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

NCT00051311 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 03007703-C-0077
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

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.

Conditions

Hematologic Neoplasms

Keywords

Lymphoma; Leukemia; Hodgkin's Disease; Multiple Myeloma; Immunotherapy

Outcome Measures

Primary Outcomes (2)

• Number of Recipients Who Developed Grades I-IV Acute Graft Versus Host Disease (GVHD) Following a Combination of Cyclosporine and a Mini-dose Methotrexate Regimen for Graft Versus Host Disease (GVHD) Prophylaxis

  Here is the number of recipients who developed grades I-IV acute graft versus host disease (GVHD) following a combination of cyclosporine and a mini-dose methotrexate regimen for graft-versus-host disease (GVHD) prophylaxis. Grades I-IV acute GVHD clinical staging was assessed by the Glucksberg Criteria. Grade I-IV acute GVHD can occur in the skin, liver, and/or gut. Grade 1: rash \< 25% body surface area (BSA), total bilirubin 2-3 mg/dl, and diarrhea 500-1000 ml/d. Grade 2: 25-50% BSA, total bilirubin 3-6 mg/dl, and diarrhea 1000-1500 ml/d. Grade 3: generalized erythroderma, total bilirubin 6-15 mg/dl, and diarrhea \>1500 ml/d. Grade 4: desquamation and bullae, total bilirubin \>15 mg/dl, and pain +/- ileus.

  At least 100 days of follow-up post reduced-intensity stem cell transplantation (RIST)

• Number of Recipients Who Developed Chronic Graft Versus Host Disease (GVHD) Following a Combination of Cyclosporine and a Mini-dose Methotrexate Regimen for Graft Versus Host Disease (GVHD) Prophylaxis

  Here is the number of recipients who developed chronic graft versus host disease (GVHD) following a combination of cyclosporine and a mini-dose methotrexate regimen for graft-versus-host disease (GVHD) prophylaxis. Grades I-IV chronic GVHD clinical staging was assessed by the Glucksberg Criteria. Grade I-IV chronic GVHD can occur in the skin, liver, and/or gut. Grade 1: rash \< 25% body surface area (BSA), total bilirubin 2-3 mg/dl, and diarrhea 500-1000 ml/d. Grade 2: 25-50% BSA, total bilirubin 3-6 mg/dl, and diarrhea 1000-1500 ml/d. Grade 3: generalized erythroderma, total bilirubin 6-15 mg/dl, and diarrhea \>1500 ml/d. Grade 4: desquamation and bullae, total bilirubin \>15 mg/dl, and pain +/- ileus.

  At least 100 days of follow-up post reduced-intensity stem cell transplantation (RIST)

Secondary Outcomes (6)

• Percentage of Recipients Who Achieved Donor Chimerism at Day +14

  Day+14

• Number of Recipients Evaluable Who Achieved Full Donor Chimerism at Day+100

  Day+100

• Median Cycles of Induction Chemotherapy With Fludarabine, Cyclophosphamide, Etoposide, Doxorubicin, Vincristine, and Prednisone Given to Recipients

  Up to cycle 3

• Median Time to Neutrophil Recovery

  Up to 2 months after stem cell transplant

• Median Time to Platelet Recovery

  Up to 2 months after stem cell transplant

Other Outcomes (1)

• Number of Recipients With Non-serious Adverse Events

  Date treatment consent signed to date off study, approximately 58 months and 13 days.

Study Arms (2)

Donor

OTHER

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

Procedure: Apheresis

Recipient

EXPERIMENTAL

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.

Procedure: Stem cell transplantation; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone; Drug: Methotrexate; Drug: Cyclosporine

Interventions

Stem cell transplantation PROCEDURE

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

Also known as: hematopoietic stem cell transplant (HSCT)

Recipient

Fludarabine 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.

Also known as: Fludara

Recipient

Cyclophosphamide 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.

Also known as: Cytoxan

Recipient

Etoposide 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.

Also known as: Toposar

Recipient

Doxorubicin 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.

Also known as: Doxil

Recipient

Vincristine 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.

Also known as: Oncovin

Recipient

Prednisone 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.

Also known as: Deltasone

Recipient

Methotrexate DRUG

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

Also known as: Rasuvo

Recipient

Cyclosporine 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).

Also known as: Neoral

Recipient

Apheresis PROCEDURE

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

Also known as: extracorporeal therapy

Donor

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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.

  PMID: 1976361 BACKGROUND

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

  PMID: 8727301 BACKGROUND

• 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.

  PMID: 3056552 BACKGROUND

• 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.

  PMID: 20661232 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

MeSH Terms

Conditions

Hematologic Neoplasms; Lymphoma; Leukemia; Hodgkin Disease; Multiple Myeloma

Interventions

Stem Cell Transplantation; fludarabine; fludarabine phosphate; Cyclophosphamide; Etoposide; Doxorubicin; liposomal doxorubicin; Vincristine; Prednisone; Methotrexate; Cyclosporine; Blood Component Removal

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Aminopterin; Pterins; Pteridines; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Ronald Gress
• Organization: National Cancer Institute

Ronald_Gress@nih.gov

240-760-6167

Study Officials

• Daniel H Fowler, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 8, 2003
• First Posted: January 8, 2003
• Study Start: January 3, 2003
• Primary Completion: September 25, 2014
• Study Completion: September 25, 2014
• Last Updated: September 9, 2021
• Results First Posted: September 9, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)