Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Follicular

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Follicular Lymphoma

All Drugs and Chemicals

Antineoplastic Agents

Anti-Infective Agents

Fluorides

Fluorodeoxyglucose F18

Bendamustine Hydrochloride

Bortezomib

Deoxyglucose

Ofatumumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Antineoplastic Agents, Alkylating

Alkylating Agents

Radiopharmaceuticals

Antimetabolites

Antiviral Agents

Immunologic Factors

INDUCTION: Patients receive ofatumumab 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.

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 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.

Fludeoxyglucose F-18

Laboratory Biomarker Analysis

Positron Emission Tomography with Radiolabeled Targeting Agent

Kristie A Blum

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.

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.

Ofatumumab and Bendamustine Hydrochloride With or Without Bortezomib in Treating Patients With Untreated Follicular Non-Hodgkin Lymphoma

A Randomized Phase II Trial of Ofatumumab and Bendamustine vs. Ofatumumab, Bortezomib (NSC # 681239) and Bendamustine in Patients With Untreated Follicular Lymphoma

The PFS will be compared among the three genotype groups of each SNP using the log-rank tests. A maxtype test will be used by taking the maximum value of the log-rank tests under dominant, recessive, and proportional hazard model. The critical value (or p-value) of the max test will be obtained by a permutation method. No multiple testing adjustment may be applied because of the small sample size.

The IHC markers will be correlated with response (using the two-sample t-test) and PFS (using the Cox regression method) data. No multiple testing adjustment will be applied because of the small sample size.

The ratio will be correlated with response (using the two-sample t-test) and PFS (using the Cox regression method) data.

A complete response was defined using International Harmonization Project Response Criteria as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy.

The complete response (CR) rate was calculated in newly diagnosed untreated follicular lymphoma patients receiving 6 cycles of ofatumumab-bendamustine (ARM A) and 6 cycles of ofatumumab, bortezomib, and bendamustine (ARM B).

The complete response rate was calculated as the number of patients with a complete response divided by the number of patients eligible for evaluation.

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. PFS rates (percentages) at 1, 2, ,3 and 4 years are defined as the percentage of patients who are alive and progression-free at the respective time points. The p-values of the log-rank test will be calculated to compare PFS between the two arms.

The number of patients who experienced grade 3+ hematologic and non-hematologic adverse events at least possibly related to treatment assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

National Cancer Institute (NCI)

INDUCTION: Patients receive:

300 mg ofatumumab IV over 2-8 hours on day 1, cycle1 and 1000 mg ofatumumab IV on day 1, cycle 2-6 and 90 mg/m2 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 1000 mg ofatumumab IV over 2-8 hours on day 1. Treatment repeats every 56 days for up to 4 courses.

Arm A (Ofatumumab, Bendamustine Hydrochloride)

INDUCTION: Patients receive 300 mg ofatumumab IV over 2-8 hours on day 1, cycle1 and 1000 mg ofatumumab IV on day 1, cycle 2-6 and 90 mg/m2 bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, and 1.6 mg/m2 bortezomib IV over 3-5 seconds or 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 1000 mg ofatumumab IV over 2-8 hours on day 1 and 1.6 mg/m2 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.

Arm B (Ofatumumab, Bendamustine Hydrochloride, Bortezomib)

INDUCTION: Patients receive:\> 300 mg ofatumumab IV over 2-8 hours on day 1, cycle1 and 1000 mg ofatumumab IV on day 1, cycle 2-6 and 90 mg/m2 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 1000 mg ofatumumab IV over 2-8 hours on day 1. Treatment repeats every 56 days for up to 4 courses.

INDUCTION: Patients receive 300 mg ofatumumab IV over 2-8 hours on day 1, cycle1 and 1000 mg ofatumumab IV on day 1, cycle 2-6 and 90 mg/m2 bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, and 1.6 mg/m2 bortezomib IV over 3-5 seconds or 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 1000 mg ofatumumab IV over 2-8 hours on day 1 and 1.6 mg/m2 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.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

All patients that were eligible for endpoint analysis were included in the baseline characteristics.

Kristie A. Blum, MD

All patients that were eligible for response assessment were included in this analysis.

Spots Global Cancer Trial Database for positron emission tomography with radiolabeled targeting agent