marrow. Thereafter, they will receive a hematopoietic cell graft from a haploidentical donor and an unrelated umbilical cord blood donor. Post-transplantation immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.

Eligibility criteria: Inclusion Criteria-Transplant Recipient:

* Age less than or equal to 21 years old.
* Does not have a suitable matched related/sibling donor (MSD) or volunteer matched unrelated donor (MUD) available in the necessary time for stem cell donation.
* Has a suitable partially human leukocyte antigen (HLA)-matched (≥ 3 of 6) family member donor.
* Has a partially HLA-matched single umbilical cord blood (UCB) unit (≥ 4 of 6) with adequate cell dose. UCB units must fulfill eligibility as outlined in 21 CFR 1271 and agency guidance.
* High-risk hematologic malignancy.

  * High risk acute lymphocytic leukemia (ALL) in complete remission-1 (CR)1. \[Examples include, but not limited to t(9;22), hypodiploid,, M2 or greater marrow at the end of induction, infants with mixed lineage leukemia (MLL) fusion or t(4;11)\].
  * ALL in High risk CR2. \[Examples include but not limited to t(9;22), bone marrow (BM) relapse \<36 mo CR1, T-ALL, very early (\< 6mo CR1) isolated central nervous system (CNS) relapse.\]
  * ALL in CR3 or subsequent.
  * Acute myeloid leukemia (AML) in high risk CR1. \[Examples include but not limited to preceding MDS, 5q-, -5, -7, FAB M6, FAB M7 not t(1;22), minimal residual disease (MRD) ≥ 5% on day 22 (AML08), M3 marrow after induction 1, M2 marrow after two cycles of induction, FLT3-ITD.\]
  * AML in CR2 or subsequent.
  * Therapy related AML, with prior malignancy in CR \> 12mo
  * Myelodysplastic syndrome (MDS), primary or secondary
  * Natural killer (NK) cell, biphenotypic, or undifferentiated leukemia in CR1 or subsequent.
  * Chronic myeloid leukemia (CML) in accelerated phase, or in chronic phase with persistent molecular positivity or intolerance to tyrosine kinase inhibitor.
  * Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous hematopoietic cell transplantation (HCT), or unable to mobilize stem cells for autologous HCT.
  * Non-Hodgkin lymphoma in CR2 or subsequent.
  * Juvenile myelomonocytic leukemia (JMML).
  * Refractory hematologic malignancies \[ALL, AML, chronic myeloid leukemia (CML) in blast crisis, Hodgkin or non-Hodgkin lymphoma\] due to chemoresistant relapse or primary induction failure.
  * All patients with evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study.
* Patient must fulfill pre-transplant evaluation:

  * Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 40% or shortening fraction (SF) ≥ 25%.
  * Creatinine clearance (CrCL) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2.
  * Forced vital capacity (FVC) ≥ 50% of predicted value or pulse oximetry (Pox) ≥ 92% on room air.
  * Karnofsky or Lansky performance score ≥ 50.
  * Bilirubin ≤ 3 times the upper limit of normal for age.
  * Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age.
  * Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal for age.

Exclusion Criteria - Transplant Recipient:

* Patient has a suitable MSD, volunteer matched unrelated donor (MURD), or killer-immunoglobulin receptors (KIR) mismatched haploidentical donor available in the necessary time for stem cell donation.
* Patient has any other active malignancy other than the one for which HCT is indicated.
* Patient is pregnant as confirmed by positive serum or urine pregnancy test within 14 days prior to enrollment.
* Patient is breast feeding.
* Patient has Down Syndrome.
* Patient has a current uncontrolled bacterial, fungal, or viral infection per the judgment of the principal investigator.

Inclusion criteria - haploidentical donor

* At least single haplotype matched (≥ 3 of 6) family member
* At least 18 years of age.
* Human immunodeficiency virus (HIV) negative.
* Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
* Not breast feeding.
* Regarding eligibility, is identified as either:

  * Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR
  * Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271.

Primary outcomes:
measure: Number of Participants With Neutrophil Engraftment
timeFrame: Until day 42 post-transplant
Secondary outcomes:
measure: Number of Participants With Malignant Relapse
timeFrame: One year after transplantation
measure: Number of Participants With Event-free Survival (EFS)
timeFrame: One year after transplantation
measure: Number of Participants With Overall Survival (OS)
timeFrame: One year after transplantation
measure: Number of Participants by Severity With Acute Graft Versus Host Disease (GVHD) in the First 100 Days After HCT
timeFrame: 100 days after transplantation
measure: Number of Participants by Severity With Chronic Graft Versus Host Disease (GVHD) in the First 100 Days After HCT
timeFrame: 100 days after transplantation
measure: Number of Participants With Secondary Graft Failure
timeFrame: 100 days after transplantation
measure: Number of Participants With Transplant-related Mortality (TRM)
timeFrame: 100 days after transplantation
measure: Number of Participants With Transplant-related Morbidity
timeFrame: 100 days after transplantation
Other outcomes:
Locations:
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Brandon Triplett, MD
role: PRINCIPAL_INVESTIGATOR
References: