T-Reg Cell Kinetics for Patients Receiving Stem Cell Transplant

Official Title: “T-Regulatory Cell Kinetics for Patients Receiving Alemtuzamb and Undergoing Stem Cell Transplantation From HLA Mismatched-Related or One Antigen Mismatched-Unrelated Donors”

Objective 1:To define the biologic recovery and behavior of T regulatory cells for patients undergoing stem cell transplantation as a necessary prelude to the design of clinical trials in which perturbation to T regulatory cells will be investigated as a means to reduce relapse, GVHD, and infection.

Objective 2: To determine that the administration of Campath 1H as part of conditioning therapy to patients undergoing stem cell transplantation from mismatched related donors or from matched unrelated donors permits T regulatory cell recovery.

The SC Transplant being given to the population will be standardized to help in evaluation of the T cell data. As such it is part of the research although not an investigational regimen.

THERAPY

Patient undergoing stem cell transplantation from HLA mismatched related donor or from HLA matched unrelated donor.

SCT Conditioning. All patients except those with T cell lymphoma will receive Ara C (3000 mg/m2) IV every 12 hours for 6 doses starting at 1400 hours on day -8. Cyclophosphamide (45mg/kg) IV once daily on day -7 and day -6 starting at 1400 hours. MESNA (45mg/kg; divided into 5 doses) will be administered 15 minutes prior to each dose of Cyclophosphamide and 3, 6, 9, and 12 hours after each dose of Cyclophosphamide. CAMPATH (3 mg IV for patients between 5 and 15 kg; 5 mg for patients between 16 and 30 kg; and 10 mg for patients greater than 30 kg) will be given on day -4, day -3, day -2 and day-1. TBI, total dose 14.0 Gy, will be delivered in 8 fractions of 1.75 Gy in two fractions on day -4, day -3, day -2, and day -1. For patients with T cell lymphoma, Ara C will be omitted.

GVHD Prevention. Patients will begin tacrolimus 0.03 mg/kg/day IV beginning on day -2.

Tacrolimus blood level will be obtained on day 0 and as clinically indicated thereafter.

Tacrolimus dose will be adjusted to maintain blood level greater than 5 ng/ml. Tacrolimus will be tapered per institutional SOP. Patients will receive Methotrexate 5 mg/m2 IV on day +1, +3, +6, and +11.

Day Treatment Dose - 8 Ara-C dose 1 3000 mg/m2/dose - 7 Ara-C doses 2 & 3 3000 mg/m2/dose Cyclophosphamide dose 1 45 mg/kg/dose Mesna 45 mg/kg divided as noted - 6 Ara C doses 4 & 5 3000 mg/m^2/dose Cyclophosphamide dose 2 45 mg/kg/dose Mesna 45 mg/kg divided as noted - 5 Ara C dose 6 3000 mg/m^2/dose - 4 TBI fraction 1 & 2 1.75 Gy/fraction - 3 TBI fraction 3 & 4 1.75 Gy/fraction - 2 TBI fraction 5 & 6 1.75 Gy/fraction Begin Tacrolimus 0.03 mg/kg - 1 TBI fraction 7 & 8 1.75 Gy/fraction

0 Stem cell infusion

1 Methotrexate 5 mg/m^2

3 Methotrexate 5 mg/m^2

6 Methotrexate 5 mg/m^2

11 Methotrexate 5 mg/m^2

Patients with CNS disease will receive additional irradiation to the craniospinal axis. See appendix.

Patients who develop acute GVHD will be managed according to CAGT SOP.

Patients who develop chronic GVHD will be managed according to CAGT SOP.

Patients will receive prophylaxis for bacterial, fungal, and viral illness according to CAGT SOP.

Patients who develop infections will be treated according to CAGT SOP.

Patients will receive hematopoietic supportive care according to CAGT SOP.

Patients will receive nutritional supportive care according to CAGT SOP.

For patients on this protocol who are eligible for and enrolled on investigational study(ies) related to supportive care, CAGT SOPs may be superseded by investigational therapies.

EVALUATION

Prior to enrollment evaluation adheres to CAGT SOP -- History and physical - Determination of disease status, with immunophenotype and cytogenetic studies as appropriate - Chest X-ray - Echocardiogram and electrocardiogram - GFR or 24 hour creatinine clearance and urinanalysis - Pulmonary function tests with DLCO if age appropriate - CAGT SOP and FACT mandated infectious disease tests - CBC, coagulation profile, chemistry 18 panel - Blood group and Rh typing - Quantitative immunoglobulin - ΒHCG for female patients - Dental, ophthalmology, and audiology consult as indicated - Neuropsychology assessment as indicated - Blood for STR determination

Commencement Of Sct Conditioning Therapy Until Discharge From The Hospital - Physical examination as appropriate - At a minimum, weekly CBC, chemistry 18 panel, urinanalysis - Determination of chimerism status as clinically appropriate - Determination of disease status as clinically appropriate

From Discharge Through Year 1 Post Transplant - Physical examination as appropriate - At a minimum monthly CBC, chemistry 18 panel, urinanalysis - Determination of chimerism status as clinically appropriate - Determination of disease status as clinically appropriate Beyond 1 Year Post Transplant -- According to CAGT SOPs

Blood +/- bone marrow for Regulatory T Cell Assay Blood will be obtained for assay of regulatory T cells and includes assessment of general immunity and reconstitution (e.g.

anti-infectious and anti-tumor specific T-cell immunity) at approximately monthly intervals during the first 6 months following transplantation; at month 9 and at 1 year, 2 years, and 3 years following transplantation. Each sample will require 30 to 40 ml (6 - 8 tsps). For patients less than 20kg no more than 1 ml/kg will be collected. Bone marrow will be collected as clinically indicated (usually pre BMT, around day +30, day +100 and 1 year post BMT). If patients are receiving a BM aspirate for clinical indications 1ml of additional sample will be collected for immunological studies as described above. No more than 5mls of total bone marrow will be collected from any patient in a 12month period.

Toxicity Evaluation Criteria - Toxicity monitoring will adhere to CAGT SOP. - Stage and grade acute and chronic GVHD will adhere to CAGT SOP. - Performance status will be according to the Karnofsky or Lansky scales - SCT engraftment will be determined thusly - Neutrophil engraftment is defined as the first day of 3 consecutive days for which the absolute neutrophil count exceeds 500/uL - Platelet engraftment is defined as the first day the platelet count exceeds 20,000/uL without transfusion. - Chimerism studies are complimentary engraftment studies and are performed in conjunction with anc recovery

Intervention(s) in this Clinical Trial

• Drug: Ara C
  • day -8: Ara C (3000 mg/m2) IV every 12 hours for 6 doses
• Drug: Cyclophosphamide
  • Cyclophosphamide (45mg/kg) IV once daily on day -7 and day -6
• Drug: MESNA
  • MESNA (45mg/kg; divided into 5 doses) will be administered 15 minutes prior to each dose of Cyclophosphamide and 3, 6, 9, and 12 hours after each dose of Cyclophosphamide.
• Procedure: TBI
  • TBI: total dose 14.0 Gy, will be delivered in 8 fractions of 1.75 Gy in two fractions on day -4, day -3, day -2, and day -1
• Biological: Campath-1h
  • CAMPATH (3 mg IV for patients between 5 and 15 kg; 5 mg for patients between 16 and 30 kg; and 10 mg for patients greater than 30 kg) will be given on day -4, day -3, day -2 and day-1.
• Procedure: Stem Cell Infusion
  • Stem Cell Infusion on day 0
• Drug: Tacrolimus
  • Patients will begin tacrolimus 0.03 mg/kg/day IV beginning on day -2. Tacrolimus blood level will be obtained on day 0 and as clinically indicated thereafter. Tacrolimus dose will be adjusted to maintain blood level greater than 5 ng/ml. Tacrolimus will be tapered per institutional SOP
• Drug: Methotrexate
  • Methotrexate 5 mg/m2 IV on day +1, +3, +6, and +11

Primary Measures

• To define the biologic recovery and behavior of T reg cells for pts undergoing SCT as a prelude to the design of clinical trials in which perturbation to T reg cells will be investigated as a means to reduce relapse, GVHD and infection.
  • Time Frame: 2 years
    Safety Issue?: No

Secondary Measures

• To determine that the administration of Campath 1H as part of conditioning therapy to patients undergoing stem cell transplantation from mismatched related donors or from matched unrelated donors permits T regulatory cell recovery.
  • Time Frame: 2 years
    Safety Issue?: Yes

Inclusion Criteria:

• Patients with acute or chronic leukemia or advanced Hodgkin or non Hodgkin lymphoma or myelodysplastic/myeloproliferative disease who are unlikely to be cured by standard chemotherapy treatments. This includes patients who have relapsed after standard chemotherapy treatments and patients in first remission with unfavorable prognostic features.
• Using the standard 6 HLA antigen profile (HLA class I, A and B, and HLA class II, DRB1) a patient must have either a one HLA antigen mismatched related donor or one antigen mismatched unrelated donor.

Exclusion Criteria:

• Patients with a life expectancy ( less than or equal to 6 weeks) limited by disease other than leukemia.
• Patients with symptomatic cardiac failure unrelieved by medical therapy or evidence of significant cardiac dysfunction by echocardiogram (shortening fraction <20%).
• Patients with severe renal disease (i.e., creatinine greater than 3 times normal for age).
• Patients with pre-existing severe restrictive pulmonary disease (FVC less than 40% of predicted).
• Patients with severe hepatic disease (direct bilirubin greater than 3 mg/dl or AST greater than 500 IU/L).
• Patients with severe personality disorder or mental illness.
• Patients with severe infection that in the estimation of the principal investigator prohibits the use of ablative chemotherapy.
• Patients who are documented HIV positive.
• Patients with a Karnofsky performance score <70% or Lansky score <50%.
• NOTE: Patients who would be excluded from treatment on this protocol strictly for laboratory abnormalities can be included at the principal investigator's discretion after consultation with the members of the SCT Policy and Procedures Committee.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 64 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Baylor College of Medicine Other

Overall Clinical Trial Officials and Contacts

Robert Krance, MD Principal Investigator Baylor College of Medicine  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00578539

Study ID Number: 21079-REGALE

ClinicalTrials.gov Identifier: NCT00578539

Health Authority: United States: Institutional Review Board