A Pilot Study of Fractionated Dose Subcutaneous Rituximab in Patients With Refractory or Relapsed Chronic Lymphocytic Leukemia

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BlankA Pilot Study of Fractionated Dose Subcutaneous Rituximab (RTX, Rituxan®

(Registered Trademark)) in Patients With Refractory or Relapsed Chronic

Lymphocytic Leukemia

This study is currently recruiting patients.

Verified by National Institutes of Health Clinical Center (CC) August 2006

Purpose

Chronic lymphocytic leukemia (CLL) originates from a malignant B cell clone.

Treatment of CLL includes chemotherapy, monoclonal antibody therapy, bone marrow

transplantation and/or watchful waiting/supportive care (treatment of infection,

blood product substitution). Chemotherapy-based regimens using fludarabine are

currently considered the standard treatment for CLL. These chemotherapy regimens

can achieve an overall response rate as high as 60 to 80 percent; however,

chemotherapy alone is never curative and relapse always occurs. Once fludarabine

failure occurs, other second line chemotherapy regimens have only modest

responses. Moreover, repeated chemotherapy bears an increased risk of

myelosuppression resulting in a higher frequency of serious infections in this

already immunocompromised and mostly elderly patient group.

Rituximab is FDA approved for the treatment of relapsed or refractory low grade

or follicular CD20+ B cell non Hodgkin's lymphoma (375 mg/m2 IV infusion once

weekly for 4 or 8 doses). Recently, rituximab (anti CD20) has been introduced to

CLL treatment regimens and has become an attractive choice in combination

chemotherapy or as single agent treatment. Rituximab has been shown to be

effective at lower doses than 375 mg/m2 when given more frequently.

Several theoretical considerations and supporting laboratory evidence suggest

that a fractionated dosing schedule using low-dose rituximab could be more

effective than the current i.v. schedule of high-dose rituximab. Main

limitations of high dose i.v. rituximab include the exhaustion of complement

components and the occurrence of a shaving reaction by which CD20 is pulled of

the surface of the CLL cells. Both of these mechanisms can reduce or cancel the

efficacy of rituximab. Indeed, preliminary clinical evidence suggests that

low-dose rituximab at 20mg/m2 i.v. 3-times per week can lead to steady clearance

of leukemic cells without inducing substantial loss of targeted CD20. More

extended periods of rituximab treatment, e.g. 8-12 weeks, rather than the

approved 4 week regimen, may be more effective to allow increased clearance of

leukemic cells.

Therefore, we propose this pilot, Phase I/II , single agent study which will

evaluate the safety and feasibility of subcutaneous rituximab (Rituxan)

administered at 20 mg/day three times a week for 12 weeks in subjects with CLL.

Patients need to have had prior treatment with fludarabine, and have an elevated

absolute lymphocyte count. The primary objective will be to test the safety and

feasibility of giving rituximab subcutaneously. We will also obtain as a

secondary endpoint an early estimate of efficacy as evidenced by (a) shrinkage

of lymphadenopathy and/or ( improvement in blood values and bone marrow biopsy

findings.

Condition Intervention Phase

Refractory Chronic Lymphocytic Leukemia

Drug: Rituximab

Phase I

Phase II

Study Type: Interventional

Study Design: Treatment

Official Title: A Pilot Study of Fractionated Dose Subcutaneous Rituximab (RTX,

Rituxan® (Registered Trademark)) in Patients With Refractory or Relapsed Chronic

Lymphocytic Leukemia

Further study details as provided by National Institutes of Health Clinical

Center (CC):

Expected Total Enrollment: 12

Study start: August 2006

Last follow-up: August 2006; Data entry closure: August 2006

Chronic lymphocytic leukemia (CLL) originates from a malignant B cell clone.

Treatment of CLL includes chemotherapy, monoclonal antibody therapy, bone marrow

transplantation and/or watchful waiting/supportive care (treatment of infection,

blood product substitution). Chemotherapy-based regimens using fludarabine are

currently considered the standard treatment for CLL. These chemotherapy regimens

can achieve an overall response rate as high as 60 to 80 percent; however,

chemotherapy alone is never curative and relapse always occurs. Once fludarabine

failure occurs, other second line chemotherapy regimens have only modest

responses. Moreover, repeated chemotherapy bears an increased risk of

myelosuppression resulting in a higher frequency of serious infections in this

already immunocompromised and mostly elderly patient group.

Rituximab is FDA approved for the treatment of relapsed or refractory low grade

or follicular CD20+ B cell non Hodgkin's lymphoma (375 mg/m2 IV infusion once

weekly for 4 or 8 doses). Recently, rituximab (anti CD20) has been introduced to

CLL treatment regimens and has become an attractive choice in combination

chemotherapy or as single agent treatment. Rituximab has been shown to be

effective at lower doses than 375 mg/m2 when given more frequently.

Several theoretical considerations and supporting laboratory evidence suggest

that a fractionated dosing schedule using low-dose rituximab could be more

effective than the current i.v. schedule of high-dose rituximab. Main

limitations of high dose i.v. rituximab include the exhaustion of complement

components and the occurrence of a shaving reaction by which CD20 is pulled of

the surface of the CLL cells. Both of these mechanisms can reduce or cancel the

efficacy of rituximab. Indeed, preliminary clinical evidence suggests that

low-dose rituximab at 20mg/m2 i.v. 3-times per week can lead to steady clearance

of leukemic cells without inducing substantial loss of targeted CD20. More

extended periods of rituximab treatment, e.g. 8-12 weeks, rather than the

approved 4 week regimen, may be more effective to allow increased clearance of

leukemic cells.

Therefore, we propose this pilot, Phase I/II , single agent study which will

evaluate the safety and feasibility of subcutaneous rituximab (Rituxan)

administered at 20 mg/day three times a week for 12 weeks in subjects with CLL.

Patients need to have had prior treatment with fludarabine, and have an elevated

absolute lymphocyte count. The primary objective will be to test the safety and

feasibility of giving rituximab subcutaneously. We will also obtain as a

secondary endpoint an early estimate of efficacy as evidenced by (a) shrinkage

of lymphadenopathy and/or ( improvement in blood values and bone marrow biopsy

findings.

Eligibility

Ages Eligible for Study: 21 Years and above, Genders Eligible for Study: Both

Criteria

a.. INCLUSION CRITERIA

b.. Patients diagnosed with Chronic Lymphocytic Leukemia

c.. Prior therapy with fludarabine or a fludarabine containing regimen

d.. CD20 expression on CLL cells

e.. Neutrophil count ANC greater than 500/mm(3)

f.. Platelet count greater than 30K/mm(3)

g.. Absolute lymphocyte count of greater than 10,000/uL

h.. Age 21-99

EXCLUSION CRITERIA

a.. Bulky lymphadenopathy, defined as greater than 1 lymph node with greater

than 5cm in largest diameter

b.. Evidence for transformation into high grade lymphoma (Richter's

transformation)

c.. ECOG performance 3 or higher

d.. Other concurrent anticancer therapies

e.. Less than 3 months from last systemic therapy for CLL

f.. Less than 6 months from last monoclonal antibody therapy

g.. More than one prior treatment course with rituximab, either as single

agent or in a combination chemotherapy regimen.

h.. Chronic or current clinically significant infection, including HIV

positivity or hepatitis C

i.. Moribund status or concurrent hepatic, renal, cardiac, neurologic,

pulmonary, infectious, or metabolic disease of such severity that it would

preclude the patient's ability to tolerate protocol therapy

j.. History of mucocutaneous reactions (paraneoplastic pemphigus,

s- syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and

toxic epidermal necrolysis)

k.. Known anaphylaxis or IgE mediated hypersensitivity to murine proteins or

to any component of this product.

l.. Inability to self inject the study medication or to have it administered

by a third person.

m.. Inability to understand the investigational nature of the study ability to

provide informed consent

Location and Contact Information

Please refer to this study by ClinicalTrials.gov identifier NCT00366418

Patient Recruitment and Public Liaison Office (800) 411-1222

prpl@...

TTY 1-866-411-1010

land

National Heart, Lung and Blood Institute (NHLBI), Bethesda, land,

20892, United States; Recruiting

More Information

NIH Clinical Center Detailed Web Page

Publications

de Vinuesa CG, Cook MC, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus GG,

MacLennan IC. Germinal centers without T cells. J Exp Med. 2000 Feb

7;191(3):485-94.

Study ID Numbers: 060228; 06-H-0228

Last Updated: August 23, 2006

Record first received: August 17, 2006

ClinicalTrials.gov Identifier: NCT00366418

Health Authority: United States: Federal Government

ClinicalTrials.gov processed this record on 2006-08-25