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

Acute Lymphoblastic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01621477
• Other study ID #: HAP3R
• Secondary ID: NCI-2012-00554
• Status: Terminated
• Phase: Phase 2
• First received: June 8, 2012
• Last updated: October 4, 2016
• Start date: August 2012
• Est. completion date: December 2015

Study information

• Verified date: September 2016
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 34
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

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) (including myeloid sarcoma)

• 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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myelocytic Leukemia
• Chronic Myelocytic Leukemia
• Hodgkin or Non-Hodgkin Lymphoma
• Juvenile Myelomonocytic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Juvenile
• Lymphoma, Non-Hodgkin
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Sarcoma, Myeloid

Intervention

Drug:
• clofarabine
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
• cytarabine
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
• busulfan
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
• Plerixafor
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: Hematopoietic Stem Cell Mobilizer
• cyclophosphamide
Given on Day -5 and Day +4 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent; immunosuppressive agent.
• 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.

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).

Drug:
• Tacrolimus
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
• mycophenolate mofetil
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.

Locations

Country	Name	City	State
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	Assisi Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	One-year survival	Evaluate the percentage of participants alive at 1 year	One year post transplant	No
Secondary	Incidence of Malignant Relapse	Estimate the incidence of malignant relapse at one-year post-transplantation.	One year post transplantation.	No
Secondary	Event-Free Survival (EFS)	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.	one year post transplant	No
Secondary	Disease-Free Survival (DFS)	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.	one year post transplant	No
Secondary	Incidence and severity of acute and chronic Graft Versus Host Disease (GVHD)	Estimate incidence of acute and chronic GVHD and describe the severity of acute and chronic GVHD.	100 days post transplant	Yes
Secondary	Rate of transplant related mortality and transplant related morbidity	Estimate the incidence of transplant related mortality and transplant related morbidity in the first 100 days after transplantation.	100 days post transplant	Yes

External Links

•   Clinical Trials Open at St. Jude
•   St. Jude Children's Research Hospital