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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01286272
First received: January 27, 2011
Last updated: October 16, 2014
Last verified: October 2014

January 27, 2011
October 16, 2014
April 2011
June 2017   (final data collection date for primary outcome measure)
CR rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
Complete response (CR) rate in newly diagnosed, high-risk follicular lymphoma patients [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01286272 on ClinicalTrials.gov Archive Site
  • PFS [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Kaplan-Meier curves of PFS and overall survival (OS) will be generated for the two arms. The p-values of the log-rank test will be calculated to compare PFS and OS between the two arms.
  • Grade 3 or higher toxicities assessed according to NCI Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    The toxicity profile of the two arms will be summarized using frequency tables. The chi-squared test will be conducted to compare the toxicity rate of grade 3 or higher between the two arms.
  • Pre-treatment single nucleotide polymorphisms (SNP) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    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.
  • Immunohistochemical (IHC) markers [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    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.
  • Predictive value of FDG-PET [ Time Frame: Baseline and at 70 days ] [ Designated as safety issue: No ]
    The ratio will be correlated with response (using the two-sample t-test) and PFS (using the Cox regression method) data.
  • Comparison of progression-free survival (PFS) and overall survival (OS) between the 2 arms [ Designated as safety issue: No ]
  • Toxicity profile of the 2 arms [ Designated as safety issue: Yes ]
  • Comparison of PFS among the 3 genotype groups of each single nucleotide polymorphism [ Designated as safety issue: No ]
  • Correlation of immunohistochemical markers with response and PFS [ Designated as safety issue: No ]
  • Predictive value of FDG-PET (ratio between the maximum standardized uptake value [SUVmax] after course 2 and the SUVmax at baseline) and correlation of the ratio with response and PFS [ Designated as safety issue: No ]
  • Correlation of the change rate of the time trajectory of FDG-PET findings with response and PFS [ Designated as safety issue: No ]
  • Validation of gene signature with respect to CR rate, PFS, and OS [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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

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 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.

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 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 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 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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Contiguous Stage II Grade 1 Follicular Lymphoma
  • Contiguous Stage II Grade 2 Follicular Lymphoma
  • Contiguous Stage II Grade 3 Follicular Lymphoma
  • Noncontiguous Stage II Grade 1 Follicular Lymphoma
  • Noncontiguous Stage II Grade 2 Follicular Lymphoma
  • Noncontiguous Stage II Grade 3 Follicular Lymphoma
  • Stage I Grade 1 Follicular Lymphoma
  • Stage I Grade 2 Follicular Lymphoma
  • Stage I Grade 3 Follicular Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Biological: ofatumumab
    Given IV
    Other Names:
    • Arzerra
    • HuMax-CD20
  • Drug: bendamustine hydrochloride
    Given IV
    Other Names:
    • bendamustin hydrochloride
    • bendamustine
    • cytostasan hydrochloride
    • Treanda
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Other: laboratory biomarker analysis
    Correlative studies
  • Procedure: positron emission tomography with radiolabeled targeting agents
    Undergo FDG-PET
    Other Name: PET with radiolabeled targeting agents
  • Radiation: fludeoxyglucose F 18
    Undergo FDG-PET
    Other Names:
    • 18FDG
    • FDG
  • Experimental: Arm A (ofatumumab, bendamustine hydrochloride)

    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.

    Interventions:
    • Biological: ofatumumab
    • Drug: bendamustine hydrochloride
    • Other: laboratory biomarker analysis
    • Procedure: positron emission tomography with radiolabeled targeting agents
    • Radiation: fludeoxyglucose F 18
  • Experimental: Arm B (ofatumumab, bendamustine hydrochloride, bortezomib)

    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.

    Interventions:
    • Biological: ofatumumab
    • Drug: bendamustine hydrochloride
    • Drug: bortezomib
    • Other: laboratory biomarker analysis
    • Procedure: positron emission tomography with radiolabeled targeting agents
    • Radiation: fludeoxyglucose F 18
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
130
Not Provided
June 2017   (final data collection date for primary outcome measure)

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 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; 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 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/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
Both
18 Years and older
No
United States
 
NCT01286272
NCI-2011-02625, NCI-2011-02625, CDR0000694298, CALGB 50904, CALGB-50904, U10CA180821, U10CA031946
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Kristie Blum Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP