Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II clinical trial is studying 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, can block cancer growth in difference ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 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.

Further Study Information

PRIMARY OBJECTIVES:

I. To determine the complete response (CR) rate 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) 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 semiquantitative 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 CD-68, bcl-2, Ki-67, FOXP3, activated cytotoxic T-cells, lymphoma-associated macrophages (LAM), MUM1, CD10, nuclear p65 and cREL subunits of 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 microRNA signatures associated with these gene signatures and outcome.

OUTLINE: This is a multicenter study. 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 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 on days 1, 8, 15, and 22. Treatment repeats every 56 days for up to 4 courses.

Blood and tumor tissue samples may be collected at baseline and at progression or relapse for correlative studies. Patients also undergo FDG-PET at baseline and periodically for restaging.

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, 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

• Patients must have at least one of the following indicators of poor risk disease:

• >= 3 risk factors by the Follicular Lymphoma International Prognostic Index (FLIPI score), or 2 risk factors by the FLIPI and at least one bulky mass or lymph node > 6 cm in size;

• FLIPI score:

• Age > 60 years

• Involvement of > 4 nodal sites

• Stage III-IV disease

• Hemoglobin < 12.0 mg/dL

• 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; due to the unknown teratogenic potential of this regimen, pregnant or nursing patients may not be enrolled; women of childbearing potential must have a negative serum or urine pregnancy test 10-14 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 due to the teratogenic potential of the therapy utilized in this trial; 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/µl; no evidence of resistant strains of HIV; on anti-HIV therapy with an HIV viral load < 50 copies HIV ribonucleic acid (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/μL

• Platelet count >= 75,000/μL

• Creatinine =< 2.0 mg/dL

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

• Bilirubin =< 2 x ULN

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Kristie Blum

Principal Investigator

U.S.A.
Illinois
	Chicago
	Cancer and Leukemia Group B
		Kristie A. Blum	Ph: 614-293-8858
			Email: osu@emergingmed.com
	University of Chicago Cancer Research Center
		Sonali Mehta Smith	Ph: 773-834-7424
	University of Illinois Cancer Center
		David J. Peace	Ph: 312-355-3046
	Evanston
	CCOP - Evanston
		Lynne S. Kaminer	Ph: 847-570-1381
	Harvey
	Ingalls Cancer Care Center at Ingalls Memorial Hospital
		Mark F. Kozloff	Ph: 708-915-4673
			Email: clinicaltrials@ingalls.org
Indiana
	Indianapolis
	St. Francis Hospital Cancer Care Services
		Howard M. Gross	Ph: 765-983-3000
	Mishawaka
	Michiana Hematology-Oncology, PC - Mishawaka
		Rafat H. Ansari	Ph: 574-234-5123
	Westville
	Michiana Hematology Oncology-PC Westville
		Rafat H. Ansari	Ph: 574-234-5123
Iowa
	Sioux City
	Siouxland Hematology-Oncology Associates, LLP
		Donald Bruce Wender	Ph: 712-252-0088
Maine
	Bangor
	CancerCare of Maine at Eastern Maine Medical Center
		Thomas Henry Openshaw	Ph: 207-973-4274
Maryland
	Baltimore
	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
		Roberto F Martinez	Ph: 410-601-6120
			Email: pridgely@lifebridgehealth.org
Michigan
	Ann Arbor
	Saint Joseph Mercy Cancer Center
		Christopher M Reynolds	Ph: 734-712-3456
	Grand Rapids
	Butterworth Hospital at Spectrum Health
		Gilbert D Padula	Ph: 616-685-5225
	Lacks Cancer Center at Saint Mary's Health Care
		Gilbert D Padula	Ph: 616-685-5225
Minnesota
	Minneapolis
	Veterans Affairs Medical Center - Minneapolis
		Sharon D Luikart	Ph: 612-467-2800
Missouri
	Columbia
	Ellis Fischel Cancer Center at University of Missouri - Columbia
		Carl E. Freter	Ph: 573-882-7440
	Kansas City
	Saint Luke's Hospital
		Rakesh Gaur	Ph: 913-948-5588
			Email: amy.krushelniski@hcahealthcare.com
	Saint Louis
	Missouri Baptist Cancer Center
		Alan Philip Lyss	Ph: 800-392-0936
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Nancy L. Bartlett	Ph: 800-600-3606
			Email: info@siteman.wustl.edu
New York
	East Syracuse
	CCOP - Hematology-Oncology Associates of Central New York
		Jeffrey J. Kirshner	Ph: 315-472-7504
	Lake Success
	Monter Cancer Center of the North Shore-LIJ Health System
		Cristina M Ghiuzeli	Ph: 516-562-3467
	Manhasset
	CCOP - North Shore University Hospital
		Cristina M Ghiuzeli	Ph: 516-562-3467
	Don Monti Comprehensive Cancer Center at North Shore University Hospital
		Cristina M Ghiuzeli	Ph: 516-562-3467
	New Hyde Park
	Long Island Jewish Medical Center
		Cristina M Ghiuzeli	Ph: 516-562-3467
	New York
	New York Weill Cornell Cancer Center at Cornell University
		Peter Martin	Ph: 212-746-1848
	Syracuse
	SUNY Upstate Medical University Hospital
		Teresa C. Gentile	Ph: 315-464-5476
North Carolina
	Asheboro
	Randolph Hospital
		Peter Rubin	Ph: 336-832-0821
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Steven I Park	Ph: 877-668-0683
	Goldsboro
	Wayne Memorial Hospital, Incorporated
		James N. Atkins	Ph: 919-580-0000
	Greensboro
	Moses Cone Regional Cancer Center at Wesley Long Community Hospital
		Peter Rubin	Ph: 336-832-0821
	Kinston
	Kinston Medical Specialists
		Peter R. Watson	Ph: 252-559-2200
	Reidsville
	Annie Penn Cancer Center
		Peter Rubin	Ph: 336-832-0821
	Statesville
	Iredell Memorial Hospital
		Ruby A. Grimm	Ph: 704-873-5661
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		David Duane Hurd	Ph: 336-713-6771
North Dakota
	Grand Forks
	Altru Cancer Center at Altru Hospital
		Grant R Seeger	Ph: 701-780-6520
Ohio
	Columbus
	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
		Kristie A. Blum	Ph: 866-627-7616
			Email: osu@emergingmed.com
	Kettering
	Charles F. Kettering Memorial Hospital
		Howard M. Gross	Ph: 765-983-3000
	Oregon
	St. Charles Mercy Hospital
		Rex B Mowat	Ph: 517-265-0116
	Toledo
	St. Anne Mercy Hospital
		Rex B Mowat	Ph: 517-265-0116
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Carla Kurkjian	Ph: 405-271-4272
			Email: julie-traylor@ouhsc.edu
South Carolina
	Greenville
	Bon Secours St. Francis Health System
		Charles E Bowers	Ph: 800-486-5941
	Spartanburg
	Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
		Charles E Bowers	Ph: 800-486-5941
Virginia
	Richmond
	Virginia Commonwealth University Massey Cancer Center
		Beata Holkova	Ph: 804-628-1939

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01286272
Information obtained from ClinicalTrials.gov on May 06, 2013

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