Melphalan, Yttrium Y 90 Ibritumomab Tiuxetan, and Rituximab Followed by Autologous Stem Cell Transplant in Treating Older Patients With Non-Hodgkin's Lymphoma That Has Relapsed or Not Responded to Previous Treatment
Condition: Lymphoma
MeSH terms: Lymphoma
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: Giving chemotherapy drugs, such as melphalan, before an autologous stem cell
      transplant helps stop the growth of cancer cells, either by killing the cells or by stopping
      them from dividing. Also, monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan
      and rituximab, can find cancer cells and carry cancer-killing substances to them without
      harming normal cells. Chemotherapy and monoclonal antibody therapy also prepares the
      patient's bone marrow for the stem cell transplant. Giving colony-stimulating factors, such
      as G-CSF, and vinorelbine helps stem cells move from the bone marrow to the blood so they can
      be collected and stored. The stem cells are returned to the patient to replace the
      blood-forming cells that were destroyed by the chemotherapy and monoclonal antibody therapy.

      PURPOSE: This phase I trial is studying the side effects and best dose of melphalan when
      given together with yttrium Y 90 ibritumomab tiuxetan and rituximab followed by autologous
      stem cell transplant in treating older patients with non-Hodgkin's lymphoma that has relapsed
      or not responded to previous treatment.
    

Detailed description: 
      OBJECTIVES:

        -  Determine the maximum tolerated dose of high-dose melphalan when given together with
           yttrium Y 90 ibritumomab tiuxetan and rituximab as a conditioning regimen followed by
           vinorelbine ditartrate- and filgrastim (G-CSF)-mobilized autologous stem cell
           transplantation in elderly patients with relapsed or refractory CD20-positive
           non-Hodgkin's lymphoma.

        -  Evaluate the feasibility and safety of this regimen in these patients.

        -  Determine the feasibility of stem cell mobilization with vinorelbine ditartrate in
           patients treated with this regimen.

      OUTLINE: This is a multicenter, dose-escalation study of high-dose melphalan.

        -  Stem cell harvest and mobilization: Patients receive vinorelbine ditartrate IV on day
           -36 and filgrastim (G-CSF) subcutaneously (SC) twice daily on days -33 to -29. Patients
           undergo peripheral blood stem cell harvest on days -29 to -26.

        -  Radioimmunotherapy: Patients receive rituximab IV. Within 4 hours after completion of
           rituximab, patients receive indium In 111 ibritumomab tiuxetan (imaging dose) IV over 10
           minutes on day -25. Patients undergo assessment of biodistribution, imaging, and
           dosimetry on days -25, -22, and optionally on day -20. Patients with acceptable
           biodistribution of indium In 111 ibritumomab tiuxetan receive rituximab IV followed by
           yttrium Y 90 ibritumomab tiuxetan (therapeutic dose) IV over 10 minutes on day -18.

        -  High-dose chemotherapy: Patients receive high-dose melphalan IV on day -1. Cohorts of
           3-6 patients receive escalating doses of high-dose melphalan until the maximum tolerated
           dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6
           patients experience dose-limiting toxicity.

        -  Autologous stem cell transplantation (ASCT): Patients undergo ASCT on day 0. Patients
           receive G-CSF SC beginning on day 5 and continuing until blood counts recover.

      After completion of study treatment, patients are followed for 100 days.

      PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.
    

Intervention name(s): ibritumomab tiuxetan; rituximab; melphalan; vinorelbine tartrate / G-CSF; autologous hematopoietic stem cell harvesting and transplantation
Intervention type(s): Drug; Drug; Drug; Drug; Procedure
Intervention description(s): 185 MBq (5mCi) of 111In-Zevalin will be used for radioimaging. and the dose is 14.8 MBq/kg (0.4 mCi/kg) total body weight of 90Y-Zevalin (max. 1184 MBq or 32 mCi at patients > 80kg) for imaging.; 250 mg/m2; Dose level 1: 100 mg/m2
Dose level 2: 140 mg/m2
Dose level 3: 170 mg/m2
Dose level 4: 200 mg/m2; on day 1: 35 mg/m2 day 4-8 (longer if required) G-CSF 5 μg/kg s.c. morning and 5 μg/kg s.c. evening for at least 5 days; Optimal mobilization usually takes place on day 8. A minimum of 2.5x106 CD34+ cells/kg should be collected (optimal 5x106 CD34+ cells/kg). If not enough CD34+ cells can be collected on day 8, it is recommended to continue with G-CSF until a sufficient collection (a minimum of 2.5x106 CD34+ cells/kg) can be obtained.
Stem cells will be reinfused approximately 24 hours after the melphalan administration. The infusion will be performed with a minimum of 2.5x106 CD34+ cells/kg body weight according to local guidelines. G-CSF (5 μg/kg/d) will be given from day 5 and continued until neutrophils > 0.5x109/l for at least 2 consecutive days.
Other intervention name(s): ZEVALIN; MabThera; Alkeran; Navelbine
Intervention MeSH terms: Rituximab; Melphalan; Vinorelbine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent adult Burkitt lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult diffuse mixed cell lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent grade 3 follicular lymphoma; recurrent mantle cell lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; Waldenström macroglobulinemia