Modified Stem Cell Transplant Procedure to Treat Patients With Blood and Immune System Cancers

NCT ID: NCT00051311

Last Updated: 2021-09-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-01-03
• Study Completion Date: 2014-09-25

Brief Summary

This study will investigate the safety and effectiveness of a modified stem cell transplant procedure for treating cancers of the blood and immune system. Patients with cancers and pre-cancerous conditions originating in blood or immune system cells can sometimes benefit greatly from, and even be cured by, transplants of stem cells (cells produced by the bone marrow that mature into blood cells). In addition to producing new bone marrow and restoring normal blood production and immunity, the donated cells fight any residual tumor cells that might have remained in the body, in what is called a graft-versus-tumor effect.

However, severe problems, and sometimes death, may follow these transplants as a result of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune system cells called T cells sometimes attack healthy tissues in a reaction called graft-versus-host-disease (GVHD), damaging organs such as the liver, intestines and skin. This study will use the following strategies to try to reduce these risks:

• induction chemotherapy to reduce patient's immunity in an attempt to prevent rejection of the donated stem cells;
• reduced-intensity conditioning chemotherapy that is easier for the body to tolerate and involves a shorter period of complete immune suppression;
• donation of immune cells called T helper type 2 (Th2) cells instead of T cells to try to reduce the risk of serious GVHD;
• treatment with methotrexate and cyclosporine to try to reduce the risk of serious GVHD.

Patients between 12 and 75 years of age with non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplasia, idiopathic myelofibrosis, polycythemia vera, or chronic myelomonocytic leukemia may be eligible for this study. Candidates will have a medical history, physical and dental examinations, blood and urine tests (including a blood test for genetic match with the donor), lung and heart function tests, and X-ray studies. A bone marrow biopsy may be done to evaluate disease status. Patients with lymphoma may have a nuclear medicine test called a positron emission tomography (PET) scan.

Participants will have a central venous line (large plastic tube) placed into a major vein. This tube can stay in the body and be used during the entire treatment period to deliver the donated stem cells and give medications, including chemotherapy and other drugs, antibiotics and blood transfusions, and to withdraw blood samples. Treatment will start with induction chemotherapy, which will include the drugs fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. Some patients may also receive an antibody called rituximab. Patients will receive one to three cycles of this treatment, depending on their response to the drugs. (One cycle consists of 5 days on drug therapy followed by a 16-day rest period.) Several days before the transplant procedure, patients will start conditioning chemotherapy with cyclophosphamide and fludarabine. Three days after the conditioning therapy is completed, the stem cells will be infused. To help prevent GVHD, patients will take four doses of methotrexate (by vein) shortly after the transplant, and cyclosporine (by mouth or by vein) for about 6 months after the transplant.

The average hospital stay for stem cell transplantation is 3 to 4 weeks. After discharge, patients will return for frequent follow-up visits for 3 months. Monthly visits will be scheduled for the next 3 months, then every 3 months for the next 18 months, and less frequently for a total of at least 5 years post-transplant. These visits will include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.

Detailed Description

Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative for refractory hematologic malignancies, but its application has been limited historically by morbidity and mortality from conventional transplant preparative regimens and graft-versus-host disease (GVHD). Donor T cells mediate GVHD and also help to eradicate malignancies through an immune-dependent graft-versus-tumor effect. Efforts to decrease preparative regimen toxicity have led to reduced-intensity or 'nonmyeloablative' regimens, facilitating the study of allogeneic HSCT in a broader population. As a promising strategy for reducing GVHD, donor T helper type 2 (Th2) cells were shown to abrogate T helper type 1 (Th1)-mediated GVHD without impairing engraftment in murine models of allogeneic HSCT. These findings led to a phase I/II clinical study of donor Th2 cells for the prevention of GVHD during reduced-intensity allogeneic HSCT (CC 99-C-0143); preliminary results suggest that a randomized trial will be necessary to evaluate donor Th2 cells further.

In CC 99-C-0143, a novel induction chemotherapy regimen, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (EPOCH)-Fludarabine (EPOCH-F), was well tolerated and effective for sequential host immune depletion. However, a significant proportion of patients failed to achieve satisfactory disease control before transplant, providing a basis for intensifying this induction regimen. Furthermore, the initial 20 patients treated on this study experienced relatively high rates of acute GVHD and considerable morbidity associated with cyclosporine monotherapy for GVHD prevention, indicating that future studies should use more aggressive prophylaxis. These observations warrant modifying our approach to allogeneic HSCT before undertaking a randomized study of donor Th2 cells.

We now propose a pilot study of human leukocyte antigens (HLA)-matched, related, reduced-intensity allogeneic HSCT in refractory hematologic malignancies, using an intensified etoposide, vincristine, doxorubicin, prednisone, cyclophosphamide and fludarabine (EPOCH-F) induction chemotherapy regimen with rituximab added for patients with cluster of differentiation 20 (CD20)+ malignancies fludarabine, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). This regimen will be evaluated for toxicity and disease control before transplantation. GVHD prophylaxis will consist of a standard dual-agent regimen, cyclosporine/methotrexate; the impact of this change on hematopoietic recovery, donor/recipient chimerism, and the incidence of acute GVHD will be assessed.

Immune reconstitution following allogeneic HSCT is an important research interest among Experimental Transplantation and Immunology Branch Investigators. Current evidence suggests a critical role for interleukin-7 (IL-7) in cluster of differentiation 4 (CD4)+ T cell homeostasis, and interleukin-15 (IL-15) appears crucial to cluster of differentiation 8 (CD8)+ T cell and NK cell homeostasis. The relationships between these cytokines and lymphocyte subpopulations have not been studied in the setting of allogeneic HSCT; such analysis may enhance our understanding of engraftment kinetics, graft-versus-host disease, and immune reconstitution. We will correlate serum IL-7 and IL-15 levels with changes in circulating T-cell and natural killer (NK)-cell subpopulations during EPOCH-F/R induction chemotherapy, after transplantation, and with the development of GVHD.

Conditions

Hematologic Neoplasms

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Donor

Donors will undergo apheresis to collect stem cells for a stem cell transplant for the recipient.

Group Type: OTHER

Apheresis

Intervention Type: PROCEDURE

Donors will undergo apheresis to collect stem cells for a stem cell transplant for the recipient.

Recipient

Recipients will receive induction chemotherapy (one cycle is 5 days on drug therapy followed by a 16 day rest period). Prior to the transplant procedure, recipients will receive conditioning therapy followed by the infusion of donor stem cells.

Group Type: EXPERIMENTAL

Stem cell transplantation

Intervention Type: PROCEDURE

Recipients will receive donor stem cells 3 days after conditioning therapy is completed.

Fludarabine

Intervention Type: DRUG

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Cyclophosphamide

Intervention Type: DRUG

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Etoposide

Intervention Type: DRUG

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Doxorubicin

Intervention Type: DRUG

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Vincristine

Intervention Type: DRUG

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Prednisone

Intervention Type: DRUG

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Methotrexate

Intervention Type: DRUG

Recipients will receive 4 doses of methotrexate by vein after the transplant to help prevent graft-versus-host disease (GVHD)..

Cyclosporine

Intervention Type: DRUG

Recipients will receive cyclosporine by vein or by mouth for about 6 months after the transplant to help prevent graft-versus-host disease (GVHD).

Interventions

Stem cell transplantation

Recipients will receive donor stem cells 3 days after conditioning therapy is completed.

Intervention Type: PROCEDURE

Fludarabine

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Intervention Type: DRUG

Cyclophosphamide

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Intervention Type: DRUG

Etoposide

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Intervention Type: DRUG

Doxorubicin

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Intervention Type: DRUG

Vincristine

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Intervention Type: DRUG

Prednisone

Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.

Intervention Type: DRUG

Methotrexate

Recipients will receive 4 doses of methotrexate by vein after the transplant to help prevent graft-versus-host disease (GVHD)..

Intervention Type: DRUG

Cyclosporine

Recipients will receive cyclosporine by vein or by mouth for about 6 months after the transplant to help prevent graft-versus-host disease (GVHD).

Intervention Type: DRUG

Apheresis

Donors will undergo apheresis to collect stem cells for a stem cell transplant for the recipient.

Intervention Type: PROCEDURE

Other Intervention Names

hematopoietic stem cell transplant (HSCT); Fludara; Cytoxan; Toposar; Doxil; Oncovin; Deltasone; Rasuvo; Neoral; extracorporeal therapy

Eligibility Criteria

Inclusion Criteria

Patients with hematologic malignancies, myelodysplasia, or myeloproliferative disorders, as summarized below:

Disease: Chronic Lymphocytic Leukemia; Disease Status: (a) Relapse post-fludarabine, (b) Non-Complete Remission (CR) after salvage regimen; Age: 18 to 75.

Disease: Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma); Disease Status: (a) Primary treatment failure, (b) Relapse after autologous stem cell transplant (SCT), (c) Hepatosplenic gamma/delta T cell lymphoma; Age: 18 to 75.

Disease: Multiple Myeloma; Disease Status: (a) Primary treatment failure, (b) Relapse after autologous SCT, (c) Non-CR after salvage regimen; Age: 18 to 75.

Disease: Acute Myelogenous Leukemia; Disease Status: (a) In Complete Remission #1, with high-risk cytogenetics [abnormalities other than t(8;21), t(15;17), or inv(16)], (b) In Complete Remission #2 or greater; Age: 18 to 75.

Disease: Acute Lymphocytic Leukemia; Disease Status: (a) In Complete Remission #1, with high-risk cytogenetics [t(9;22) or bcr-abl rearrangement; t(4;11), 1(1;19), t(8;14)], (b) In Complete Remission #2 or greater; Age: 18 to 75.

Disease: Myelodysplastic Syndrome; Disease Status: (a) refractory anemia with excess blasts (RAEB), (b) refractory anemia with excess blasts in transformation (RAEB-T) (if blasts are less than 10% in marrow and blood after induction chemotherapy); Age: 18 to 75.

Disease: Myeloproliferative disorders; Disease Status: (a) Idiopathic myelofibrosis, (b) Polycythemia vera, (c) Essential thrombocytosis, (d) Chronic myelomonocytic leukemia; Age: 18 to 75.

Disease: Chronic Myelogenous Leukemia (CML); Disease Status: (a) Chronic phase CML, (b) Accelerated phase CML; Age 50 to 75; (c) Not eligible for myeloablative allogeneic HSCT; Age: 18 to 50.

Patients 18-75 years of age. Patients older than 75 years of age will be considered on an individual basis.

Consenting first degree relative matched at 6/6 human leukocyte antigen (HLA) antigens (A, B, and DR).

Patient or legal guardian must be able to give informed consent.

All previous therapy must be completed at least 2 weeks prior to study entry, and any grade 3 or 4 non-hematologic toxicity of previous therapy must be resolved to grade 2 or less, unless specified elsewhere.

Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1.

Life expectancy of at least 3 months.

Patients with acute leukemia must be in hematologic remission, defined as less than 5% blasts present in blood or bone marrow.

Left ventricular ejection fraction greater than 45% by either multi-gated acquisition (MUGA) scan or 2-D echo, obtained within 28 days of enrollment. The cumulative dose of doxorubicin received by patients will not be considered, as the cardiac ejection fraction appears to indicate the safe cumulative doxorubicin dose in the setting of etoposide phosphate, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride (EPOCH)-based chemotherapy.

Diffusing capacity for carbon monoxide (DLCO) greater than 50% of the expected value when correlated for hemoglobin (Hb), obtained within 28 days of enrollment.

Creatinine less than or equal to 1.5 mg/dl and creatinine clearance greater than or equal to 50 ml/min/1.73 m(2).

Serum total bilirubin less than 2.5 mg/dl, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values less than or equal to 2.5 times the upper limit of normal. Values above these levels may be accepted, at the discretion of the principal investigator (PI) or study chairman, if such elevations are thought to be due to liver involvement by malignancy. If these values do not normalize during induction chemotherapy, such patients will not be eligible for the transplant phase of the protocol, and will thus be taken off study.

Minimum absolute neutrophil count of 1,000 cells/microliter and minimum platelet count (without transfusion) of 20,000/mm(3).

First-degree relative with genotypic identity at 6/6 HLA loci (HLA-A, B and DR).

Ability to give informed consent. For donors under 18 years of age, the donor must complete an assent form, and the donors legal guardian must complete an informed consent form.

Age 12-75 years. As the potential cerebrovascular and cardiac complications may potentially increase with age, age 75 has been chosen arbitrarily as the upper age limit. However, if it is determined after initial accrual of patients in this upper age range that this procedure is relatively safe, the age range may be extended.

Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.

Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface antigen negative, and hepatitis C antibody negative. This is to prevent the possible transmission of these infections to the recipient.

A donor who is lactating must substitute formula feeding for her infant during the period of cytokine administration. Filgrastim may be secreted in human milk, although its bioavailability from this source is not known. Limited clinical data suggest that short-term administration of filgrastim or sargramostim to neonates is not associated with adverse outcomes.

Exclusion Criteria

Active infection that is not responding to antimicrobial therapy.

Active central nervous system (CNS) involvement by malignancy.

HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.

Chronic active hepatitis B. Patients may be hepatitis B core antibody positive but must be surface antigen negative and without evidence of active infection.

Hepatitis C infection.

Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.

History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by principal investigator or study chairman).

History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.

History of hypertension that is not controlled by medication, stroke, or severe heart disease. Individuals with symptomatic angina will be considered to have severe heart disease will not be eligible to be a donor.

No other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, cerebrovascular accident, prior malignancy). Patients with a history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis. Persons with a history of non-hematologic malignancy must have undergone potentially curative therapy for that malignancy and (1) have had no evidence of that disease for 5 years, and/or (2) be deemed at low risk for recurrence (less than or equal to 20% at 5 years). Such persons will be considered eligible for stem cell donation at the discretion of the principal investigator. Prospective donors with a history of non-hematologic malignancy who have received potentially curative therapy and are in remission, but whose estimated risk of recurrence is greater than 20% at 5 years, will be considered on an individual basis in consultation with the National Cancer Institute (NCI) Institutional Review Board (IRB).

Donors must not be pregnant. The effects of cytokine administration on a fetus are unknown. Donors of childbearing potential must use an effective method of contraception.

Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microliter).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Ronald Gress, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel H Fowler, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

Champlin RE. T-cell depletion for bone marrow transplantation: effects on graft rejection, graft-versus-host disease, graft-versus-leukemia, and survival. Cancer Treat Res. 1990;50:99-111. doi: 10.1007/978-1-4613-1493-6_6.

Reference Type: BACKGROUND

PMID: 1976361 (View on PubMed)

Giralt SA, Kolb HJ. Donor lymphocyte infusions. Curr Opin Oncol. 1996 Mar;8(2):96-102. doi: 10.1097/00001622-199603000-00004.

Reference Type: BACKGROUND

PMID: 8727301 (View on PubMed)

Martin PJ, Hansen JA, Torok-Storb B, Durnam D, Przepiorka D, O'Quigley J, Sanders J, Sullivan KM, Witherspoon RP, Deeg HJ, et al. Graft failure in patients receiving T cell-depleted HLA-identical allogeneic marrow transplants. Bone Marrow Transplant. 1988 Sep;3(5):445-56.

Reference Type: BACKGROUND

PMID: 3056552 (View on PubMed)

Jamshed S, Fowler DH, Neelapu SS, Dean RM, Steinberg SM, Odom J, Bryant K, Hakim F, Bishop MR. EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011 May;46(5):676-81. doi: 10.1038/bmt.2010.173. Epub 2010 Jul 26.

Reference Type: DERIVED

PMID: 20661232 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 19667400 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form: Donor Consent

View Document

Document Type: Informed Consent Form: Recipient Consent

View Document

Other Identifiers

03-C-0077

Identifier Type: -

Identifier Source: secondary_id

030077

Identifier Type: -

Identifier Source: org_study_id

NCT00055744

Identifier Type: -

Identifier Source: nct_alias