Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

Refractory Acute Myeloid Leukemia Clinical Trial

Official title:

A Phase II Study Evaluating Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors for Prevention of GVHD

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02220985
• Other study ID #: 2684.00
• Secondary ID: NCI-2014-0130126
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: February 3, 2015
• Est. completion date: April 1, 2025

Study information

• Verified date: February 2024
• Source: Fred Hutchinson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial is for patients with acute lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome or chronic myeloid leukemia who have been referred for a peripheral blood stem cell transplantation to treat their cancer. In these transplants, chemotherapy and total-body radiotherapy ('conditioning') are used to kill residual leukemia cells and the patient's normal blood cells, especially immune cells that could reject the donor cells. Following the chemo/radiotherapy, blood stem cells from the donor are infused. These stem cells will grow and eventually replace the patient's original blood system, including red cells that carry oxygen to our tissues, platelets that stop bleeding from damaged vessels, and multiple types of immune-system white blood cells that fight infections. Mature donor immune cells, especially a type of immune cell called T lymphocytes (or T cells) are transferred along with these blood-forming stem cells. T cells are a major part of the curative power of transplantation because they can attack leukemia cells that have survived the chemo/radiation therapy and also help to fight infections after transplantation. However, donor T cells can also attack a patient's healthy tissues in an often-dangerous condition known as Graft-Versus-Host-Disease (GVHD). Drugs that suppress immune cells are used to decrease the severity of GVHD; however, they are incompletely effective and prolonged immunosuppression used to prevent and treat GVHD significantly increases the risk of serious infections. Removing all donor T cells from the transplant graft can prevent GVHD, but doing so also profoundly delays infection-fighting immune reconstitution and eliminates the possibility that donor immune cells will kill residual leukemia cells. Work in animal models found that depleting a type of T cell, called naïve T cells or T cells that have never responded to an infection, can diminish GVHD while at least in part preserving some of the benefits of donor T cells including resistance to infection and the ability to kill leukemia cells. This clinical trial studies how well the selective removal of naïve T cells works in preventing GVHD after peripheral blood stem cell transplants. This study will include patients conditioned with high or medium intensity chemo/radiotherapy who can receive donor grafts from related or unrelated donors.

Description:

OUTLINE: Patients are assigned to 1 of 4 treatment arms. CONDITIONING: ARMS A AND C (high-intensity myeloablative conditioning): Patients undergo total body irradiation twice daily (BID) on days -10 to -7. Patients also receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. ARMS B AND D (lower-intensity myeloablative conditioning): Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation once daily (QD) on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with granulocyte colony-stimulating factor (GCSF)-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: ARMS A AND C: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or orally (PO) (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. ARMS B AND D: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on days -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the principal investigator. After completion of study treatment, patients are followed up at 80-100 days, 360 days, and then yearly for up to 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 84
• Est. completion date: April 1, 2025
• Est. primary completion date: April 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 60 Years

Eligibility

Inclusion Criteria:

• Patients who are considered appropriate candidates for allogeneic hematopoietic stem

cell transplantation and have one of the following diagnoses:

• Acute lymphocytic leukemia in first or subsequent remission
• Acute myeloid leukemia in first or subsequent remission
• Acute lymphocytic leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 (Arms A or C only)
• Acute myeloid leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3 (Arms A or C only)
• Refractory anemia with excess blasts (RAEB-1 and RAEB-2) (if the patient has received previous induction chemotherapy within 60 days)
• Chronic myelogenous leukemia with a history of accelerated phase or blast crisis (if the patient has received at least one course of induction chemotherapy)
• Other acute leukemia or related neoplasm (including but not limited to 'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma)
• Patients 0-49 years old will be enrolled in Arm A or C (high-intensity)
• Patients 50-60 years old will be enrolled in Arm B or D (lower intensity); patients eligible for Arms B or D also include those who have received previous allogeneic HCT, or who have co-morbid conditions rendering them unsuitable for high-dose conditioning, determined in consultation with the principal investigator
• Patient with a HLA-matched (HLA-A, B, C, and DR beta 1 [DRB1] molecularly matched) unrelated donor or related donor capable of donating PBSC
• DONOR INCLUSION:
• HLA-matched related donors >= 18 years and capable and willing to donate PBSC (Arms A and B)
• HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution typing) capable and willing to donate PBSC (Arms C and D)

Exclusion Criteria:

• Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation
• Patients on other experimental protocols for prevention of acute GVHD
• Patient weight >= 100 kg; patients >= 70 kg with MUDs must be discussed with the principal investigator
• Patients who are human immunodeficiency virus positive (HIV+)
• Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician (upper respiratory tract viral infection does not constitute an uncontrolled infection in this context)
• Patients with organ dysfunction
• ARM A OR C EXCLUSION:
• Creatinine > 1.5 mg/dl at the present time; patients with a known history of creatinine > 1.5 mg/dl must have a current estimated creatinine clearance of > 40 ml/min
• Cardiac ejection fraction < 45%
• Diffusing capacity of the lung for carbon monoxide (DLCO) corrected < 60%; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air
• Liver function abnormality; patients who have liver function tests (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician; unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); if the GI physician considers that HCT on the high-intensity arms of protocol is contraindicated for that patient the patient may be considered for treatment on the lower intensity arm of the protocol or excluded from the protocol; patients with Gilbert's syndrome and no other known liver function abnormality and patients with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the high-intensity arms of the protocol
• ARM B OR D EXCLUSION:
• Creatinine > 2.0 mg/dl at the present time; patients with a known history of creatinine > 1.5 mg/dl must have a current estimated creatinine clearance > 40 ml/min
• Cardiac ejection fraction < 35%
• DLCO corrected < 50%; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the O2 saturation is < 92% on room air; patients with a DLCO 50-60% must also have a partial pressure of oxygen (pO2) of > 80 mmHg
• Liver function abnormality; patients who have LFTs >= twice the upper limit of normal should be evaluated by a GI physician unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded
• Patients will be excluded from Arms A and C if they have received a previous myeloablative transplant; patients who have received a prior HCT at least 6 months prior may be considered for inclusion on Arms B or D after discussion with the principal investigator (PI)
• Patients with a life expectancy < 3 months from co-existing disease other than the leukemia or RAEB
• Patients who are pregnant or breast-feeding
• Fertile patients of child bearing age unwilling to use contraception during and for 12 months post-transplant
• Patients with a significant other medical conditions that would make them unsuitable for transplant
• Patients with a known hypersensitivity to tacrolimus, methotrexate (Arm A or C) or MMF (Arm B or D)
• DONOR EXCLUSION:
• Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
• Donors who fail eligibility requirements for donation of cells or tissue for donation of a Human Cell and Tissue Products (HCT/P) will be excluded unless use of the cells complies urgent medical need or allogeneic use in a first-degree or second-degree relative
• Unrelated donors donating outside of the United States of America (USA)

Related Conditions & MeSH terms

• Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Acute Biphenotypic Leukemia
• Acute Leukemia of Ambiguous Lineage
• Acute Lymphoblastic Leukemia in Remission
• Acute Myeloid Leukemia in Remission
• Acute Undifferentiated Leukemia
• Allogeneic Hematopoietic Stem Cell Transplant Recipient
• Anemia, Refractory, with Excess of Blasts
• Blast Crisis
• Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Blastic Plasmacytoid Dendritic Cell Neoplasm
• Childhood Acute Lymphoblastic Leukemia in Remission
• Childhood Acute Myeloid Leukemia in Remission
• Donor
• Leukemia
• Leukemia, Biphenotypic, Acute
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoblastic Lymphoma
• Myelodysplastic Syndrome With Excess Blasts
• Myelodysplastic Syndrome With Excess Blasts-1
• Myelodysplastic Syndrome With Excess Blasts-2
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Recurrence
• Recurrent Acute Lymphoblastic Leukemia
• Recurrent Acute Myeloid Leukemia
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Refractory Acute Lymphoblastic Leukemia
• Refractory Acute Myeloid Leukemia
• Syndrome

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HSCT

Drug:
• Cyclophosphamide
Given IV
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Methotrexate
Given IV
• Mycophenolate Mofetil
Given IV and PO

Procedure:
• Peripheral Blood Stem Cell Transplantation
Undergo PBSCT with GCSF-mobilized CD34-enriched PBSC
• Peripheral Blood Stem Cell Transplantation
Undergo PBSCT with CD45RA-depleted cells

Drug:
• Tacrolimus
Given IV or PO
• Thiotepa
Given IV

Radiation:
• Total-Body Irradiation
Undergo TBI

Locations

Country	Name	City	State
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center	National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of chronic graft-versus-host disease (GHVD), defined operationally as the occurrence of compatible symptoms meeting National Institutes of Health criteria and requiring systemic pharmacological immunosuppression	Match related donor (MRD)-high intensity (Arm A), MRD-lower intensity (Arm B), match unrelated donor (MUD)-high intensity (Arm C) and MUD-lower intensity (Arm D) cohorts will be analyzed separately.	Up to 5 years
Primary	Use of additional immune suppressive agents other than first line therapy (prednisone and tacrolimus/cyclosporine)		Up to 5 years
Primary	Time to completion of prednisone		Up to 5 years
Primary	Time to completion of all immunosuppression		Up to 5 years
Primary	Requirement of immunosuppression after transplant		At 2 years after transplant
Primary	Presence of acute graft-versus-host disease (GVHD) grades II-IV	Defined operationally as the occurrence of compatible symptoms or signs in the skin, gastrointestinal tract, or liver.	Up to day 100
Primary	Requirement for secondary systemic therapy for acute graft-versus-host disease (GVHD) management		Up to day 100
Primary	Graft failure	Defined operationally as failure to reach an absolute neutrophil count (ANC) of > 500/ul for 3 consecutive days by day 28 or irreversible decrease in ANC to < 100 after an established donor graft.	Up to day 28
Secondary	Time to absolute neutrophil count (ANC) of > 500/uL on the first of three consecutive days		Up to 5 years
Secondary	Time to absolute neutrophil count (ANC) of > 1,000/uL on the first of three consecutive test results		Up to 5 years
Secondary	Time to platelet count > 20,000/uL for 3 days without transfusion		Up to 5 years
Secondary	Time to platelet count > 50,000/uL for 3 days without transfusion		Up to 5 years
Secondary	Chimerism analysis	Will be analyzed from peripheral blood or marrow.	Up to 360 days
Secondary	Relapse	Defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology.	Up to 5 years
Secondary	Transplant related mortality	Defined as mortality in any patient for whom there has not been a diagnosis of relapse.	Up to 5 years