Leukemia and Myeloproliferative Disorders

June Greenberg, RN
212-746-2651

Patients will be randomized into one of two study groups. Patients with high-risk CLL will be randomized (Arm A or B) in this way because it is not known whether either approach offers a benefit over the other. Patients with low-risk CLL, will be placed in Arm C.

Arm A ("Early Treatment") - Patients will begin treatment within one month of randomization. Patients will be given rituximab on days 1, 3, and 5 of week 1, and then on the first day during weeks 5, 9, 13, 17, and 21. There will be a total of eight doses of rituximab. Patients will also receive fludarabine by IV infusion. Fludarabine will be given each day for five days during weeks 1, 5, 9, 12, 17, and 21.

Arm B ("Observation with Later Treatment") - If patients are placed in Arm B, they will see their doctor every three months for physical exams and blood tests. When they begin to experience symptoms related to the disease, they will begin treatment. They will be given rituximab on days 1, 3, and 5 of week 1, and then on the first day during weeks 5, 9, 13, 17, and 21. They will also receive fludarabine by IV infusion. Fludarabine will be given over a period of 30 minutes each day for five days during weeks 1, 5, 9, 13, 17, and 21.

Arm C ("Low-Risk CLL") - If the patient's blood test reveals that they have "low-risk CLL", they will see their doctor every three months for physical exams and blood tests. When they begin to experience symptoms related to the disease, they will begin treatment.

June Greenberg, RN
212-746-2651

During the Phase I portion of study, patients will receive increasing doses of GRN163L depending upon when they enroll onto the study. Additional patients will continue to be treated at the Phase II dose.

GRN163L will be administered as a 6-hour IV infusion once a week for 4 weeks.

Patients who DO NOT experience any intolerable side effects may receive an additional 4-week cycle of GRN163L.

Patients who continue to respond to GRN163L after 8 weeks of treatment may continue to receive treatment for as long as the study doctor recommends provided that the patient continues to respond to GRN163L and does not experience any intolerable side effects.

GRN162L is a telomerase inhibitor.

June Greenberg, RN
212-746-2651

Each patient will receive 8 weekly infusions of HuMax-CD20, followed by 4 monthly infusions of HuMax-CD20.

HuMax-CD20 is a human monoclonal antibody directed against CD20.

June Greenberg, RN
212-746-2651

Patients must have progressing disease, Rai Stage III or IV, and received at least one prior therapy. Additional eligibility criteria include:
1) documented lymphocytosis of greater than 5 x 109/L since initial diagnosis of CLL
2) B-cells that co-express CD5 with CD19 or CD20 and CD23 surface antigens, and have low density (dim expression) of surface immunoglobulin light chain (sIg)
3) if B-cells are bright surface immunoglobulin positive or CD23 negative then they must lack 11:14 translocation.

Each patient will receive alvocidib every week for 4 consecutive weeks, followed by a 2-week rest period (1 cycle of study treatment every 42 days) for up to a total of 6 cycles.

Day 1 and Day 8 of Cycle 1 will be administered as an in-patient treatment. The rest of the treatments in Cycle 1 and subsequent cycles may be administered as an out-patient basis.

Patient will receive the first dose of alvocidib 30 mg/m2 IV over 30 minutes followed by 30mg/m2 continuous infusion over 4 hours (Total alvocidib 60 mg/m2) on Cycle 1 Day 1. A dose escalation of alvocidib may be performed at Day 8 (dose 2) of Cycle 1 depending upon the patient’s objective response to initial therapy.

Patient who attains evidence of response as defined by a >25% decrease in blood lymphocyte count and/or lymphadenopathy from baseline as assessed by physical examination after completion of at least 2 cycles may receive up to a maximum of 6 cycles of alvocidib therapy.

CLL patients who are refractory to or relapsed after at least 2 prior therapies, including fludarabine, alone or in combination.

Patients must be symptomatic.

The study drug should be taken twice a day. The patient should take the morning dose with water on an empty stomach; food can be consumed at least an hour after dosing. The evening dose should be taken with water approximately 12 hours after the morning dose and at least 2 hours after a
meal.

Each patient will be assessed for clinical response after completing 1 cycle of 28 days of treatment. Treatment may continue for up to a total of 6 cycles.

hLL1 (humanized anti-CD74 monoclonal antibody) administered intravenously daily, five days
per week (Monday to Friday), for two weeks at one of 4 planned dose levels. Treatment occurs over 2 weeks
with post-treatment evaluations over 12 weeks. Follow-up is required in all patients until resolution of any treatment related abnormalities or until relapse occurs.