Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

NCT00914940 | Terminated Phase 2 Results DMC

• 8 other identifiers: 2222.00P30CA015704P01CA018029IR-6907CDR00006442010903004832NCI-2010-00713RG2810004
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 2

Brief Summary

RATIONALE: Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment that can cure acute leukemia and myelodysplasia. After giving the patient chemotherapy and total body irradiation to stop the growth of cancer and remove the patient's diseased bone marrow, healthy stem cells from a donor are infused into the patient to replace the patient's bone marrow and make red and white blood cells and platelets. Unfortunately HSCT is often complicated by 'graft versus host disease' (GVHD) in which the transplanted cells from a donor can make an immune response against the body's normal cells and cause tissue damage and severe symptoms. Removing a subset of the donor T cells, called 'naive T cells', before transplant may reduce the frequency and intensity of GVHD. PURPOSE: This phase II trial will determine whether the removal of the naive T cells from donor cells can decrease the rate and severity of graft-vs-host disease while preserving specific immunity against infections in patients with acute leukemia or advanced myelodysplastic syndromes.

Conditions

Graft Versus Host Disease; Leukemia; Myelodysplastic Syndromes

Keywords

graft versus host disease; adult acute lymphoblastic leukemia in remission; recurrent adult acute lymphoblastic leukemia; childhood acute lymphoblastic leukemia in remission; recurrent childhood acute lymphoblastic leukemia; adult acute myeloid leukemia in remission; recurrent adult acute myeloid leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); childhood acute myeloid leukemia in remission; recurrent childhood acute myeloid leukemia; childhood myelodysplastic syndromes; previously treated myelodysplastic syndromes; refractory anemia with excess blasts; de novo myelodysplastic syndromes; secondary myelodysplastic syndromes

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD

  Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.

  Within 360 days of transplant

• Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant

  Graft failure is defined as either a failure to reach an ANC of \>500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC \<100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.

  Up to 5 years post transplant

Secondary Outcomes (3)

• Transplant-related Mortality by Day 100

  Transplant to day 100

• Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant

  Up to 5 years post transplant

• Number of Participants With Chronic GVHD

  Up to 5 years post transplant

Study Arms (1)

Arm 1

EXPERIMENTAL

CONDITIONING: Patients undergo total-body irradiation twice daily on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine IV over 30 minutes on days -6 to -2. TRANSPLANTATION: Patients undergo infusion of CD34+ enriched allogeneic peripheral blood stem cells (PBSC) followed by CD45RA+ T-cell-depleted allogeneic PBSC on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Cohort A: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50 followed by standard taper in the absence of grade II-IV acute GVHD. Cohort B: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30 followed by rapid taper in the absence of grade II-IV acute GVHD.

Drug: Fludarabine Phosphate; Drug: Tacrolimus; Drug: Thiotepa; Radiation: Total-Body Irradiation (TBI); Other: Magnetic Affinity Cell Sorting; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation

Interventions

Fludarabine Phosphate DRUG

Fludarabine will be administered in a dose of 25 mg/m2/day IV over approximately 30 minutes for 5 consecutive days (day -6 to -2). The total dose of fludarabine will be 125 mg/m2.

Also known as: 2-F-ara-AMP, Beneflur, Fludara

Arm 1

Tacrolimus DRUG

Tacrolimus will be administered beginning on day -1 at a dose of 0.03 mg/kg/day by continuous IV infusion. For the first cohort of 35 patients, if there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus should then be tapered at the rate of approximately 5% of the day 50 dose each week for liquid, and 20% of the day 50 dose per month for capsules. In the second cohort of 25 patients if there is no evidence of grade II GVHD on or prior to day 30, tacrolimus should then be tapered at the rate of approximately 8% of the day 30 dose each week for liquid, and 33% of the day 30 dose per month for capsules.

Also known as: Advagraf, FK 506, Prograf, Protopic

Arm 1

Thiotepa DRUG

Thiotepa will be administered in a dose of 5 mg/kg/day (adjusted body weight) IV over approximately 4 hours for 2 consecutive days (day -6 and day -5).

Also known as: Oncotiotepa, STEPA, TESPA, Tespamin, Tespamine, TSPA

Arm 1

Total-Body Irradiation (TBI) RADIATION

TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).

Also known as: TBI

Arm 1

Magnetic Affinity Cell Sorting OTHER

Device

Also known as: Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi)

Arm 1

Peripheral Blood Stem Cell Transplantation PROCEDURE

Patient will undergo a PBSC transplantation

Also known as: PBPC transplantation, PBSC transplantation, Peripheral Blood Progenitor Cell Transplantation, Transplantation, Peripheral Blood Stem Cell

Arm 1

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation

Arm 1

T Cell-Depleted Hematopoietic Stem Cell Transplantation BIOLOGICAL

Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

Arm 1

Eligibility Criteria

• Age: 14 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

DISEASE CHARACTERISTICS: * Diagnosis of 1 of the following: * Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or subsequent remission * ALL or AML in relapse or primary refractory ALL or AML with a circulating blast count ≤ 10,000/mm\^3 * Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has received induction chemotherapy within the past 60 days * Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT) * No CNS involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy PATIENT CHARACTERISTICS: * Age 14-55 * Creatinine \< 1.5 mg/dL * Cardiac ejection fraction \> 45% * DLCO corrected \> 60% of predicted * Total bilirubin \< 2 times upper limit of normal (ULN) (unless attributed to Gilbert syndrome) * AST and ALT \< 2 times ULN * Not pregnant or nursing * Fertile patients must use effective contraception during and for 12 months after transplantation * HIV negative * No co-existing disease (other than leukemia or RAEB) that would limit life expectancy to \< 3 months * No uncontrolled infection that, in the opinion of the consulting infectious disease physician, would contraindicate myeloablative HSCT * No other medical condition that would contraindicate HSCT * No known hypersensitivity to tacrolimus PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior HSCT * No concurrent participation in other experimental studies for the prevention of graft-vs-host disease DONOR CHARACTERISTICS: * Genotypic or phenotypic HLA-identical related donor * Able to donate peripheral blood stem cells * Age \> 14 years * Applicable to male patients only: No female donors who have previously given birth to a male child or have had a pregnancy beyond the first trimester miscarriage or termination of pregnancy or nursing * No donors who have received blood transfusions * No CD45 Mutation with aberrant CD45RA isoform expression

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Yale University School of Medicine/Yale New Haven Hospital

New Haven, Connecticut, 06520, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109-1024, United States

Location

Related Publications (2)

• Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, Persinger H, Hilzinger B, Martin PJ, Carpenter PA, Flowers ME, Voutsinas J, Gooley TA, Loeb K, Wood BL, Heimfeld S, Riddell SR, Shlomchik WD. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease. J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10.

  PMID: 35007144 DERIVED

• Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8.

  PMID: 26053664 DERIVED

MeSH Terms

Conditions

Graft vs Host Disease; Leukemia; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Congenital Abnormalities; Anemia, Refractory, with Excess of Blasts

Interventions

fludarabine phosphate; Tacrolimus; Thiotepa; Whole-Body Irradiation; Peripheral Blood Stem Cell Transplantation; Transplantation

Condition Hierarchy (Ancestors)

Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Myeloid; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Anemia, Refractory; Anemia

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Surgical Procedures, Operative

Results Point of Contact

• Title: Marie Bleakley, MD
• Organization: Fred Hutchinson Cancer Research Center

mbleakle@fredhutch.org

206-667-6572

Study Officials

• Marie Bleakley, MD

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

• Warren Shlomchik, MD

  Yale University School of Medicine/Yale New Haven Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 4, 2009
• First Posted: June 5, 2009
• Study Start: December 17, 2009
• Primary Completion: December 1, 2019
• Study Completion: May 26, 2020
• Last Updated: August 20, 2020
• Results First Posted: August 20, 2020

Record last verified: 2020-07

Locations

US (2)