Non Hodgkin Lymphoma Clinical Trial
Ofatumumab and Bendamustine Hydrochloride With or Without Bortezomib in Treating Patients With Untreated Follicular Non-Hodgkin Lymphoma
Summary
This randomized phase II trial studies how well ofatumumab and bendamustine hydrochloride with or without bortezomib works in treating patients with untreated follicular non-Hodgkin lymphoma. Monoclonal antibodies, such as ofatumumab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as bendamustine hydrochloride, 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. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of cancer cells by blocking blood flow to the tumor. It is not yet known whether ofatumumab and bendamustine hydrochloride are more effective with bortezomib in treating patients with follicular non-Hodgkin lymphoma.
Full Description
PRIMARY OBJECTIVES:
I. To determine the complete response (CR) rate in newly diagnosed, untreated follicular lymphoma patients receiving 6 cycles of ofatumumab-bendamustine (bendamustine hydrochloride) (ARM A) and 6 cycles of ofatumumab, bortezomib, and bendamustine (ARM B) using International Harmonization Project Response Criteria.
SECONDARY OBJECTIVES:
I. To determine progression-free survival (PFS) of patients with untreated follicular lymphoma after 6 cycles of ofatumumab-bendamustine (ARM A) followed by maintenance ofatumumab and after 6 cycles of ofatumumab, bortezomib, and bendamustine followed by maintenance ofatumumab and bortezomib (ARM B).
II. To determine the toxicity profile of ofatumumab and bendamustine and ofatumumab, bortezomib, and bendamustine in patients with untreated high-risk follicular lymphoma.
III. To determine if changes in both qualitative and semi-quantitative fludeoxyglucose (FDG)-positron-emission tomography (PET) findings at baseline, after cycle 2 (day 32-35), and at end of therapy (6-8 weeks after the last cycle of induction chemotherapy but prior to maintenance therapy) with ofatumumab-bendamustine and ofatumumab, bortezomib, and bendamustine correlate with response and PFS in patients with high-risk follicular lymphoma.
IV. To assess if a combinatorial approach using both qualitative and semi-quantitative changes in FDG-PET and computed tomography (CT) or magnetic resonance imaging (MRI) studies at baseline, after cycle 2 (day 32-35), and at end of therapy (6-8 weeks after the last cycle of induction chemotherapy prior to maintenance therapy) would result in a higher predictive value for response and PFS in patients with high-risk follicular lymphoma.
V. To correlate all molecular parameters with FDG-PET parameters in determination of response and PFS.
VI. To correlate pre-treatment single nucleotide polymorphisms with response and PFS following ofatumumab-bendamustine and ofatumumab, bortezomib, and bendamustine therapy in patients with untreated high-risk follicular lymphoma.
VII. To correlate cluster of differentiation (CD)-68, B-cell chronic lymphocytic leukemia (CLL)/lymphoma (bcl)-2, marker of proliferation Ki-67 (Ki-67), forkhead box P3 (FOXP3), activated cytotoxic T-cells, lymphoma-associated macrophages (LAM), melanoma associated antigen (mutated) 1 (MUM1), CD10, nuclear v-rel avian reticuloendotheliosis viral oncogene homolog A (p65) and v-rel avian reticuloendotheliosis viral oncogene homolog C (cREL) subunits of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFkB), and selected genetic translocations by fluorescent in situ hybridization (FISH) analysis (such as Bcl-2 and Bcl-6) with response and PFS in patients receiving initial therapy for high-risk follicular lymphoma.
VIII. To determine whether immune gene signatures previously identified as prognostic factors in follicular lymphoma can be applied to paraffin-embedded tissues in ofatumumab and bendamustine or ofatumumab, bendamustine, and bortezomib treated patients; evaluate micro-ribonucleic acid (RNA) signatures associated with these gene signatures and outcome.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A:
INDUCTION: Patients receive ofatumumab intravenously (IV) over 2-8 hours on day 1 and bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2. Treatment repeats every 35 days for up to 6 courses. Patients without disease progression continue on to maintenance therapy.
MAINTENANCE: Beginning 8 weeks after the start of induction course 6, patients receive ofatumumab IV over 2-8 hours on day 1. Treatment repeats every 56 days for up to 4 courses.
ARM B:
INDUCTION: Patients receive ofatumumab IV over 2-8 hours on day 1, bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, and bortezomib IV over 3-5 seconds or subcutaneously (SC) on days 1, 8, 15, and 22. Treatment repeats every 35 days for up to 6 courses. Patients without disease progression continue on to maintenance therapy.
MAINTENANCE: Beginning 8 weeks after the start of induction course 6, patients receive ofatumumab IV over 2-8 hours on day 1 and bortezomib IV over 3-5 seconds or SC on days 1, 8, 15, and 22. Treatment repeats every 56 days for up to 4 courses.
After completion of study treatment, patients are followed up every 4 months for 2 years and then every 6 months for up to 10 years.
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed follicular non-Hodgkin lymphoma, World Health Organization (WHO) classification grade 1, 2, or 3a (> 15 centroblasts per high-power field with centrocytes present)
Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies
Fine-needle aspirates are not acceptable
Failure to submit pathology within 60 days of patient registration will be considered a major protocol violation
Patients must have at least one of the following indicators of poor risk disease:
>= 3 risk factors by the Follicular Lymphoma International Prognostic Index, or 2 risk factors by the Follicular Lymphoma International Prognostic Index and at least one bulky mass or lymph node > 6 cm in size
Follicular Lymphoma International Prognostic Index (FLIPI score):
Age > 60 years
Involvement of > 4 nodal sites
Stage III-IV disease
Hemoglobin < 12.0 g/dL
Lactate dehydrogenase (LDH) > upper limit of normal (ULN)
0-1 of the above risk factors: low risk
2 risk factors: intermediate risk
>= 3 risk factors: poor risk
No prior cytotoxic chemotherapy, radiotherapy, immunotherapy, or radioimmunotherapy
No corticosteroids are permitted, except for maintenance therapy for a non-malignant disease or to prevent treatment-related ofatumumab reactions (maintenance therapy dose must not exceed 20 mg/day prednisone or equivalent)
Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable; lesions that are considered non-measurable include the following:
Bone lesions
Leptomeningeal disease
Ascites
Pleural/pericardial effusion
Inflammatory breast disease
Lymphangitis cutis/pulmonis
Bone marrow involvement (involvement by non-Hodgkin lymphoma should be noted)
Patients must have no known central nervous system (CNS) involvement by lymphoma
Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Patients must be non-pregnant and non-nursing; pregnant or nursing patients may not be enrolled; women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to registration; in addition, women and men of childbearing potential must commit to use an effective form of contraception throughout their participation in this study; appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives (Norplant), or double barrier method (diaphragm plus condom)
Patients with human immunodeficiency virus (HIV) infection are eligible; patients with HIV infection must meet the following: no evidence of co-infection with hepatitis B or C; CD4+ count > 400/ul; no evidence of resistant strains of HIV; on anti-HIV therapy with an HIV viral load < 50 copies HIV RNA/mL; no history of acquired immunodeficiency syndrome (AIDS)-defining conditions; no zidovudine or stavudine are allowed owing to overlapping toxicity with chemotherapy
Patients must have no evidence of active hepatitis B or C infection (i.e., no positive serology for anti-hepatitis B core [HBc] or anti-hepatitis C virus [HCV] antibodies); hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen [HBsAg] +) are eligible if HBV deoxyribonucleic acid (DNA) is undetectable at baseline and they are closely monitored for evidence of active HBV infection by HBV DNA testing at each treatment cycle; after completing treatment, HBsAg + patients must be monitored by HBV DNA testing every 2 months for 6 months post-treatment, while continuing lamivudine
Granulocytes >= 1,000/uL
Platelet count >= 75,000/uL
Creatinine =< 2.0 mg/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limits of normal (ULN)
Bilirubin =< 2 x ULN
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There are 84 Locations for this study
La Jolla California, 92093, United States
Saint Helena California, 94574, United States
Middletown Connecticut, 06457, United States
Miami Beach Florida, 33140, United States
'Aiea Hawaii, 96701, United States
'Aiea Hawaii, 96701, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96817, United States
Honolulu Hawaii, 96817, United States
Honolulu Hawaii, 96826, United States
Kailua Hawaii, 96734, United States
Lihue Hawaii, 96766, United States
Boise Idaho, 83706, United States
Post Falls Idaho, 83854, United States
Chicago Illinois, 60612, United States
Chicago Illinois, 60637, United States
Chicago Illinois, 60640, United States
Decatur Illinois, 62526, United States
Decatur Illinois, 62526, United States
Evanston Illinois, 60201, United States
Harvey Illinois, 60426, United States
Springfield Illinois, 62702, United States
Springfield Illinois, 62702, United States
Springfield Illinois, 62781, United States
Fort Wayne Indiana, 46845, United States
Indianapolis Indiana, 46237, United States
Mishawaka Indiana, 46545, United States
Mishawaka Indiana, 46545, United States
South Bend Indiana, 46601, United States
Westville Indiana, 46391, United States
Cedar Rapids Iowa, 52403, United States
Cedar Rapids Iowa, 52403, United States
Sioux City Iowa, 51101, United States
Augusta Maine, 04330, United States
Bangor Maine, 04401, United States
Rockport Maine, 04856, United States
Baltimore Maryland, 21215, United States
Ann Arbor Michigan, 48106, United States
Detroit Michigan, 48236, United States
Grand Rapids Michigan, 49503, United States
Grand Rapids Michigan, 49503, United States
Burnsville Minnesota, 55337, United States
Edina Minnesota, 55435, United States
Maplewood Minnesota, 55109, United States
Maplewood Minnesota, 55109, United States
Minneapolis Minnesota, 55417, United States
Saint Louis Park Minnesota, 55416, United States
Saint Paul Minnesota, 55101, United States
Bolivar Missouri, 65613, United States
Columbia Missouri, 65212, United States
Kansas City Missouri, 64111, United States
Saint Louis Missouri, 63110, United States
Saint Louis Missouri, 63131, United States
Saint Louis Missouri, 63141, United States
Springfield Missouri, 65804, United States
Springfield Missouri, 65807, United States
Billings Montana, 59101, United States
Great Falls Montana, 59405, United States
Las Vegas Nevada, 89169, United States
Lebanon New Hampshire, 03756, United States
East Syracuse New York, 13057, United States
Lake Success New York, 11042, United States
Lake Success New York, 11042, United States
Manhasset New York, 11030, United States
New Hyde Park New York, 11040, United States
New York New York, 10065, United States
Syracuse New York, 13210, United States
Asheboro North Carolina, 27203, United States
Chapel Hill North Carolina, 27599, United States
Goldsboro North Carolina, 27534, United States
Greensboro North Carolina, 27403, United States
Kinston North Carolina, 28501, United States
Reidsville North Carolina, 27320, United States
Statesville North Carolina, 28677, United States
Winston-Salem North Carolina, 27157, United States
Grand Forks North Dakota, 58201, United States
Columbus Ohio, 43210, United States
Dayton Ohio, 45415, United States
Kettering Ohio, 45429, United States
Maumee Ohio, 43537, United States
Oregon Ohio, 43616, United States
Sylvania Ohio, 43560, United States
Toledo Ohio, 43623, United States
Toledo Ohio, 43623, United States
Oklahoma City Oklahoma, 73104, United States
Oklahoma City Oklahoma, 73120, United States
Portland Oregon, 97213, United States
Portland Oregon, 97225, United States
Sayre Pennsylvania, 18840, United States
Greenville South Carolina, 29601, United States
Greenville South Carolina, 29607, United States
Spartanburg South Carolina, 29303, United States
Richmond Virginia, 23298, United States
Morgantown West Virginia, 26506, United States
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