A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma - Full Text View

Sponsor:	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators:	University of Virginia GlasoSmithKline
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT01145209

Purpose

Background:

- Ofatumumab has been approved by the U.S. Food and Drug Administration to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not responded to standard chemotherapy. Ofatumumab is a substance that recognizes specific types of white blood cells called B-lymphocytes, which become cancerous in CLL/SLL. Ofatumumab attaches to a molecule called CD20, which is found on the surface of B-cells, and destroys them. Previous studies have shown that ofatumumab can decrease the number of B-cells in patients with CLL/SLL who have been treated with chemotherapy, but more research is needed to determine it if can also be used to treat patients with previously untreated CLL/SLL.

Objectives:

- To determine a safe and effective dose of ofatumumab, along with chemotherapy, to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with CLL or SLL that has not been treated with chemotherapy.

Design:

Eligible participants will be screened with a physical examination, blood samples, lymph node and bone marrow biopsies, and imaging studies.
Participants will be separated into two groups: all participants will receive ofatumumab and fludarabine, and some participants will be selected to also receive cyclophosphamide (based on the results of certain blood tests).
Participants will receive the study drugs (ofatumumab and fludarabine, and optional cyclophosphamide) by infusion for a maximum of 6 days, followed by 21 days off the drug.
Participants will have six cycles of treatment according to a schedule set by the study doctors, and may have their dose levels adjusted if side effects develop.
Participants who have disease remaining after six cycles will receive additional ofatumumab every 2 months, starting 2 months after the end of the sixth cycle and continuing for a total of four doses, before entering the follow-up phase of the trial. Participants who do not have residual disease after six cycles will not receive additional therapy, and will immediately enter the follow-up phase of the trial.
Participants will have a follow-up exam every 2 to 4 months for 2 years after the end of treatment, and then as required by the study doctors for as long as the study remains open. These visits will involve a full medical examination, blood samples, lymph node and bone marrow biopsies, and imaging studies.

Condition	Intervention	Phase
Small Lymphocytic Lymphoma CLL (Chronic Lymphocytic Leukemia)	Drug: Fludarabine Phosphate Biological: Ofatumumab Drug: Cyclophosphamide	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Resource links provided by NLM:

MedlinePlus related topics: Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Leukemia Lymphoma

Drug Information available for: Cyclophosphamide Fludarabine Fludarabine phosphate Ofatumumab

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

2-year progression -free survival rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

response rate (complete response and partial response); toxicity profile; rate of minimal residual disease positivity after completion of induction therapy; rate of conversion to minimal residual disease negativity after consolidation therapy [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	46
Study Start Date:	June 2010
Estimated Study Completion Date:	December 2014
Estimated Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Intervention Details:

Given IV

Detailed Description:

OUTLINE:

Patients with adverse interphase cytogenetics (11q22 or 17p13 deletion) receive FCO induction therapy:

Ofatumumab is given IV on day 1 (300 mg) and day 8 (1000 mg) of course 1 and on day 1 (1000 mg) of all subsequent courses.
Fludarabine phosphate (25mg/m2/d) and cyclophosphamide (250mg/m2/d) are given IV on days 2 through 4 of course 1 and on days 1 through 3 of all subsequent courses. Patients age 70 or older will be given reduced doses of fludarabine (20mg/m2/d) and cyclophosphamide (150mg/m2/d).
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

Patients without adverse interphase cytogenetics receive FO induction therapy:

Ofatumumab is given IV on day 1 (300mg) and day 8 (1000mg) of course 1 and on day 1 (1000mg) of all subsequent courses.
Fludarabine phosphate (25mg/m2/d) is given IV on days 2 through 6 of course 1 and on days 1 through 5 of all subsequent courses.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

All patients are evaluated for minimal residual disease (MRD) by four-color flow cytometric analysis of the peripheral blood after completion of FO or FCO induction therapy, and are subsequently stratified into two groups:

Patients who are MRD-positive and without evidence of disease progression proceed to consolidation therapy beginning approximately 5 months after completion of induction therapy, consisting of ofatumumab (1000mg) given IV on day 1 of all courses. Treatment repeats every 2 months for up to 4 courses in the absence of disease progression. Patients are followed clinically 2 and 6 months after the last dose of ofatumumab is given, and then every 6 months thereafter.
Patients who are MRD-negative and without evidence of disease progression are followed clinically every 4 months for 1 year and every 6 months thereafter.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:

Histologically confirmed CLL or SLL as defined by the following:

B-lymphocytosis greater than 5000 cells/micro L (may be less than 5000 cells/micro L if lymphadenopathy is present with histologic confirmation of lymph node involvement by SLL).
Immunophenotypic profile consistent with CLL as demonstrated by flow cytometry
Appropriate immunophonotype (CD5/19/23+)
Clonality of lymphocytosis confirmed by flow cytometry
large lymphocytes less than 55 % of blood lymphocytes

Active disease as defined by at least one of the following:

Weight loss greater than or equal to10 percent within the previous 6 months
Extreme fatigue
Fevers of greater than 100.5 degree F for greater than or equal to 2 weeks without evidence of infection
Night sweats for more than one month without evidence of infection
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
Massive or progressive splenomegaly
Massive nodes or clusters or progressive lymphadenopathy
Progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months 0

Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic disease).

Ages 18 and over.

EXCLUSION CRITERIA:

Prior monoclonal antibody therapy with agents having anti-CLL activity

Prior cytotoxic chemotherapy with agents having anti-CLL activity

Transformed CLL

Active autoimmune hemolytic anemia or thrombocytopenia

Any medical condition that requires the chronic use of corticosteroids

Active or latent Hepatitis B infection

HIV infection

Severe chronic obstructive pulmonary disease, severe cardiac disease, or other uncontrolled medical condition that would, in the opinion of the principal investigator, place the subject at an unreasonable risk of life-threatening adverse events due to chemoimmunotherapy

ECOG performance status 3 or worse

Creatinine greater than or equal to 2 mg/dL or creatinine clearance less than or equal to 30 mL/min

Bilirubin greater than or equal to 2 mg/dL or active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment)

Female patients: Current pregnancy or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol.

Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements.

Unable to understand the investigational nature of the study or give informed consent.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01145209

Contacts

Contact: Susan Soto, R.N.	(301) 402-0797	jordansk@cc.nih.gov
Contact: Mohammed Z Farooqui, D.O.	(301) 402-1806	farooquimz@mail.nih.gov

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
Contact: Susan Soto 301-402-0797 jordansk@cc.nih.gov

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

University of Virginia

GlasoSmithKline

Investigators

Principal Investigator:

Mohammed Z Farooqui, D.O.

National Heart, Lung, and Blood Institute (NHLBI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14. Epub 2002 Jul 05.

Tsimberidou AM, Tam C, Abruzzo LV, O'Brien S, Wierda WG, Lerner S, Kantarjian HM, Keating MJ. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer. 2009 Jan 15;115(2):373-80.

Del Poeta G, Del Principe MI, Buccisano F, Maurillo L, Capelli G, Luciano F, Perrotti AP, Degan M, Venditti A, de Fabritiis P, Gattei V, Amadori S. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer. 2008 Jan 1;112(1):119-28.

Responsible Party:	Mohammed Z. Farooqui, D.O./National Heart, Lung, and Blood Institute, National Institutes of Health
ClinicalTrials.gov Identifier:	NCT01145209 History of Changes
Other Study ID Numbers:	100141, 10-H-0141
Study First Received:	June 15, 2010
Last Updated:	April 24, 2012
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Arzerra
Chemoimmunotherapy
CLL (Chronic Lymphocytic Leukemia)
SLL
Small Lymphocytic Lymphoma (SLL)

Additional relevant MeSH terms:

Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Vidarabine

Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on May 23, 2012