OTI-010 for Graft-Versus-Host Disease Prophylaxis in Treating Patients Who Are Undergoing Donor Peripheral Stem Cell Transplantation for Hematologic Malignancies

RATIONALE: OTI-010 may be effective for graft-versus-host disease prophylaxis (prevention) in patients who are undergoing donor peripheral stem cell transplantation for hematologic malignancies (cancer of the blood or bone marrow).

PURPOSE: This randomized phase II trial is studying how well OTI-010 works in preventing graft-versus-host disease in patients who are undergoing donor peripheral stem cell transplantation for hematologic cancer.

OBJECTIVES:

• Compare the safety and efficacy of OTI-010 vs placebo as graft-versus-host disease prophylaxis in patients with hematologic malignancies undergoing HLA-identical sibling matched peripheral blood stem cell transplantation.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to age (18 to 34 vs 35 to 55) and donor/recipient gender (female donor/male recipient vs female donor/female recipient vs male donor/female recipient vs male donor/male recipient).

• Conditioning regimen: Patients receive cyclophosphamide IV once daily on days -5 and -4 and undergo total body irradiation twice daily on days -3 to -1 OR busulfan IV over 2 hours every 6 hours on days -7 to -4 and cyclophosphamide IV once daily on days -3 and -2.
• Graft-versus-host disease prophylaxis: Patients receive methotrexate IV on days 1, 3, 6, and 11. Patients also receive cyclosporine orally or IV (over 1-4 hours) twice daily beginning on day -1 and continuing for at least 6 months followed by a taper until 1 year after transplantation.

• OTI-010 therapy: Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Patients receive placebo IV 4 hours before peripheral blood stem cell transplantation (PBSCT) on day 0.
  • Arm II: Patients receive OTI-010 IV 4 hours before PBSCT on day 0.
  • Arm III: Patients receive a higher dose of OTI-010 IV 4 hours before PBSCT on day 0.
• Allogeneic stem cell transplantation: Patients undergo allogeneic PBSCT on day 0.

Patients are followed at 18 weeks, at 6, 9, and 12 months, every 6 months for 1 year, and then annually for 3 years.

PROJECTED ACCRUAL: A total of 99 patients (33 per treatment arm) will be accrued for this study within 5 months.

• Graft Versus Host Disease
• Leukemia
• Myelodysplastic Syndromes

• Biological: autologous expanded mesenchymal stem cells OTI-010
• Drug: busulfan
• Drug: cyclophosphamide
• Drug: cyclosporine
• Drug: methotrexate
• Procedure: peripheral blood stem cell transplantation
• Radiation: radiation therapy

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following hematologic malignancies:

  • Acute lymphoblastic leukemia, meeting 1 of the following criteria:

    • In first or second remission
    • In early first or second relapse*

  • Acute myeloid leukemia, meeting 1 of the following criteria:

    • In first or second remission
    • In early first or second relapse*

  • Chronic myelogenous leukemia

    • Chronic or accelerated phase

  • Any of the following myelodysplastic syndromes:

    • Refractory anemia (RA)
    • RA with ringed sideroblasts
    • RA with excess blasts NOTE: *< 24% marrow blasts and < 5% peripheral blood blasts (within 10 days of beginning conditioning regimen)
• No secondary acute leukemia
• Prior CNS tumor involvement allowed provided patient is asymptomatic and there is no evidence of CNS disease on lumbar puncture and CT scan of the brain
• Must have a 6/6 HLA-identical sibling donor available

PATIENT CHARACTERISTICS:

Age

• 18 to 55

Performance status

• Karnofsky 70-100%

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin < 2 times upper limit of normal (ULN)
• SGOT < 10 times ULN
• Hepatitis B core antigen, surface antigen, and e-antigen negative
• Hepatitis B DNA negative
• Hepatitis C RNA negative

Renal

• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• LVEF ≥ 50% by MUGA or echocardiogram
• No right sided heart failure

Pulmonary

• FEV_1 > 50% of predicted
• DLCO ≥ 50% of predicted (corrected for anemia)
• Oxygen saturation ≥ 97% on room air
• No pulmonary hypertension

Immunologic

• HIV-1 and 2 antibody negative
• HIV-1 antigen negative
• HTLV-I and II antibody negative
• No active infection

Other

• CNS function normal
• No uncontrolled alcohol or substance abuse within the past 6 months
• No other concurrent underlying medical condition that would preclude study participation
• Not pregnant
• Negative pregnancy test
• Fertile patients must use 2 effective methods of contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior allogeneic or autologous hematopoietic stem cell transplantation
• No concurrent medication to accelerate neutrophil or platelet engraftment except filgrastim (G-CSF)

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• No prior solid organ transplantation

Other

• More than 30 days since prior investigational agents or devices
• No other concurrent investigational agents or devices
• No concurrent anti-infective therapy except prophylactic therapy
• No other concurrent conditioning regimen agents
• No concurrent herbal remedies except multivitamins
• No other concurrent graft-versus-host disease prophylaxis medications (e.g., ursodeoxycholic acid)