Clinical trial NCT01286272: Ofatumumab and Bendamustine Hydrochloride With or Without Bortezomib in Treating Patients With Untreated Follicular Non-Hodgkin Lymphoma
Official title: A Randomized Phase II Trial of Ofatumumab and Bendamustine vs. Ofatumumab, Bortezomib (NSC # 681239) and Bendamustine in Patients With Untreated Follicular Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Ann Arbor Stage III Grade 1 Follicular Lymphoma
Ann Arbor Stage III Grade 2 Follicular Lymphoma
Ann Arbor Stage III Grade 3 Follicular Lymphoma
Ann Arbor Stage IV Grade 1 Follicular Lymphoma
Ann Arbor Stage IV Grade 2 Follicular Lymphoma
Ann Arbor Stage IV Grade 3 Follicular Lymphoma
Grade 3a Follicular Lymphoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2011-01-31
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Primary outcomes:
measure: Complete Response Rate
timeFrame: From date of randomization until patient stops treatment for any reason, up to 484 days post-randomization
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to 4 years
measure: The Number of Patients Who Experienced Grade 3+ Hematologic and Non-hematologic Adverse Events at Least Possibly Related to Treatment
timeFrame: From date of randomization until patient stops treatment for any reason, up to 484 days post-randomization
Other outcomes:
measure: Pre-treatment Single Nucleotide Polymorphisms (SNP)
timeFrame: Up to 10 years
measure: Immunohistochemical (IHC) Markers
timeFrame: Up to 10 years
measure: Predictive Value of Fludeoxyglucose-positron-emission Tomography
timeFrame: Up to 36-38 weeks (6-8 weeks after course 6, day 1 after last course of induction chemotherapy)
Locations:
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Saint Helena
country: United States
facility: Saint Helena Hospital
state: California
city: Middletown
country: United States
facility: Middlesex Hospital
state: Connecticut
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: 'Aiea
country: United States
facility: Pali Momi Medical Center
state: Hawaii
city: 'Aiea
country: United States
facility: Queen's Cancer Center - Pearlridge
state: Hawaii
city: Honolulu
country: United States
facility: Hawaii Cancer Care Inc - Waterfront Plaza
state: Hawaii
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Straub Clinic and Hospital
state: Hawaii
city: Honolulu
country: United States
facility: Hawaii Cancer Care Inc-Liliha
state: Hawaii
city: Honolulu
country: United States
facility: Kuakini Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Kailua
country: United States
facility: Castle Medical Center
state: Hawaii
city: Lihue
country: United States
facility: Wilcox Memorial Hospital and Kauai Medical Clinic
state: Hawaii
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Post Falls
country: United States
facility: Kootenai Clinic Cancer Services - Post Falls
state: Idaho
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Weiss Memorial Hospital
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Specialists of Illinois - Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Springfield
country: United States
facility: Springfield Memorial Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Mishawaka
country: United States
facility: Memorial Regional Cancer Center Day Road
state: Indiana
city: Mishawaka
country: United States
facility: Michiana Hematology Oncology PC-Mishawaka
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: Westville
country: United States
facility: Michiana Hematology Oncology PC-Westville
state: Indiana
city: Cedar Rapids
country: United States
facility: Mercy Hospital
state: Iowa
city: Cedar Rapids
country: United States
facility: Oncology Associates at Mercy Medical Center
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Augusta
country: United States
facility: Harold Alfond Center for Cancer Care
state: Maine
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Rockport
country: United States
facility: Penobscot Bay Medical Center
state: Maine
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Ann Arbor
country: United States
facility: Trinity Health Saint Joseph Mercy Hospital Ann Arbor
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health Saint John Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: Corewell Health Grand Rapids Hospitals - Butterworth Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: Trinity Health Grand Rapids Hospital
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Maplewood
country: United States
facility: Saint John's Hospital - Healtheast
state: Minnesota
city: Minneapolis
country: United States
facility: Minneapolis VA Medical Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Bolivar
country: United States
facility: Central Care Cancer Center - Bolivar
state: Missouri
city: Columbia
country: United States
facility: MU Health - University Hospital/Ellis Fischel Cancer Center
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation NCORP
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
state: New Hampshire
city: East Syracuse
country: United States
facility: Hematology Oncology Associates of Central New York-East Syracuse
state: New York
city: Lake Success
country: United States
facility: Northwell Health NCORP
state: New York
city: Lake Success
country: United States
facility: Northwell Health/Center for Advanced Medicine
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Asheboro
country: United States
facility: Randolph Hospital
state: North Carolina
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Kinston
country: United States
facility: ECU Health Oncology Kinston
state: North Carolina
city: Reidsville
country: United States
facility: Annie Penn Memorial Hospital
state: North Carolina
city: Statesville
country: United States
facility: Iredell Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Grand Forks
country: United States
facility: Altru Cancer Center
state: North Dakota
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital North
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Maumee
country: United States
facility: Toledo Clinic Cancer Centers-Maumee
state: Ohio
city: Oregon
country: United States
facility: Saint Charles Hospital
state: Ohio
city: Sylvania
country: United States
facility: ProMedica Flower Hospital
state: Ohio
city: Toledo
country: United States
facility: Mercy Health - Saint Anne Hospital
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Centers-Toledo
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Oklahoma City
country: United States
facility: Mercy Hospital Oklahoma City
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Sayre
country: United States
facility: Guthrie Medical Group PC-Robert Packer Hospital
state: Pennsylvania
city: Greenville
country: United States
facility: Saint Francis Hospital
state: South Carolina
city: Greenville
country: United States
facility: Saint Francis Cancer Center
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Center
state: South Carolina
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Kristie A Blum
role: PRINCIPAL_INVESTIGATOR
References:
citation: Blum KA, Polley MY, Jung SH, Dockter TJ, Anderson S, Hsi ED, Wagner-Johnston N, Christian B, Atkins J, Cheson BD, Leonard JP, Bartlett NL. Randomized trial of ofatumumab and bendamustine versus ofatumumab, bendamustine, and bortezomib in previously untreated patients with high-risk follicular lymphoma: CALGB 50904 (Alliance). Cancer. 2019 Oct 1;125(19):3378-3389. doi: 10.1002/cncr.32289. Epub 2019 Jun 7.