Intergroup Randomized Phase 2 Four Arm Study In Patients ≥ 60 With Previously Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation (RBV → LR)
Description
Brief Summary
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different
ways. Some find cancer cells and help kill them or carry cancer-killing substances to them.
Others interfere with the ability of cancer cells to grow and spread. Drugs used in
chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer
cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking
some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell
lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab
together with bendamustine and bortezomib is more effective than rituximab and bendamustine,
followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.
PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and
lenalidomide in treating previously untreated older patients with mantle cell lymphoma.
Detailed Description
OBJECTIVES:
Primary
- To determine whether the addition of bortezomib (RBV) to an induction regimen of
rituximab-bendamustine hydrochloride (RB) improves progression-free survival (PFS)
compared to RB alone in patients ≥ 60 years of age with previously untreated mantle cell
lymphoma.
- To determine whether the addition of lenalidomide to a consolidation regimen of
rituximab following an induction regimen of RB or RBV improves PFS compared to
consolidation rituximab alone in this patient population.
Secondary
- To determine whether the addition of bortezomib to induction therapy improves the
positron emission tomography (PET)-documented complete response (CR) rate compared to RB
alone.
- To determine the objective response rate (ORR) for RB and RBV.
- Among patients who do not have PET-documented CR at the end of induction, to determine
whether the addition of lenalidomide to consolidation therapy improves CR and ORR
compared with rituximab alone.
- To determine overall survival (OS) in the treatment arms.
- To determine safety, with attention to the addition of bortezomib in the induction
regimen and lenalidomide-rituximab (LR) as consolidation therapy.
- To collect paraffin-embedded tissue for creation of tissue microarray.
- To collect and bank serum and blood mononuclear cells for future studies.
- To collect formalin-fixed paraffin-embedded (FFPE) tissue to analyze potential
prognostic factors (Ki-67 proliferation index by immunohistochemistry and correlation
with proposed 5-gene set of proliferation markers analyzed by RNA PCR; SOX 11 expression
by immunohistochemistry; and Micro-RNA levels by microarray).
- Using patient-reported outcomes data, to determine the extent and severity of neuropathy
associated with the addition of bortezomib to induction treatment.
- Using patient-reported outcomes data, to determine the extent and severity of fatigue
associated with the addition of lenalidomide to consolidation treatment.
- To evaluate the effects of the addition of bortezomib and lenalidomide on
patient-reported health-related quality of life.
- To evaluate the effects of bortezomib-related neuropathy on patient-reported
health-related quality of life.
- To evaluate the response of lymphoma-specific symptoms to treatment.
- Using longitudinal patient-reported outcomes data, to describe the trajectory of
lymphoma symptoms, neuropathy, fatigue, and overall health-related quality of life prior
to, during, and following treatment among older adults with MCL.
Tertiary
- To assess the proportion of patients up and down staging when fludeoxyglucose F 18-
(FDG) PET/CT is added to standard Ann Arbor staging.
- To assess the ability of pre-treatment FDG-PET/CT (SUVmax) to predict response rate and
PFS.
- Among patients with interim (post-cycle 3) FDG-PET/CT imaging, to assess the correlation
of interim FDG-PET/CT imaging with response rate and PFS both during induction and
consolidation therapy.
- To assess standard FDG-PET/CT metrics including SUVmax, tumor metabolic burden, total
tumor burden, and association with pathology features (blastoid variant vs other, and
Ki67) in the setting of MCL.
- To assess differences in overall and CR rates when using Deauville vs International
Harmonization Project FDG-PET/CT interpretation criteria.
- To determine whether there is a correlation between FDG-PET/CT response and residual
disease assessment by molecular and/or flow cytometric techniques.
- To determine whether the number of malignant cells in circulation predict the number of
cells in marrow.
- To determine whether the number of malignant cells in circulation/in marrow at the end
of induction correlate with CR and 2-year PFS.
- To determine whether there is a higher rate of minimal residual disease (MRD) negativity
among patients randomized to RBV as compared with RB, and among patients treated with LR
maintenance compared with rituximab.
- To compare the two methods of MRD detection - molecular techniques and flow cytometry -
as prognostic markers for outcome.
OUTLINE: This is a multicenter study. Patients are stratified according to mantle cell
lymphoma International Prognostic Index risk score (low vs intermediate vs high). Patients
are randomized to 1 of 4 treatment arms.
- Arm A: Patients receive induction therapy comprising rituximab IV on day 1 and
bendamustine hydrochloride IV over 60 minutes on days 1-2. Treatment repeats every 4
weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
- Arm E: Patients receive consolidation therapy comprising rituximab IV on day 1.
Courses repeat every 8 weeks for 2 years in the absence of disease progression or
unacceptable toxicity.
- Arm B: Patients receive induction therapy comprising bortezomib IV or subcutaneously
(SC) on days 1, 4, 8, and 11 and rituximab and bendamustine hydrochloride as patients in
arm A. Treatment repeats every 4 weeks for 6 courses in the absence of disease
progression or unacceptable toxicity.
- Arm F: Patients receive consolidation therapy comprising rituximab IV on day 1.
Courses repeat every 8 weeks for 2 years in the absence of disease progression or
unacceptable toxicity.
- Arm C: Patients receive induction therapy comprising rituximab and bendamustine
hydrochloride as patients in arm A. Treatment repeats every 4 weeks for 6 courses in the
absence of disease progression or unacceptable toxicity.
- Arm G: Patients receive consolidation therapy comprising lenalidomide orally (PO)
daily on days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the
absence of disease progression or unacceptable toxicity.
- Arm D: Patients receive bortezomib, rituximab, and bendamustine hydrochloride as
patients in arm B. Treatment repeats every 4 weeks for 6 courses in the absence of
disease progression or unacceptable toxicity.
- Arm H: Patients receive consolidation therapy comprising lenalidomide PO daily on
days 1-21 every 4 weeks and rituximab IV every 8 weeks for 2 years in the absence
of disease progression or unacceptable toxicity.
Patients may undergo blood and bone marrow sample collection at baseline and during treatment
for correlative studies.
Patients complete the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym), the
FACT/GOG-Neurotoxicity scale (FACT/GOG-Ntx), FACT-Fatigue, and FACT-General questionnaires at
baseline and periodically during study and follow up.
After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually for 10 years.
Phase
Phase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.Inclusion and Exclusion Criteria
- Histologically confirmed untreated mantle cell lymphoma (MCL), with documented cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or fluorescence in situ hybridization (FISH)
- Patients must have at least one objective measurable disease parameter
- Abnormal PET scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging
- Measurable disease in the liver is required if the liver is the only site of lymphoma
- Patient must have no CNS involvement PATIENT CHARACTERISTICS:
- ECOG performance status 0-2
- ANC ≥ 1,500/mcL (1.5 x 10^9/L)*
- Platelets ≥ 100,000/mcL (100 x 10^9/L)* NOTE: *Unless due to marrow involvement.
- AST/ALT ≤ 2 times upper limit of normal (ULN)
- Bilirubin ≤ 2 times ULN
- Calculated creatinine clearance by Cockroft-Gault formula ≥ 30 mL/min
- Women (sexually mature female) must not be pregnant or breast-feeding
- Negative pregnancy test
- Women of childbearing potential and sexually active males use an accepted and effective method of contraception
- Men must agree to use a latex condom during sexual contact with a female of child-bearing potential, even if they have had a successful vasectomy
- All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
- No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma, or any surgically or radiation-cured malignancy continuously disease free for ≥ 5 years so as not to interfere with interpretation of radiographic response
- Patient agrees that if randomized to Arms C or D, and proceed onto Arms G or H, they must register into the mandatory RevAssist
Sites
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Idaho
- Idaho Urologic Institute, PA, Meridian, Idaho, 83642
-
Colorado
- CCOP - Colorado Cancer Research Program, Denver, Colorado, 80222
-
Montana
- Sletten Cancer Institute at Benefis Healthcare, Great Falls, Montana, 59405
-
Minnesota
- Willmar Cancer Center at Rice Memorial Hospital, Willmar, Minnesota, 56201
- New Ulm Medical Center, New Ulm, Minnesota, 56073
- Hutchinson Area Health Care, Hutchinson, Minnesota, 55350
- Ridgeview Medical Center, Waconia, Minnesota, 55387
- St. Francis Cancer Center at St. Francis Medical Center, Shakopee, Minnesota, 55379
- Fairview Ridges Hospital, Burnsville, Minnesota, 55337
- Park Nicollet Cancer Center, Saint Louis Park, Minnesota, 55416
- CCOP - Metro-Minnesota, Saint Louis Park, Minnesota, 55416
- Mercy and Unity Cancer Center at Mercy Hospital, Coon Rapids, Minnesota, 55433
- Mercy and Unity Cancer Center at Unity Hospital, Fridley, Minnesota, 55432
- United Hospital, Saint Paul, Minnesota, 55102
- HealthEast Cancer Care at St. John's Hospital, Maplewood, Minnesota, 55109
- Minnesota Oncology - Maplewood, Maplewood, Minnesota, 55109
- Minnesota Oncology - Woodbury, Woodbury, Minnesota, 55125
- Lakeview Hospital, Stillwater, Minnesota, 55082
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Missouri
- Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis, Saint Louis, Missouri, 63110
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Wisconsin
- Langlade Memorial Hospital, Antigo, Wisconsin, 54409
- St. Mary's Hospital Medical Center - Green Bay, Green Bay, Wisconsin, 54303
- Green Bay Oncology, Limited at St. Mary's Hospital, Green Bay, Wisconsin, 54303
- Green Bay Oncology, Limited - Oconto Falls, Oconto Falls, Wisconsin, 54154
- St. Nicholas Hospital, Sheboygan, Wisconsin, 53081
- Bay Area Cancer Care Center at Bay Area Medical Center, Marinette, Wisconsin, 54143
- Green Bay Oncology, Limited - Sturgeon Bay, Sturgeon Bay, Wisconsin, 54235
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Illinois
- Provena St. Mary's Regional Cancer Center - Kankakee, Kankakee, Illinois, 60901
- North Shore Oncology and Hematology Associates, Limited - Libertyville, Libertyville, Illinois, 60048
- Cancer Care and Hematology Specialists of Chicagoland - Niles, Niles, Illinois, 60714
- Kellogg Cancer Care Center, Highland Park, Illinois, 60035
- Hematology Oncology Associates - Skokie, Skokie, Illinois, 60076
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Michigan
- Dickinson County Healthcare System, Iron Mountain, Michigan, 49801
- Green Bay Oncology, Limited - Escanaba, Escanaba, Michigan, 49431
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