Stem Cell Transplant Therapy With Campath-1H for Treating Advanced Mycosis Fungoides and Sezary Syndrome

Study Overview
=================
Brief Summary
-----------------
This study will investigate the safety and effectiveness of a modified donor stem cell transplantation procedure for treating advanced mycosis fungoides (MF), a lymphoma primarily affecting the skin, and Sezary syndrome (SS), a leukemic form of the disease. Donated stem cells (cells produced by the bone marrow that mature into the different blood components white cells, red cells and platelets) can cure patients with certain leukemias and lymphomas and multiple myeloma. These cells generate a completely new, functioning bone marrow. In addition, immune cells from the donor grow and generate a new immune system to help fight infections. The new immune cells also attack any residual tumor cells left in the body after intensive chemotherapy. However, stem cell transplantation carries a significant risk of death, because it requires completely suppressing the immune system with high-dose chemotherapy and radiation. In addition, lymphocytes from the donor may cause what is called graft vs. host disease (GvHD), in which these cells see the patient s cells as foreign and mount an immune response to destroy them. To try to reduce these risks, patients in this study will be given low-dose chemotherapy and no radiation, a regimen that is easier for the body to tolerate and involves a shorter period of complete immune suppression. In addition, a monoclonal antibody called Campath-1H will be given to target lymphocytes, including those that have become cancerous. Patients with advanced MF or SS who are between 18 and 70 years of age and have a matched family donor 18 years of age or older may be eligible for this study. Candidates will have a medical history, physical examination and blood tests, lung and heart function tests, X-rays of the chest, eye examination, and bone marrow sampling (withdrawal through a needle of about a tablespoon of marrow from the hip bone), and small skin biopsy (surgical removal of a piece of tissue for microscopic examination) or needle biopsy of the tumor. Stem cells will be collected from both the patient and donor. To do this, the hormone G-CSF will be injected under the skin for several days to push stem cells out of the bone marrow into the bloodstream. Then, the stem cells will be collected by apheresis. In this procedure the blood is drawn through a needle placed in one arm and pumped into a machine where the required cells are separated out and removed. The rest of the blood is returned through a needle in the other arm. Before the transplant, a central venous line (large plastic tube) is placed into a major vein. This tube can stay in the body and be used the entire treatment period to deliver the donated stem cells, give medications, transfuse blood, if needed, and withdraw blood samples. Several days before the transplant procedure, patients will start a conditioning regimen of low-dose chemotherapy with Campath 1H, fludarabine, and, if necessary, cyclophosphamide. When the conditioning therapy is completed, the stem cells will be infused over a period of up to 4 hours. To help prevent rejection of donor cells and GvHD, cyclosporine and mycophenolate mofetil will be given by mouth or by vein for about 3 months starting 4 days before the transplantation. The anticipated hospital stay is 3 to 4 days, when the first 3 doses of Campath will be monitored for drug side effects. The rest of the procedures, including the transplant, can be done on an outpatient basis. Follow-up visits for the first 3 months after the transplant will be scheduled once or twice a week for a physical examination, blood tests and symptoms check. Then, visits will be scheduled at 6, 12, 18, 24, 30, 36, and 48 months post-transplant. Visits for the first 3 years will include blood tests, skin biopsies, and bone marrow biopsies.

Detailed Description
-----------------
Primary cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders characterized by localization of neoplastic T cells to the skin at presentation. Mycosis fungoides (MF) and its leukemic variant Sezary syndrome (SS) are the most prevalent forms of CTCL. While early stage MF is restricted to patches and plaques involving the skin, most patients eventually develop cutaneous tumors, generalized erythroderma, or dissemination to peripheral blood, lymph nodes or visceral organs. Currently existing therapy of tumor-stage and disseminated CTCL is palliative, with most patients dying within 1-5 years. The presence of CD8+ cells in close proximity to dermal neoplastic infiltrates in early stages of the disease, and the clinical response seen with some immunomodulatory agents suggests that CTCL may be potential targets for immunotherapy-based interventions. Allogeneic stem cell transplantation is a curative treatment modality successfully employed in a number of hematologic malignancies. The curative effect of this approach is in part mediated by donor-derived T lymphocytes with reactivity for patient leukemic cells. The power of this graft versus leukemia effect (GVL) is best illustrated in patients with relapsed Chronic Myeloid Leukemia (CML) after an allogeneic bone marrow transplant, in whom a single donor lymphocyte infusion (DLI) can induce remission. We hypothesize that neoplastic T cells in MF/SS may similarly be susceptible to a graft vs. tumor (GVT) effect. Unfortunately, advanced patient age and a 25% to 35% risk of transplant related mortality (TRM) preclude the use of conventional 'dose- intensive' allogeneic peripheral blood stem cell transplantation (PBSCT) in patients with advanced CTCL who might otherwise benefit from this approach. The risk of TRM related to conditioning can be circumvented at least partially by using a reduced-intensity conditioning regimen to prepare the patient for transplantation. In this study, we will treat male and non-pregnant female subjects between the ages of 18 and 70 years (both inclusive) suffering from advanced MF/SS with an allogeneic peripheral blood stem cell (PBSC) transplant from an HLA-matched family donor or an HLA matched (10/10 allele level match) unrelated donor. A low intensity, nonmyeloablative conditioning regimen employing the anti-CD52 monoclonal antibody Campath-1H (alemtuzumab) and fludarabine will be used to induce host immunosuppression to facilitate donor hematopoietic and lymphoid engraftment. We anticipate minimal host myelosuppression and consequently reduced early transplant toxicity with this conditioning regimen. Immune and hematopoietic reconstitution will be achieved by infusion of unmanipulated donor-derived granulocyte colony stimulation factor (G-CSF) mobilized peripheral blood stem cells. Infusion of donor lymphocytes in incremental doses will be used to promote engraftment or disease regression when indicated. Cyclosporine A (CSA) will be used as prophylaxis against graft vs host disease (GVHD), with dose adjustments made as necessary to favor complete donor chimerism and disease regression. A total of up to 25 subjects (transplant recipients) will be treated on this protocol. The primary end point of this study is efficacy (proportion of subjects achieving a complete response). Other end points include assessment of donor-host chimerism in various hematopoietic and lymphoid cells, overall response, incidence of acute and chronic GVHD, graft failure, assessment of lymphoid subset reconstitution, transplant related morbidity and mortality and disease-free and overall survival and the outcomes of transplantation by the donor type (related vs. unrelated).

Official Title
-----------------
A Phase I/II Study of HLA-matched Mobilized Peripheral Blood Hematopoietic Stem Cell Transplantation for Advanced Mycosis Fungoides/Sezary Syndrome Using Nonmyeloablative Conditioning With Campath-1H

Conditions
-----------------
Mycosis Fungoides, Sezary Syndrome

Intervention / Treatment
-----------------
* Other: A matched peripheral donor stem cells
* Drug: cyclosporine
* Drug: fludarabine
* Drug: Campath


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA-RECIPIENT: Ages 18-70 years (both inclusive) Stages IIb to IVb patients with MF (biopsy diagnostic or consistent with MF) who have progressed despite at least one treatment regimen and all patients with SS AND Anticipated median survival less than 5 years or debilitation as a result of their disease. Recovery from acute toxicity of prior treatment for MF/SS (to less than or equal to grade 1 [CTCAE v3.0]) or stabilization of toxicity occurring from prior therapy for MF/SS. HIV negative ECOG performance status of 1 or less. No major organ dysfunction precluding transplantation. DLCO greater than or equal to 60 percent predicted Left ventricular ejection fraction greater than or equal to 40 percent. Less than or equal to 25 percent of liver involved with metastatic tumor by CT scan. 6/6 HLA matched family donor or 10/10 matched unrelated donor at the allelic level available Ability to comprehend the investigational nature of the study and provide informed consent. INCLUSION CRITERIA-RELATED and UNRELATED DONOR:<TAB> 6/6 HLA- matched family donor or 10/10 HLA-matched unrelated donor Age greater than or equal to 18 years Ability to comprehend the investigational nature of the study and provide informed consent. For unrelated donor, the NMDP unrelated donor inclusion criteria will be used as outlined in document (http://bethematch.org/WorkArea/DownloadAsset.aspx?id=1960). Donor eligibility will be completed per NMDP standards and in accordance with most recent and stringent FDA guidelines. EXCLUSION CRITERIA (ANY OF THE FOLLOWING)-RECIPIENT Patient pregnant or lactating Age greater than 70 or less than 18 years ECOG performance status of 2 or more. Psychiatric disorder or mental deficiency of the recipient or donor sufficiently 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 BMT and where survival is considered insufficient to assess transplant outcome (i.e. less than 3 months). DLCO less than 60 percent predicted Left ventricular ejection fraction less than 40 percent Serum creatinine greater than 2.0 mg/dl Serum bilirubin greater than 4 mg/dl, transaminases greater than 5 times the upper limit of normal HIV positive History of other malignancies in the last five years with the exception of basal cell or squamous cell carcinoma of the skin Evidence for CNS metastatic disease Disease involving greater than 25 percent of the liver radiographically. EXCLUSION CRITERIA (any of the following)-RELATED AND UNRELATED DONOR: Donor pregnant or lactating Age less than 18 years HIV positive (donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human T-cell lymphotropic virus (HTLV-1) will be used at the discretion of the investigator following counseling and approval from the recipient). Sickling hemoglobinopathy including HbSS or HbsC (for unrelated donors, testing for hemoglobinopathies will only be done when clinically indicated). History of malignancy within 5 years except basal cell or squamous carcinoma of the skin. Donor unfit to receive G-CSF and undergo apheresis (Uncontrolled hypertension, history of stroke, thrombocytopenia). Psychiatric disorder or mental deficiency of the donor sufficiently severe as to make compliance with the BMT treatment unlikely and making informed consent impossible.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stem Cell Transplant Therapy With Campath-1H<br>Recipients received a nonmyeloablative preparative regimen of alemtuzumab 30mg iv three times a week for two weeks followed by fludarabine 25mg/m2/day for five days followed by a PBPC graft targeted to deliver ≥ 5x106 CD34+ cells/kg. Cyclosporine A (CSA) for GVHD prophylaxis used initially with target CSA levels in the therapeutic range (200 -400 ng/ml). | Other: A matched peripheral donor stem cells<br>* A matched peripheral donor stem cells<br>* Other names: Allogeneic peripheral stem cell transplant;Drug: cyclosporine<br>* cyclosporine<br>* Other names: CSA;Drug: fludarabine<br>* fludarabine<br>* Other names: fludara;Drug: Campath<br>* Campath<br>* Other names: Alemtuzumab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Nonmyeloablative Preparative Regimen | Proportion of subjects achieving a complete response. Complete response (CR) is defined as: disappearance of all signs and symptoms of cutaneous T-cell lymphomas (CTCL) for a period of at least one month. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Acute GVHD Grades II-IV | Number of participants who experienced acute GVHD grades II-IV Acute-GVHD was graded and staged prospectively using criteria from the 1994 Consensus Conference on Acute- GVHD Grading. Grades are defined as: Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day. Grade III: Skin = Rash on >50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea > 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin >15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. | up to 100 days | 
| Number of Participant Who Experienced Chronic Graft Versus Host Disease | Number of participant who experienced chronic graft versus host disease (GVHD) following stem cell transplant The diagnosis of clinical features of chronic-GVHD was determined prospectively and classified retrospectively into limited or extensive based on the Revised Seattle Classification. Chronic GvHD severity categorized as limited is defined as: localized skin lesions with or without limited hepatic involvement and extensive is defined as: generalized skin involvement, major hepatic complications, or involvement of any other organ. | Day 100 up to 3 years | 
| Number of Participants That Experienced Graft Failure | Number of participants that experienced graft failure. Graft failure is defined as: the failure to achieve sustained engraftment following stem cell transplantation. | up to 100 days | 
| Overall Response | Overall response following stem cell transplant. Complete response (CR) is defined as: disappearance of all signs and symptoms of cutaneous T-cell lymphomas (CTCL) for a period of at least one month. Partial response (PR) - a 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions (a greater than 50% reduction in area of disease involvement in the case of cutaneous disease) lasting for a period of at least one month. No new metastatic lesions may appear. Stable disease is defined as: tumor measurements not meeting the criteria of CR, PR, or PD. Progressive disease (PD) - increase of 25% or greater in the sum of the products of the longest perpendicular diameters of all measured lesions (a greater than 25% increase in area of disease involvement in the case of cutaneous disease) compared to the smallest previous measurements, or the development of any new metastatic or cutaneous disease. | Up to 3 years | 
| Number of Participants Who Experienced Transplant Related Mortality | Number of Participants who experienced transplant related mortality by day 100 | day 100 | 
| Number of Participants Overall Survival | Number of participants overall survival following stem cell transplant. Overall survival is defined as number participants alive following stem cell transplant | up to 5 years | 
| Number of Participants That Remained Disease-free | Number of participants that remained Disease-free survival following stem cell transplant. Disease-free survival is defined as survival free of disease relapse or disease progression following stem cell transplant. | up to 100 days | 
| Number of Participants That Experienced Engraftment | Number of participants that experienced engraftment following stem cell transplant. Engraftment is defined as neutrophil count is greater than 0.5 x10^9. | up to 100 days | 
| Number of Participants That Experienced Platelet Recovery | Number of participants that experienced platelet recovery up to day 100 following stem cell transplant. Platelet recovery is defined as platelet count is greater than 50 x 10^9/l without platelet transfusion. | up to 100 days | 
| Number of Participants That Experienced Red Blood Cell Recovery | Number of participants that experienced red blood cell recovery following stem cell transplant. Red blood cell recovery is defined as achieving transfusion independence. | up to 100 days | 
| Median Time in Months to Achieve Full Myeloid and Full Donor T-cell Chimerism | Median time in months to achieve full myeloid and full donor T-cell Chimerism. Myeloid (CD34+) and T-cell (CD3+) chimerisms were determined by PCR analysis of short tandem repeats (STR). Full donor chimerism is defined as >95% donor- derived cells in the peripheral blood in a specific lineage. | Up to 22 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sezary Syndrome, Cutaneous T Cell Lymphoma, Allogeneic PBSCT, Mycosis Fungoides, CTCL, Low Intensity Regimen