T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by St. Jude Children's Research Hospital
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT01621477
First received: June 8, 2012
Last updated: August 8, 2014
Last verified: August 2014
  Purpose

The primary aim of this protocol is to evaluate if the one-year survival is significantly improved in the group of patients who receive a T-cell replete haploidentical donor hematopoietic cell transplant (HCT) with a novel reduced intensity conditioning regimen. Study population will consist of patients (21 years or under) with hematologic malignancies that have relapsed or are refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate of transplant related mortality and the rates of moderate and severe graft-versus-host disease (GvHD) at day 100. The investigators will describe event-free, and disease-free survival at one year, as well as the rates of hematopoietic recovery and donor engraftment and study comprehensively immune reconstitution following T-cell replete haploidentical transplantation.


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Acute Myelocytic Leukemia
Chronic Myelocytic Leukemia
Juvenile Myelomonocytic Leukemia
Myelodysplastic Syndrome
Hodgkin or Non-Hodgkin Lymphoma
Drug: clofarabine
Drug: cytarabine
Drug: busulfan
Drug: Plerixafor
Drug: cyclophosphamide
Drug: antithymocyte globulin (rabbit)
Biological: stem cells
Drug: Tacrolimus
Drug: mycophenolate mofetil
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: T-Cell Replete Haploidentical Donor Hematopoietic Stem Cell Plus Natural Killer (NK) Cell Transplantation in Patients With Hematologic Malignancies Relapsed or Refractory Despite Previous Allogeneic Transplant

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • One-year survival [ Time Frame: One year post transplant ] [ Designated as safety issue: No ]
    Evaluate the percentage of participants alive at 1 year


Secondary Outcome Measures:
  • Incidence of Malignant Relapse [ Time Frame: One year post transplantation. ] [ Designated as safety issue: No ]
    Estimate the incidence of malignant relapse at one-year post-transplantation.

  • Event-Free Survival (EFS) [ Time Frame: one year post transplant ] [ Designated as safety issue: No ]
    Estimate the EFS at one-year post-transplantation. EFS is defined as the time from date of HCT to the minimum value of date of last follow-up, date of relapse, and date of death due to any cause. All participants surviving at the time of analysis will be censored.

  • Disease-Free Survival (DFS) [ Time Frame: one year post transplant ] [ Designated as safety issue: No ]
    Estimate the DFS at one-year post-transplantation. DFS is defined as the time from date of HCT to the minimum value of date of last follow-up, date of relapse, and date of death due to relapse. All participants surviving at the time of analysis and those who die due to other causes will be censored at the time of their event.

  • Incidence and severity of acute and chronic Graft Versus Host Disease (GVHD) [ Time Frame: 100 days post transplant ] [ Designated as safety issue: Yes ]
    Estimate incidence of acute and chronic GVHD and describe the severity of acute and chronic GVHD.

  • Rate of transplant related mortality and transplant related morbidity [ Time Frame: 100 days post transplant ] [ Designated as safety issue: Yes ]
    Estimate the incidence of transplant related mortality and transplant related morbidity in the first 100 days after transplantation.


Estimated Enrollment: 39
Study Start Date: August 2012
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment

All study participants.

Interventions: clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, antithymocyte globulin (rabbit), stem cells, tacrolimus, mycophenolate mofetil

Drug: clofarabine
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
Other Names:
  • Cl-F-Ara-A
  • CAFdA
  • Clofarex
  • Clolar(TM)
Drug: cytarabine
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
Other Name: Ara-C
Drug: busulfan
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
Other Names:
  • Myleran(R)
  • Busulfex
Drug: Plerixafor
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: Hematopoietic Stem Cell Mobilizer
Other Names:
  • AMD3100
  • Mozobil(R)
Drug: cyclophosphamide
Given on Day -5 and Day +4 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent; immunosuppressive agent.
Other Name: Cytoxan
Drug: antithymocyte globulin (rabbit)
Given on Day -4, Day -3, Day -2, and Day -1 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Other Names:
  • Rabbit ATG
  • Rabbit Thymoglobulin(R)
Biological: stem cells
Patients undergo T cell replete Hematopoietic stem cell infusion on Day 0 and Day +1. Patients undergo natural killer (NK) cell transplantation on day +6 (Day 0 is first stem cell infusion).
Other Name: HSC infusion
Drug: Tacrolimus
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Other Names:
  • FK506
  • Prograf(R)
  • Protonic(R)
Drug: mycophenolate mofetil
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Other Names:
  • MMF
  • CellCept(R)

Detailed Description:

Patients with refractory hematologic malignancies, including those who develop recurrent disease after allogeneic hematopoietic cell transplantation, have a dismal prognosis. Historically, both regimen-related mortality and disease recurrence have been significant causes of treatment failure in this heavily pre-treated patient population. Our institution has utilized mismatched family member (haploidentical) donors for these patients for a number of years for the following reasons: (1) Only 30% of patients have matched related donors available; (2) transplantation can be performed more rapidly since the time to unrelated donor transplantation averages 3 to 4 months; (3) no other curative treatment options are available. These therapeutic interventions have been largely successful given the dismal prognosis in this patient group; however disease recurrence remains the most significant cause of treatment failure. To provide maximum benefit for this challenging population, the goals of a therapeutic transplant protocol should include: (1) a conditioning regimen that is well tolerated, even in a heavily pre-treated population; but it should also provide substantial antileukemia effects, and (2) should establish rapid immune recovery such that the patient may benefit from graft versus leukemia effect and early protection from life threatening infections while also limiting dangerous and counter-productive graft versus host disease.

The primary aim of this protocol will be to evaluate if the one-year survival is significantly improved in the group of patients receiving T-cell replete haploidentical donor HCT with a novel clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, and ATG based reduced intensity conditioning regimen whose hematologic malignancy has relapsed or is refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate of transplant related mortality and the rates of moderate and severe graft versus host disease at day 100. The investigators will also describe event-free, and disease-free survival at one year, as well as the rates of hematopoietic recovery and donor engraftment. Additionally, the investigators will study comprehensively immune reconstitution following T-cell replete haploidentical transplantation.

PRIMARY OBJECTIVE:

  • Evaluate if the one-year survival is significantly improved in a group of children receiving a therapeutic regimen for high-risk hematologic malignancy that is relapsed or refractory despite previous allogeneic hematopoietic cell transplantation (HCT) using a novel reduced intensity conditioning and T-cell replete haploidentical donor hematopoietic stem cell plus NK cell transplantation.

SECONDARY OBJECTIVES:

  • Estimate the incidence of malignant relapse, event-free survival, and disease free survival (DFS) at one-year post-transplantation.
  • Estimate incidence and severity of acute and chronic (GVHD).
  • Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.
  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria - for transplant recipient:

  • Age less than 21 years.
  • One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic HCT:

    • Acute lymphoblastic leukemia (ALL)
    • Acute myeloid leukemia (AML)
    • Chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), Hodgkin or non-Hodgkin lymphoma (NHL)
  • Has a suitable single haplotype matched (≥ 3 of 6) family member donor.
  • Does not have any other active malignancy other than the one for which this transplant is indicated.
  • If prior central nervous system (CNS) leukemia, it must be treated and have no evidence of CNS disease
  • Does not have current uncontrolled bacterial, fungal, or viral infection per the judgment of the principal investigator.
  • Patient must fulfill pre-transplant evaluation:

    • Left ventricular ejection fraction greater than 40%, or shortening fraction greater than or equal to 25%.
    • Creatinine clearance or Glomerular Filtration Rate of ≥70 ml/min/1.73m^2.
    • Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing.
    • Karnofsky or Lansky (age-dependent) performance score ≥ 50.
    • Total bilirubin ≤ 1.5 times the upper limit of normal for age.
    • Alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal for age.
    • Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment.
    • Not breast feeding.
    • Does not have active acute bronchiolitis obliterans or bronchiolitis obliterans organizing pneumonia.

Inclusion Criteria - for 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.
  • A suitable donor is identified as either:

    • Has 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.

Exclusion Criteria:

  • Does not meet above inclusion criteria.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01621477

Contacts
Contact: Brandon M. Triplett, MD 866-278-5833 info@stjude.org

Locations
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Brandon M. Triplett, MD    866-278-5833    info@stjude.org   
Principal Investigator: Brandon M. Triplett, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Brandon M. Triplett, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT01621477     History of Changes
Other Study ID Numbers: HAP3R
Study First Received: June 8, 2012
Last Updated: August 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by St. Jude Children's Research Hospital:
Hematologic malignancy
Hematopoietic cell transplant

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Lymphoma, Non-Hodgkin
Myelodysplastic Syndromes
Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma
Lymphoproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms by Histologic Type
Precancerous Conditions
Antilymphocyte Serum
Clofarabine
Cyclophosphamide
Cytarabine
Immunosuppressive Agents
Mycophenolate mofetil

ClinicalTrials.gov processed this record on October 29, 2014