Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow

NCT00003838 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 99005099-H-0050
• Study Type: interventional
• Target: 202
• Locations: 1 country
• Sites: 1

Brief Summary

The are a variety of cancerous diseases of the blood and bone marrow that can be potentially cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple myeloma are among the conditions that can be treated with BMT. Some patients with these diseases can be treated with medical chemotherapy alone. However, patients who relapse following chemotherapy are usually not curable with additional chemotherapy treatments. The only option known to provide a potential cure if this occurs is BMT. Allogenic transplants are cells collected from relatives of the patient. The transplant requires additional high intensity chemotherapy and radiation in order to destroy cancerous cells. In the process, many normal bone marrow cells are also destroyed. This is the reason for transplanting stem cells. The stem cells help to build new functioning bone marrow, red cells, white cells, and platelets. In addition, the immune cells from the donor are implanted into the recipient s body and help to fight off infection and kill remaining cancerous cells. Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many patients. In order to reduce the complications of BMT, and make it a safer available option for patients with cancers of the blood and bone marrow, researchers have developed a new approach to the BMT. In this study researchers plan to use stem cells collected from the blood stream of patient s relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In addition, researchers plan to use low doses of chemotherapy and no radiation therapy to reduce side effects. The majority of the cancer killing effect will be the responsibility of the stem cell transplant rather than the chemotherapy.

Conditions

Myeloproliferative Disorders; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Acute Lymphoblastic Leukemia

Keywords

Graft vs. Host Disease; Peripheral Blood Stem Cells; Non-Myeloablative Bone Marrow Transplantation; Engraftment; graft versus leukemia

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Experienced Transplant Related Mortality

  Number of Participants who experienced transplant related mortality by Day 200

  200 days

Secondary Outcomes (6)

• Number of Participants With Complete Donor Myeloid (CD34+) and T-cell (CD3+) Chimerism

  Up to Day 100

• Median Days to Neutrophil Engraftment

  Day 30

• Number of Participants Who Experienced Acute GVHD Grades II-IV

  Up to Day 100

• Number of Participant Who Experienced Chronic Graft Versus Host Disease Following Stem Cell Transplant

  Day 100 up to 3 years

• Number of Participants Overall Survival

  enrollment to date of death, up to 5 years

Study Arms (3)

Donor

OTHER

The HLA matched donor will receive granulocyte colony-stimulating factor (G-CSF) with apheresis collections of PBPC on day 5 and day 6 if required. G-CSF will be administered based on body weight for at least 5, and up to 7 days, subcutaneously.

Drug: G-CSF

Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality

EXPERIMENTAL

Participants at high risk for transplant related complications and mortality will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.

Procedure: T-cell replete PBPC allograft; Drug: Methotrexate; Drug: Cyclosporine

Group B: Stem Cell Transplant in Debilitating Hematologic Diseases

EXPERIMENTAL

Participants with hematologic diseases associated with reasonable longevity, shown to be curable by allogeneic Bone Marrow Transplant (BMT) but where concern for a high procedural mortality with conventional BMT will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m\^2 intravenously daily x 5 days followed by a peripheral blood hematopoietic progenitor cell graft targeted to deliver \>5x10\^6 CD34+ cells/kg.

Procedure: T-cell replete PBPC allograft; Drug: Methotrexate; Drug: Cyclosporine

Interventions

T-cell replete PBPC allograft PROCEDURE

Subjects will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m2 intravenously (IV) over 30 minutes daily x 5 days with or without ATG followed by a PBPC graft targeted to deliver \>5x10\^6 CD34+ cells/kg.

Also known as: Peripheral blood hematopoietic progenitor cell (PBPC) transplant

Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality; Group B: Stem Cell Transplant in Debilitating Hematologic Diseases

Methotrexate DRUG

IV MTX on days +1, +3, and +6 will be given

Also known as: MTX

Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality; Group B: Stem Cell Transplant in Debilitating Hematologic Diseases

Cyclosporine DRUG

CSA will be given beginning on day -4 for graft versus host disease prophylaxis. Participants with mixed T-cell chimerism on day 30 will begin a CSA taper. Participants with 100% donor T-cell chimerism by day 30 will be tapered off CSA from days 60 through 100 (25% reduction in dose every 10 days-off by day 100). CSA will not be tapered in any subjects with grade \> II acute GVHD regardless of chimerism results. In addition, participants with evidence of disease progression without grade \> II GVHD will have CSA discontinued regardless of chimerism results.

Also known as: CSA

Group A: Stem Cell Transplant in High Risk for Transplant Related Complications and Mortality; Group B: Stem Cell Transplant in Debilitating Hematologic Diseases

G-CSF DRUG

G-CSF will be administered based on body weight for at least 5, and up to 7 days, subcutaneously.

Also known as: granulocyte colony-stimulating factor (G-CSF)

Donor

Eligibility Criteria

• Age: 2 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Group A: Subjects at high risk for transplant related complications and mortality as defined below:
• Ages 10 to 75 (both inclusive) with a history of one of the following:
• Treatment with dose intensive chemotherapy and/or radiotherapy
• Previous history of allo/auto transplant
• History of multiple myeloma or extramedullary plasmacytoma
• Chronic disease or co-morbid medical condition including subjects with symptoms or signs of significant pulmonary disease, hepatic disease, kidney disease, cardiac disease or disease of other organ systems which would result in increased risk of morbidity or death from a standard myeloablative transplant.
• Diseases to be included:
• CML chronic phase
• Acute lymphoblastic leukemia (ALL), all subjects in complete or partial remission.
• AML: AML in first complete or partial remission Exceptions: AML with good risk karyotypes: AML M3 t(15:17), AML M4Eo (inv. 16), AML t(8;21). All AML in second or subsequent complete remission.
• MDS: refractory anemia with excess blasts (RAEB), or chronic myelomonocyte leukemia (CMML).
• Myeloproliferative diseases associated with either cytopenia or uncontrolled proliferation.
• CLL or small lymphocytic lymphoma (SLL) with bulky or progressive disease despite prior treatment with chemotherapy which includes purine analogs.
• NHL
• A) Intermediate or high grade relapsed or progressive despite treatment with standard therapy ineligible for autologous PBSC transplant.

You may not qualify if:

• Pregnant or lactating
• Group A: age less than 10 or greater than 75 (multiple myeloma age less than 8 or greater than 65);
• Group B: Age less than 8 or greater than 80 years.
• ECOG performance status of 3 or more (See NIH Bone and Marrow Consortium Supportive Care Guidelines for Allogeneic Hematopoietic Stem Cell Transplant Recipients - http://intranet.cc.nih.gov/bmt/\_pdf/ECOG\_Karnofsky\_Lansky\_Scales.pdf)
• Psychiatric disorder or mental deficiency severe as to make compliance with the BMT treatment unlikely and making informed consent impossible
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant
• Diffusion capacity of carbon monoxide (DLCO) less than 40% predicted.
• Left ventricular ejection fraction: less than 30%.
• Serum creatinine greater than 2.5 mg/dl or creatinine clearance less than 50 cc/min by 24 hr urine collection
• Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal,
• Other malignant diseases liable to relapse or progress within 5 years.
• Pregnant or lactating
• Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of congestive heart failure or unstable angina, thrombocytopenia)
• HIV positive donor. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human T-cell lymphotropic virus (HTLV I/II) will be used at the discretion of the investigator following counseling and approval from the recipient

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Buchan A, Merideth MA, Childs RW, Stratton P. Novel management of vaginal chronic graft-versus-host disease causing haematometra and haematocolpos. BMJ Case Rep. 2018 Apr 28;2018:bcr2017222720. doi: 10.1136/bcr-2017-222720.

  PMID: 29705733 DERIVED

• Pantin J, Tian X, Shah AA, Kurlander R, Ramos C, Cook L, Khuu H, Stroncek D, Leitman S, Barrett J, Donohue T, Young NS, Geller N, Childs RW. Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes. Am J Hematol. 2013 Oct;88(10):874-82. doi: 10.1002/ajh.23526. Epub 2013 Sep 3.

  PMID: 23813900 DERIVED

• Sri T, Merideth MA, Pulanic TK, Childs R, Stratton P. Human papillomavirus reactivation following treatment of genital graft-versus-host disease. Transpl Infect Dis. 2013 Aug;15(4):E148-51. doi: 10.1111/tid.12098. Epub 2013 May 28.

  PMID: 23710698 DERIVED

• Baskar S, Suschak JM, Samija I, Srinivasan R, Childs RW, Pavletic SZ, Bishop MR, Rader C. A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display. Blood. 2009 Nov 12;114(20):4494-502. doi: 10.1182/blood-2009-05-222786. Epub 2009 Aug 10.

  PMID: 19667400 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Myeloproliferative Disorders; Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Graft vs Host Disease

Interventions

Transplantation; Methotrexate; Cyclosporine; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Surgical Procedures, Operative; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Proteins; Biological Factors

Limitations and Caveats

Group B: Stem Cell Transplant in Debilitating Hematologic Diseases was closed to enrollment in 2010.

Results Point of Contact

• Title: Richard Childs, M.D. Principal Investigator, NIH, NHLBI
• Organization: National Heart Lung and Blood Institute (NHLBI)

childsr@nhlbi.nih.gov

301.451.7128

Study Officials

• Richard W Childs, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 1999
• First Posted: January 27, 2003
• Study Start: April 15, 1999
• Primary Completion: December 14, 2018
• Study Completion: June 18, 2020
• Last Updated: September 21, 2023
• Results First Posted: October 7, 2022

Record last verified: 2022-04

Locations

US (1)