Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT ID: NCT01024010

Last Updated: 2018-09-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 82 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2017-09-28

Brief Summary

This phase II trial studies how well giving ofatumumab together with pentostatin and cyclophosphamide works in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Monoclonal antibodies, such as ofatumumab, can block the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as pentostatin and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ofatumumab together with pentostatin and cyclophosphamide may be a better way to block cancer growth.

Detailed Description

PRIMARY OBJECTIVES:

I. Arm A: To assess the rate of complete response using pentostatin, cyclophosphamide, and ofatumumab in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) requiring therapy.

II. Arm B: To assess the treatment-free survival rate at 18 months using pentostatin, cyclophosphamide, and ofatumumab induction therapy followed by ofatumumab consolidation in patients with previously untreated CLL or SLL requiring therapy.

SECONDARY OBJECTIVES:

I. Arm A and Arm B: To assess the rate of overall response in patients with previously untreated CLL or SLL requiring therapy and to determine the proportion of patients who achieve a minimal residual disease (MRD) negative state as assessed by flow cytometry in each arm independently.

II. Arm A and Arm B: To monitor and assess toxicity in patients with previously untreated CLL or SLL in each arm independently.

III. Arm A and Arm B: To determine the progression-free survival, treatment-free survival, and duration of response in each arm independently.

IV. Arm A and Arm B: To determine if molecular prognostic parameters (zeta-chain-associated protein [ZAP]-70, cluster of differentiation [CD]38, cytogenetic abnormalities identified by fluorescence in situ hybridization [FISH], immunoglobulin heavy-chain variable-region [IgVH] mutation status, etc) relate to response to therapy in each arm independently.

V. Arm B: To assess the rate of complete response using pentostatin, cyclophosphamide, and ofatumumab induction followed by ofatumumab consolidation in patients with previously untreated CLL or SLL requiring therapy.

VI. Arm B: To evaluate whether consolidation therapy with ofatumumab after pentostatin, cyclophosphamide, and ofatumumab (PCO) induction improves the depth of response.

TERTIARY OBJECTIVES:

I. Arm A and Arm B: To assess the complete and overall response as well as treatment free survival in each arm as compared to a historic control of patients treated with pentostatin, cyclophosphamide, and rituximab in an exploratory manner.

II. Arm A and Arm B: To assess the complete and overall response as well as treatment free survival of patients treated with PCO induction followed by ofatumumab consolidation (Arm B) as compared to patients treated with PCO induction who did not receive ofatumumab consolidation (Arm A) in an exploratory manner.

III. Arm A and Arm B: Assess the mechanisms of ofatumumab induced cell death and explore methods to enhance ofatumumab cytotoxicity.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM A (closed to accrual as of 8/23/2011): Patients receive induction therapy comprising ofatumumab intravenously (IV) on day 1 (days 1-2 of course 1 only), pentostatin IV over 30 minutes on day 1, and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive induction therapy as in Arm A. Patients then receive consolidation therapy comprising ofatumumab IV on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 90 days for 1 year.

Conditions

Chronic Lymphocytic Leukemia; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A (PCO, closed to accrual as of 8/23/2011)

Patients receive induction therapy comprising ofatumumab IV on day 1 (days 1-2 of course 1 only), pentostatin IV over 30 minutes on day 1, and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Ofatumumab

Intervention Type: BIOLOGICAL

Given IV

Pentostatin

Intervention Type: DRUG

Given IV

Arm B (PCO with ofatumumab consolidation)

Patients receive induction therapy as in Arm A. Patients then receive consolidation therapy comprising ofatumumab IV on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Ofatumumab

Intervention Type: BIOLOGICAL

Given IV

Pentostatin

Intervention Type: DRUG

Given IV

Interventions

Cyclophosphamide

Given IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Ofatumumab

Given IV

Intervention Type: BIOLOGICAL

Pentostatin

Given IV

Intervention Type: DRUG

Other Intervention Names

(-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Arzerra; GSK1841157; HuMax-CD20; HuMax-CD20, 2F2; (R)-3-(2-Deoxy-.beta.-D-erythro-pentofuranosyl)-3,6,7, 8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol; 2'-Deoxycoformycin; CI-825; Co-Vidarabine; Covidarabine; DCF; Deoxycoformycin; Nipent; PD-81565; Pentostatine

Eligibility Criteria

Inclusion Criteria

• Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria, including previous documentation of:
• Biopsy-proven SLL
• Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:

• Peripheral blood lymphocyte count of > 5,000/mm^3 consisting of small to moderate size lymphocytes, with < 55% prolymphocytes
• Immunophenotyping consistent with CLL defined as:

• The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
• Clonality as evidenced by kappa or lambda light chain expression (typically dim immunoglobulin expression)
• Note: splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
• Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative FISH analysis for t(11;14)(immunoglobulin heavy [IgH]/cyclin D1 [CCND1]) on peripheral blood or tissue biopsy or negative immunohistochemical stains for CCND1 on involved tissue biopsy
• Patients must be previously untreated and meet at least one of the following indications for chemotherapy:

• Evidence of progressive marrow failure as manifested by the development of or worsening anemia (=< 11 g/dl) and/or thrombocytopenia (=< 100,000/mm^3) not due to autoimmune disease
• Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly
• One or more of the following disease-related symptoms:

• Weight loss > 10% within the previous 6 months
• Extreme fatigue attributed to CLL
• Fevers > 100.5 degree Fahrenheit for 2 weeks without evidence of infection
• Drenching night sweats without evidence of infection
• Progressive lymphocytosis due to CLL with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months

• Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL will be considered prior therapy; nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate [EGCG], found in green tea or other herbal treatments) will not be considered "prior treatment"
• Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy
• Serum creatinine =< 1.5 x upper normal levels (UNL)
• Total bilirubin =< 1.5 x UNL unless due to Gilbert's disease; if total bilirubin is > 1.5 x UNL, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed
• Aspartate aminotransferase (AST) =< 3.0 x UNL and alanine aminotransferase (ALT) =< 3.0 x UNL (unless due to hemolysis or CLL)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1, or 2
• Willingness to provide blood samples as required
• Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria

• Any of the following comorbid conditions:

• New York Heart Association Class III or IV heart disease
• Recent myocardial infarction (< 1 month)
• Uncontrolled infection
• Infection with the human immunodeficiency virus (HIV/acquired immunodeficiency syndrome [AIDS])
• Infection with known chronic, active Hepatitis C
• Positive serology for hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg); in addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HBsAb status), a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception
• Other active primary malignancy requiring treatment or limiting survival to =< 2 years
• Any radiation therapy =< 4 weeks prior to registration
• Any major surgery =< 4 weeks prior to registration
• Current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical conditions; Note: previous use of corticosteroids is allowed
• Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tait Shanafelt

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

Mayo Clinic in Florida

Jacksonville, Florida, United States

Mayo Clinic

Rochester, Minnesota, United States

Duke University Medical Center

Durham, North Carolina, United States

Countries

United States

References

Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. doi: 10.1016/S2352-3026(16)30064-3. Epub 2016 Aug 1.

Reference Type: DERIVED

PMID: 27570087 (View on PubMed)

Baig NA, Taylor RP, Lindorfer MA, Church AK, LaPlant BR, Pettinger AM, Shanafelt TD, Nowakowski GS, Zent CS. Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia. J Immunol. 2014 Feb 15;192(4):1620-9. doi: 10.4049/jimmunol.1302954. Epub 2014 Jan 15.

Reference Type: DERIVED

PMID: 24431228 (View on PubMed)

Other Identifiers

NCI-2009-01437

Identifier Type: REGISTRY

Identifier Source: secondary_id

MC0983

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA015083

Identifier Type: NIH

Identifier Source: secondary_id

View Link

MC0983

Identifier Type: -

Identifier Source: org_study_id