Higher Dose of Rituxan Versus Standard Doses of Rituxan With Cyclophosphamide, Vincristine, and Prednisone in Subjects With Chronic ITP
Condition: Immune Thrombocytopenic Purpura
MeSH terms: Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      This study is designed to compare the efficacy and safety of higher doses of Rituxan with a
      regimen combining standard doses of Rituxan + CVP in patients with chronic ITP who did not
      respond to or relapsed after standard doses of Rituxan. Patients eligible for this protocol
      will be stratified into two subgroups according to their initial response to Rituxan.
    

Detailed description: 
      The rationale for using chemotherapy in combination with Rituximab:

      Since Rituximab is an anti-B cell therapy, in order to improve the rate of durable responses
      beyond the 32% (18 of 57) seen with Rituximab alone, it seems appropriate to combine it with
      a therapy that would also target T cells and/or macrophages. Our plan is therefore to combine
      Rituximab with a standard chemotherapy (CHOP)-like regimen as previously successfully tested
      in patients with follicular or diffuse large-B-cell lymphomas 13-15. The "CHOP" chemotherapy
      regimen is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (or
      prednisolone) that has been considered the "gold standard" for treating lymphomas for more
      than 20 years.

      This combination of medications was used in a Hodgkin's patient with refractory ITP and
      became the template for developing the use of cyclophosphamide, vincristine, and prednisone
      for ITP as initially reported in 1993. Since reports on doxorubicin efficacy by itself in ITP
      are only anecdotal 16 and this drug has a potential cardiac toxicity, a CVP regimen (namely a
      combination of cyclophosphamide + vincristine and prednisone) should be similar in efficacy
      to CHOP in patients with ITP and have less toxicity. Indeed, the efficacy of such a
      chemotherapy12 as well as pulses cyclophosphamide therapy alone11 have already been reported
      in patients with refractory ITP.

      Since attempts to increase the efficacy of CHOP by increasing the doses or adding other
      cytotoxic drugs have failed, a new therapeutic strategy combining CHOP with Rituxan has been
      successfully developed in the last few years in various types of B-cell lymphomas 13-15. In
      elderly patients with diffuse large-B-cell lymphoma, the addition of Rituxan to standard CHOP
      chemotherapy significantly reduced the risk of treatment failure and deaths without
      increasing toxicity 13. Moreover, in autoimmune disorders, there are few preliminary data
      suggesting that Rituxan and cyclophopshamide given in combination could be effective and
      relatively safe in patients with active rheumatoid arthritis 17.

      Therefore, the rationale for combining Rituxan with a CHOP-like regimen in ITP is threefold:

      Both Rituxan and CHOP or IV cyclophosphamide have efficacy in ITP The treatments have
      different mechanisms of action. They have minimally-overlapping toxicities.

      The rationale for using higher doses of Rituxan in patients who had no response, or relapsed,
      to the drug at the standard dose:

      The standard dose of Rituxan is arbitrary in that one dose of Rituxan has been used in the
      great majority of the clinical trials and virtually all patients since the FDA approval of
      Rituxan in 1997: 375 mg/m2 weekly x 4 weeks. To date, because Rituxan is a monoclonal
      antibody rather than a chemotherapeutic agent, it was recognized that a true maximum
      tolerated dose (MTD) might not be achieved. Among other factors that could influence the
      tolerance of higher doses of Rituxan are the rate of CD20 surface expression and the serum
      level of the antibody11. Limited trials of higher doses have been pursued in CLL18 (up to
      2,250 mg/m2 per dose), but not in other types of lymphoma or in autoimmune diseases. In CLL,
      mild to severe toxicity was exclusively observed with the first dose (375 mg/m2) while
      toxicity on subsequent higher doses was minimal. In ITP, some of the few patients that have
      been retreated responded better to the second dose of rituximab than to the initial treatment
      (although the opposite is also true). Full depletion of the marrow and especially the lymph
      nodes is not achieved by the current dose regimen and B cells return in substantial number to
      the peripheral blood within 3-6 months in patients with ITP treated at the conventional dose.
      We therefore anticipate that in ITP patients who relapsed or did not respond after a previous
      course of rituximab, doubling the dose could lead to a deeper and more prolonged B cell
      depletion and to a better increase in the platelet count without enhancing toxicity.
    

Intervention name(s): Rituxan, Cyclophosphamide, Vincristine, Prednisone; Higher Dose of Rituximab
Intervention type(s): Drug; Drug
Intervention description(s): 'Rituximab, Cyclophosphamide, Vincristine, Prednisone interventions are as follows: Rituximab will be administered as an IV infusion at the standard dose of 375 mg/m2 for 4 doses. However, the schedule of the infusions will be different than the usual one: Rather than administrating the 4 doses once weekly, the first infusion will be given 5 days (± 3 days) prior to the first infusions of C and V and oral P, and the following 3 rituximab infusions will be given on the same day as the 3 cycles of C, V, and P.; rituximab 750mg/m2 (twice the standard dose of 375mg/m2) will be given weekly for 4 weeks. Premedication and infusion rate escalation will be exactly the same as for standard dose rituximab. The additional dose will thus run at 400ml/hr.
Other intervention name(s): Rituximab
Intervention MeSH terms: Prednisone; Cyclophosphamide; Rituximab; Vincristine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Pts w/ Chronic ITP who have fail/relap after Rituxan rx