Higher Dose of Rituxan Versus Standard Doses of Rituxan With Cyclophosphamide, Vincristine, and Prednisone in Subjects With Chronic ITP

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.

Inclusion Criteria:

Patients will be eligible to participate in the study if they:

- Have chronic ITP19 (> 6 months duration)

- Have received Rituximab a minimum of 3 months prior to entry

- Have received no more than 2 courses of Rituximab at standard dose separated by a
minimum of 12 weeks

- Have not achieved a durable response to Rituximab, with platelet counts < 30,000/ml
when not supported by other treatment

- Have a platelet count of < 30,000/ul on two separate occasions 1-2 weeks apart within
the past month prior to the inclusion

- We will allow patients who do not have 2 platelet counts < 30,000 on two separate
occasions 1-2 weeks apart in the past month, as long as they have either Evan's
Syndrome or autoimmune neutropenia (have hemoglobin < 10 g/dL and reticulocytes > 4%,
or an absolute neutrophil count < 1.0 K/uL twice within 1 month)

- Are age ≥ 10 years old

- Male and Female

- Had a splenectomy at least 60 days prior to study entry, or a contraindication to
splenectomy

- Give written informed consent

- Use an effective means of contraception during treatment and for six months after
completion of treatment

- Have negative serum pregnancy test, for all women who are able to have children,
within 14 days prior to study entry

Exclusion Criteria:

Male and female subjects will be ineligible to participate if they:

- Received prior treatment with cyclophosphamide within the last 3 months

- Received prior treatment with > 4 infusions of vinca alkaloids within the 6 months

- Had previous or concomitant malignancy other than basal cell or squamous cell
carcinoma of the skin, carcinoma-in-situ of the cervix, or other malignancy for which
the patient had not been disease-free for at least 5 years

- Have a HIV infection

- Have hepatitis Bs antigen positivity or active hepatitis C infection

- Have an absolute neutrophil count < 1.000/mm3 at study entry (unless related to
autoimmune neutropenia)

- Have a Hemoglobin level < 10 g/dl other than caused by thalassemia trait, iron
deficiency or autoimmune hemolytic anemia (patients with Evan's syndrome will not be
excluded)

- Have an impaired renal function as indicated by a serum creatinine level > 2.0 mg/dL

- Have an inadequate liver function as indicated by a total bilirubin level > 2.0 mg/dL
and/or an AST or ALT level > 3x upper limit of normal

- Have active infection requiring antibiotic therapy within 7 days prior to study entry

- Are pregnant or lactating women, or plan to become pregnant or impregnated within 12
months of receiving study drug

- Have had a prior severe reaction to Rituximab, leading to discontinuation of treatment

- Have a New York Heart Classification III or IV heart disease

- Have a history of severe psychiatric disorder or are unable to comply with study and
follow-up procedures