Repeat Transplantation for Relapsed or Refractory Hematologic Malignancies Following Prior Transplantation

CD45A-Depleted Haploidentical Hematopoietic Progenitor Cell and Natural Killer Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

This pilot phase II trial studies how well a new reduced intensity conditioning regimen that includes haploidentical donor NK cells followed by the infusion of selectively T-cell depleted progenitor cell grafts work in treating younger patients with hematologic malignancies that have returned after or did not respond to treatment with a prior transplant. Giving chemotherapy and natural killer cells before a donor progenitor cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (progenitor cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy progenitor cells from a related donor are infused into the patient they make red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Removing specific T cells from the donor cells before the transplant may prevent this.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Myeloid Sarcoma; Chronic Myelogenous Leukemia (CML); Non-Hodgkin Lymphoma (NHL); Juvenile Myelomonocytic Leukemia (JMML)
• Intervention / Treatment: Drug: Fludarabine; Drug: Melphalan; Drug: Thiotepa; Drug: Cyclophosphamide; Drug: Rituximab; Biological: G-CSF; Biological: Interleukin-2; Biological: Natural killer cell therapy; Biological: T-cell depleted HPC transplant; Biological: CD45RA-depleted HPC transplant

Detailed Description

PRIMARY OBJECTIVE:

• To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical natural killer (NK) cells.

SECONDARY OBJECTIVES:

• Estimate the incidence of malignant relapse, event-free survival, and overall survival 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.

Blood progenitor cells will be collected from adult donors to be used for transplantation. Donor cells will be processed and filtered in a laboratory at St. Jude using a machine called the CliniMACS™ device, and later infused (transplanted) into the participant through his/her veins.

Participants undergo a conditioning regimen beginning Day 21 prior to progenitor cell transplantation that includes chemotherapy medications and natural killer cells in preparation for transplantation. They will then receive T-cell depleted HPC transplant followed by CD45RA-depleted HPC transplant the following day.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age less than or equal to 21 years.

• One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic hematopoietic cell transplant (HCT):

  • ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), 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 in CNS complete remission (CR)
• Does not have current uncontrolled bacterial, fungal, or viral infection.
• Patient must fulfill pre-transplant evaluation:
• Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%.
• Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2.
• 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 (See Appendix A).
• Bilirubin ≤ 3 times the upper limit of normal for age.
• Alanine aminotransferase (ALT) ≤ 5 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
• DONOR: At least single haplotype matched (≥ 3 of 6) family member
• DONOR: At least 18 years of age.
• DONOR: HIV negative.
• DONOR: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
• DONOR: Not breast feeding.

• DONOR: Regarding donation 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Participants; Participants undergo a conditioning regimen with cyclophosphamide, fludarabine, aldesleukin (interleukin-2), natural killer cell therapy, anti-thymocyte globulin, rituximab, thiotepa, and melphalan prior to transplantation of T-cell depleted HPC transplant on day 0 and CD45RA-depleted HPC transplant on day 1. Beginning Day 6 post-transplant, patients receive G-CSF daily until ANC recovers to normal level.

Drug: Fludarabine; Given IV; Other Names: Fludara; Fludarabine monophosphate; Drug: Melphalan; Given IV; Other Names: Phenylalanine mustard; L-PAM; L-phenylalanine mustard; L-sarcolysin; Alkeran®; Drug: Thiotepa; Given IV; Other Names: TESPA; TSPA; ThioplexV; Drug: Cyclophosphamide; Given intravenously (IV); Other Names: Cytoxan; Drug: Rituximab; Given IV; Other Names: Rituxan™; Biological: G-CSF; Given IV or subcutaneously (SQ); Other Names: Filgrastim; Neupogen®; Biological: Interleukin-2; Given SQ; Other Names: Aldesleukin; IL-2; Biological: Natural killer cell therapy; Given IV; Other Names: NK cell therapy; Biological: T-cell depleted HPC transplant; T-cell depleted hematopoietic stem cells will be infused on day 0.; Other Names: HPC,A Infusion(ɑ/β T cell depleted); Biological: CD45RA-depleted HPC transplant; CD45RA depleted stem cells will be infused on day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Engrafted by Day 42 Post-transplant	To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical NK cells. Engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm^3 with evidence of donor cell engraftment.	Day 42 post transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Malignant Relapse	The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The number of participants with incidence of malignant relapse is given. Relapse was evaluated using standard WHO criteria for each disease.	one year post transplantation
Event-free Survival (EFS)	The Kaplan-Meier estimate of event-free survival (EFS) along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given.	one year post transplantation
Overall Survival (OS)	The Kaplan-Meier estimate of OS along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of transplant and all participants surviving at the time of analysis without events will be censored. The number of participants surviving to one-year post-transplantation is given.	one year post transplantation
Incidence and Severity of Acute GvHD	The cumulative incidence of acute GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GvHD. The number of participants with incidence by grade is given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.	100 days post transplantation
Incidence and Severity of Chronic GvHD	The cumulative incidence of chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of chronic GvHD will be described. Chronic GvHD was evaluated using NIH Consensus Global Severity Scoring." The number of participants with incidence by severity is given.	one year post transplantation
Rate of Transplant-related Mortality (TRM)	The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.	100 days post transplantation

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: October 3, 2014
• First Submitted That Met QC Criteria: October 3, 2014
• First Posted (Estimate): October 8, 2014

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 24, 2017
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Hematological malignancies; Relapsed hematologic malignancy; Allogeneic hematopoietic cell transplant; Refractory hematologic malignancy
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Lymphoid; Sarcoma; Lymphoma; Neoplasms; Myelodysplastic Syndromes; Hematologic Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Preleukemia; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Sarcoma, Myeloid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Aldesleukin; Cyclophosphamide; Rituximab; Melphalan; Fludarabine; Fludarabine phosphate; Thiotepa; Interleukin-2; Mechlorethamine
• Other Study ID Numbers: REFNK1; NCI-2014-01925 (Registry Identifier: NCI Clinical Trial Registration Program)