Clinical trial NCT01145209: Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Small Lymphocytic Lymphoma
CLL (Chronic Lymphocytic Leukemia)
Keywords: Arzerra
Chemoimmunotherapy
SLL
Monoclonal Antibody Therapy
CLL
Ofatumumab
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: University of Virginia
name: GlaxoSmithKline
First posted: 2010-06-16
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

- Ofatumumab was 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 exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.
* Participants will be separated into 2 groups: all participants will receive ofatumumab and fludarabine, and some participants will be selected to also receive cyclophosphamide (based on 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 drug.
* Participants will have 6 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 6 cycles will receive additional ofatumumab every 2 months, starting 2 months after the end of the 6th cycle and continuing for a total of 4 doses, before entering the follow-up phase of the trial. Participants who do not have residual disease after 6 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 exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.

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 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 (Fludarabine, Cyclophosphamide, Bendamustine, Chlorambucil)

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.

Primary outcomes:
measure: Progression Free Survival Rate 2 Years After Initiation of Induction Therapy
timeFrame: 2 years
Secondary outcomes:
measure: Number of Grade 3 and 4 Treatment Related Adverse Events
timeFrame: 2 years
measure: Participants With Minimal Residual Disease (MRD) Negativity
timeFrame: 2 years
measure: Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity
timeFrame: 2 years
measure: Participants With Complete Response Rates Following Induction Chemoimmunotherapy.
timeFrame: 2 years
measure: Participants Overall Response Rates Following Induction Chemoimmunotherapy.
timeFrame: 2 years
measure: Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy
timeFrame: Up to 2 years
measure: Median Relationship of CD20 Expression With MRD Negativity Rate
timeFrame: 2 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Inhye Ahn, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ahn I, Farooqui M, Lee YS, Marti G, Soto S, Tian X, Stetler-Stevenson M, Yuan CM, Maric I, Wiestner A. Risk-Adapted Induction and Maintenance with Ofatumumab in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL). Blood 2015 126(23):1750-1750.
citation: Desai S, Mo C, Gaglione EM, Yuan CM, Stetler-Stevenson M, Tian X, Maric I, Wake L, Farooqui MZ, Drinkwater DC, Soto S, Valdez J, Hughes TE, Nierman P, Lotter J, Marti GE, Pleyer C, Sun C, Superata J, Nichols C, Herman SEM, Lindorfer MA, Taylor RP, Wiestner A, Ahn IE. Risk-adapted, ofatumumab-based chemoimmunotherapy and consolidation in treatment-naive chronic lymphocytic leukemia: a phase 2 study. Leuk Lymphoma. 2021 Aug;62(8):1816-1827. doi: 10.1080/10428194.2021.1888379. Epub 2021 Mar 2.