Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

Background:

• Patients with cancers of the blood and immune system often benefit from transplants of stem cells from a genetically well-matched sibling. However, severe problems may follow these transplants because of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune cells sometimes attack healthy tissues in a reaction called graft-versus-host disease (GVHD), damaging organs such as the liver, intestines and skin.

• To reduce toxicity of high-dose preparative chemotherapy, this study uses low-intensity preparative chemotherapy or no preparative chemotherapy.

• To reduce GVHD, this study uses donor immune cells (Th2 cells) grown in the laboratory with an immune modulating drug called sirolimus, plus therapy with sirolimus and cyclosporine A (CSA).

Objective: To determine the safety, treatment effects and rate of GVHD in patients treated with CSA plus sirolimus together with: 1) low-intensity preparative chemotherapy plus Th2 cells; or 2) Th2 cells alone.

Eligibility:

• Patients 18 to 75 years of age with acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome.

• Patients must have a suitable genetically matched sibling donor and adequate kidney, heart and lung function.

Design:

• Subjects will initially receive outpatient induction chemotherapy (EPOCH, fludarabine, and when applicable, Rituxan; total cycle number, 1 to 3).

• 25 subjects will be accrued to arm IV and 25 subjects will be accrued to arm V. On arm IV, subjects will receive transplantation after a low-intensity preparative regimen (cyclophosphamide [total of 1200 mg/m(2)] and fludarabine) with Th2 cell administration on day 14 post-HSCT. On arm V, subjects will receive transplantation after EPOCH-F chemotherapy, with Th2 cell infusion on day 0 of HSCT.

• Subjects will receive a G-CSF mobilized, T cell replete peripheral blood allograft (or alternatively, a non-mobilized marrow allograft), conventional cyclosporine GVHD prophylaxis, and short-course sirolimus therapy (through day 14 post-transplant).

Further Study Information

Background:

In protocol 99-C-0143, we evaluated a new approach to allogeneic HSCT that involved intensive host T cell ablation and graft augmentation with in vitro generated donor Th2 cells. Rapid full donor engraftment occurred with this regimen; however, grade II to IV acute GVHD was not significantly reduced in Th2 cell recipients. In an attempt to improve clinical results using Th2 cell graft engineering, this second-generation Th2 cell clinical trial was developed that incorporates the following interventions: (1) In an attempt to reduce transplant-related toxicity, this protocol now uses a very low-intensity host preparative chemotherapy; (2) In an attempt to reduce GVHD, this study will utilize Th2 cells expanded in the presence of the immune modulation agent, rapamycin (sirolimus), as murine Th2 cells grown in rapamycin reduce GVHD more effectively than control Th2 cells; and (3) To further reduce GVHD, subjects will receive a short-course of sirolimus therapy in addition to standard cyclosporine GVHD prophylaxis.

Objectives:

In the setting of HLA-matched sibling allogeneic HSCT using GVHD prophylaxis of cyclosporine A (CSA) and short-course sirolimus (to day 14 post-HSCT), determine the safety, feasibility, alloengraftment, clinical anti-tumor effects, and GVHD rate of low-intensity Preparative Chemotherapy plus Th2 cells at day 14 post-HSCT.

Eligibility:

Subjects that are 18 to 75 years of age that have a suitable 6/6 HLA-matched sibling donor are potentially eligible. Subjects with a diagnosis of acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome are potentially eligible. Adequate kidney, cardiac, and pulmonary function are required.

Design:

All subjects will initially receive outpatient induction chemotherapy (EPOCH, fludarabine, and when applicable, Rituxan; total cycle number, 1 to 3). A total of 120 patients will be enrolled to this transplant approach using low-intensity chemotherapy and donor Th2 cell infusion on day 14 posttransplant; 40 patients will receive Th2 cells manufactured by a 12-day culture method; 40 patients will receive Th2 cells manufactured by a 6-day culture method; and 40 patients will receive the 6-day manufactured Th2 cells in combination with a higher target dose of sirolimus for GVHD prophylaxis. All subjects will receive a G-CSF mobilized, T cell replete peripheral blood allograft (or alternatively, a non-mobilized marrow allograft), conventional cyclosporine GVHD prophylaxis, and short-course sirolimus therapy (through day 14 post-transplant).

Eligibility Criteria

• INCLUSION CRITERIA: PATIENT RECIPIENT

1. Patients with hematologic malignancies, myelodysplasia, or myeloproliferative disorders, as summarized in the following table. The diagnosis must be histologically confirmed by the Laboratory of Pathology of NCI or Hackensack (There will be not central pathology review).

Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b) Non-CR after salvage regimen.

Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma) - Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT, c) Non-CR after salvage regimen

Special Cases of High-Risk Lymphoma, including but not limited to : (1) plasma dendritic cell type, 2) Hepato-splenic T cell type, 3) gamma delta pinniculitic T cell type, 4) Muco-cutaneous NK cell type and 5) stage III-IV nasal NK cell type- Disease Status: a) Primary treatment failure, b) Relapse after autologous, c) Non-CR after salvage regimen, d) In forist CR or any later CR

Chronic EBV-associated lymphoproliferative disease a) At any point after diagnosis, including up-front therapy

Multiple Myeloma - Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT, c) Non-CR after salvage regimen.

Acute Myelogenous Leukemia - Disease Status: a) CR number 1 and high-risk [excludes t(8;21), t(15;17), or inv(16)], b) CR number 2 or greater).

Acute Lymphocytic Leukemia - Disease Status: a) CR number 1 plus high-risk [t(9;22) or bcr-abl(+); t(4;11), 1(1;19), t(8;14)], b) In CR number2 or greater.

Myelodysplastic Syndrome - Disease Status: a) RAEB, b) RAEB-T (requires marrow and blood blasts less than 10% after induction chemotherapy).

Myeloproliferative disorders - Disease Status: a) Idiopathic myelofibrosis, b) Polycythemia vera, c) Essential thrombocytosis, d) Chronic myelomonocytic leukemia.

Chronic Myelogenous Leukemia - Disease Status: a) Chronic phase CML, refractory to imatinib treatment b) Accelerated phase CML. b) Accelerated phase CML

Patients with myeloproliferative disorders must be end-stage, which is primarily defined as disease severity refractory to splenectomy.

2. Patient age of 18 to 75 years.

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

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

5. All previous therapy must be completed at least 2 weeks prior to study entry, with recovery to less than or equal to non-hematologic grade 2 toxicity of previous therapy.

6. ECOG performance status equal to 0 or 1.

7. Life expectancy of at least 3 months.

8. Acute leukemia must be in hematologic remission (less than 10% blood or marrow blasts).

9. Left ventricular ejection fraction greater than or equal to 45%, preferably by 2-D echo, or by MUGA. However, patients with LVEF of between 35% and 44% may also be eligible provided that such patients are cleared by a Cardiology Consultation that must include a cardiac stress test.

10. Corrected DLCO greater than 50% of expected value.

11. Creatinine less than or equal to1.5 mg/dl and creatinine clearance greater than or equal to 50 ml/min.

12. Serum total bilirubin less than 2.5 mg/dl; serum ALT and AST equal 2.5 times upper limit of normal. Values above these levels may be accepted, at the discretion of the PI or study chairman, if such elevations are thought to be due to liver involvement by malignancy.

13. Adequate central venous access potential.

14. Potential patients referred for the study may not be eligible for the experimental protocol therapy due to reasons such as uncertainty about donor HLA typing or need to control malignant disease, infection, or metabolic abnormality such as hypercalcemia on a emergent basis. Should a referred patient present to us in such a scenario, the patient will be referred back to their primary hematologist-oncologist for treatment. However, if referral back to the referring physician is not in the best interest of the patient according to the clinical judgement of the PI, then the patient may receive standard treatment for the malignant disease or complicating conditions (infection, metabolic problems under the durrent study. If it becomes apparent that the patient will not be able to proceed to experimental therapy, then he/she must come off study. Recipient-Subjects receiving a standard therapy, and availability of receiving the same treatment elsewhere, outside of a research protocol. Because such standard care therapy is not experimental, it is not necessary to complete the eligibility criteria prior to receiving such standard care; however, prior to initiation of the experimental therapy, the patient must meet each of the eligibility crieteria detailed above.

INCLUSION CRITERIA: DONOR

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

2. Age 18 to 90 years.

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

4. Alternatively, in the event that a potential donor either has a contra-indication to apheresis, is not able to mobilize adequate hematopoietic stem cells, or refuses the mobilization procedure, then a potential donor may be offered stem cell collection via bone marrow harvest.

5. Donors must be HIV negative.

6. Donors with a history of hepatitis B or hepatitis C infection may be eligible. However, eligibility determination of such patients will require a hepatology consultation. The risk/benefit of the transplant and the possibility of transmitting hepatitis will be discussed with the patient and eligibility will then be determined by the principle investigator and Lead Associate Investigator.

7. Lactating donors must substitute formula feeding for her infant during period of filgrastim administration (to prevent any filgrastim effect on infant).

EXCLUSION CRITERIA: PATIENT

1. Active infection that is not responding to antimicrobial therapy.

2. Active CNS involvement by malignancy.

3. HIV infection (treatment may result in progression of HIV and other viral infections).

4. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with concomitant positive hepatitis B surface antigen, patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis B will be discussed with the patient and eligibility determined by the principal investigator and Lead Associate Investigator.

5. Hepatitis C infection. Patient may have hepatitis C infection. However, each patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis C will be discussed with the patient and eligibility determined by the principal investigator and Lead Associate Investigator.

6. Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the 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.

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

EXCLUSION CRITERIA: DONOR

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

2. History of hypertension that is not controlled by medication, stroke, autoimmune disease, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.

3. History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-by-case basis. In addition, donors with localized cancer such as prostate cancer that are on a watch-and-wait management due to the low-risk of disease progression may also be considered for stem cell donation on a case-by-case basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient.

4. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of childbearing potential must use an effective method of contraception.

5. Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microliter). However, potential donors with Hb levels less than 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy and the case is individually approved by NIH or Hackensack Blood Bank.

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

NCI Referral Office

Ph: 1-888-NCI-1937

U.S.A.
Maryland
	Bethesda
	NIH - Warren Grant Magnuson Clinical Center
		National Cancer Institute Referral Office For more information at the NIH Clinical Center contact	Sub-Investigator
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00074490
Information obtained from ClinicalTrials.gov on January 09, 2012

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