Rituximab and Combination Chemotherapy With or Without Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Diffuse Large B Cell Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01856192
First received: May 14, 2013
Last updated: August 25, 2016
Last verified: August 2016
  Purpose
This randomized phase II trial studies how well rituximab and combination chemotherapy with or without lenalidomide work in treating patients with newly diagnosed stage II-IV diffuse large B cell lymphoma. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, 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. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether rituximab and combination chemotherapy are more effective when given with or without lenalidomide in treating patients with diffuse large B cell lymphoma.

Condition Intervention Phase
Stage II Diffuse Large B-Cell Lymphoma
Stage III Diffuse Large B-Cell Lymphoma
Stage IV Diffuse Large B-Cell Lymphoma
Drug: Cyclophosphamide
Drug: Doxorubicin Hydrochloride
Other: Laboratory Biomarker Analysis
Drug: Lenalidomide
Drug: Prednisone
Biological: Rituximab
Drug: Vincristine Sulfate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Open Label Study of Lenalidomide R-CHOP (R2CHOP) vs RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) in Patients With Newly Diagnosed Diffuse Large B Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS [ Time Frame: Time from randomization to the earliest of documented disease progression, new primaries of the same type or death without progression, assessed up to 10 years ] [ Designated as safety issue: No ]
    The primary analysis of PFS will be performed including all randomized eligible patients using a one-sided log-rank test stratified on IPI (2-3 vs. 4-5), age (< 60 years vs >= 60 years) and molecular subtype (germinal center B-cell type [GCB] vs. activated B-cell type [ABC]). Cox proportional hazards models will be used to assess possible effects of baseline clinical and biological characteristics on outcome, including age, gender, disease stage, and IPI. Treatment and covariate interactions will also be examined.


Secondary Outcome Measures:
  • CR rate based on PET-CT scan [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    The comparison of CR between two arms will be performed with CMH test, stratified on IPI (2-3 vs 4-5), age (< 60 yrs vs >= 60 yrs) and molecular subtype (GCB vs. ABC). Exploratory logistic regression will be used to assess possible effects of baseline clinical and biological characteristics on outcome, including age, gender, disease stage, and IPI. Treatment and covariate interactions will also be examined.

  • OS [ Time Frame: Time from randomization until death due to any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
    The method of Kaplan and Meier will be used to estimate OS, and stratified log-rank test will be used to compare OS between two arms.

  • Overall RR based on PET-CT scan [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    The comparison of RR between two arms will be performed with Cochran-Mantel-Haenszel (CMH) test, stratified on IPI (2-3 vs 4-5), age (< 60 yrs vs >= 60 yrs) and molecular subtype (GCB vs. ABC). Exploratory logistic regression will be used to assess possible effects of baseline clinical and biological characteristics on outcome, including age, gender, disease stage, and IPI. Treatment and covariate interactions will also be examined.


Other Outcome Measures:
  • Impact of DLBCL molecular subtype on outcome [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Analysis will be based on classification by gene expression profile from paraffin-embedded tissue. A stratified log-rank test and Cochran-Mantel-Haenszel test will be used to compare PFS and RR between two molecular subtypes, respectively. Other secondary outcomes, including overall RR and OS will be compared using similar methods.

  • Relation between interim PET scan and study outcome [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 345
Study Start Date: August 2013
Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (rituximab, combination chemotherapy, lenalidomide)
Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1; prednisone PO on days 1-5; and lenalidomide PO on days 1-10. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • Revlimid
Drug: Prednisone
Given PO
Other Names:
  • .delta.1-Cortisone
  • 1, 2-Dehydrocortisone
  • Adasone
  • Cortancyl
  • Dacortin
  • DeCortin
  • Decortisyl
  • Decorton
  • Delta 1-Cortisone
  • Delta-Dome
  • Deltacortene
  • Deltacortisone
  • Deltadehydrocortisone
  • Deltasone
  • Deltison
  • Deltra
  • Econosone
  • Lisacort
  • Meprosona-F
  • Metacortandracin
  • Meticorten
  • Ofisolona
  • Orasone
  • Panafcort
  • Panasol-S
  • Paracort
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisonum
  • Prednitone
  • Promifen
  • Servisone
  • SK-Prednisone
Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate
Active Comparator: Arm B (rituximab, combination chemotherapy)
Patients receive rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone as in Arm A. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Prednisone
Given PO
Other Names:
  • .delta.1-Cortisone
  • 1, 2-Dehydrocortisone
  • Adasone
  • Cortancyl
  • Dacortin
  • DeCortin
  • Decortisyl
  • Decorton
  • Delta 1-Cortisone
  • Delta-Dome
  • Deltacortene
  • Deltacortisone
  • Deltadehydrocortisone
  • Deltasone
  • Deltison
  • Deltra
  • Econosone
  • Lisacort
  • Meprosona-F
  • Metacortandracin
  • Meticorten
  • Ofisolona
  • Orasone
  • Panafcort
  • Panasol-S
  • Paracort
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisonum
  • Prednitone
  • Promifen
  • Servisone
  • SK-Prednisone
Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

Detailed Description:

PRIMARY OBJECTIVES:

I. Progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. Response rate (RR). II. Complete remission (CR) rate as defined by positron emission tomography (PET)-computed tomography (CT) criteria.

III. Overall survival (OS).

TERTIARY OBJECTIVES:

I. Impact of diffuse large B cell lymphoma (DLBCL) molecular subtype on outcome.

II. Interim PET scan results in relation to treatment outcome.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive rituximab intravenously (IV), cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1; prednisone orally (PO) on days 1-5; and lenalidomide PO on days 1-10. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone as in Arm A. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patient are followed up every 3 months for 2 years, every 6 months for 1 year, and then annually for up to 7 years.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION (STEP 0)
  • Histologically confirmed DLBCL expressing cluster of differentiation (CD)20 antigen; patients with transformed lymphoma are excluded; in this regard, patients with composite lymphoma in the diagnostic tissue (concomitant DLBCL and follicular or other low-grade lymphoma component) are excluded; however, patients with DLBCL in primary diagnostic tissue but a bone marrow that shows low grade or indeterminate lymphoma are eligible; patients with known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; similarly, patients with known v-myc myelocytomatosis viral oncogene homolog (avian) (c-myc) translocation (by fluorescence in situ hybridization) positive DLBCL are encouraged to participate in trials specifically designed for these patients; however patients with known c-myc DLBC positive are NOT excluded from this study; c-myc testing prior to study enrollment is NOT required
  • Stages II bulky disease (defined as mass size of more than 10 cm), stage III, or IV (Ann Arbor staging); patients with stage I and stage II non-bulky disease are excluded from this study
  • A paraffin-embedded tumor tissue specimen from the initial diagnostic biopsy has been located and ready to ship to the Mayo Clinic Lymphoma Laboratory following pre-registration; Note: exisional tumor biopsy is preferred; core needle biopsies will be considered adequate if there is enough tissue for the mandatory central pathology review immunohistochemistry and Genomics Education Partnership (GEP); submission of a tumor block is preferred, but if unavailable submit alternative materials
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Previously untreated and not receiving any other agent that would be considered as a treatment for the lymphoma; for subjects with severe systemic symptoms, compressive disease, or rapidly progressing symptomatic adenopathy, are allowed for lymphoma associated symptom treatment with up to 1 mg/kg/day prednisone, or equivalent, for a maximum of 7 days is permitted prior to beginning the treatment, at the discretion of the investigator; a washout period does not apply
  • No known central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells; these patients are usually treated with CNS directed therapy; screening for cerebrospinal fluid (CSF)/CNS involvement is NOT required but can be performed per treating medical doctor (MD) discretion; intrathecal (IT) methotrexate or IT cytarabine prophylaxis in patients with negative CSF who are felt to be at high risk of CNS relapse is allowed per local MD discretion; this should be noted on the treatment form
  • Absence of history of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Absence of history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia; patients with a history of deep vein thrombosis(DVT)/pulmonary embolism (PE) or thrombophilia may participate if they are willing to be on full anticoagulation during the treatment if randomized to rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R2CHOP) arm A; full anticoagulation is defined as warfarin, factor X inhibitors, or low molecular weight heparin at therapeutic doses
  • Patient must be able and willing to receive anticoagulation therapy with aspirin 70-325 mg daily prophylaxis, low molecular weight heparin, factor X inhibitors or warfarin; patients unable or unwilling to take any prophylaxis are NOT eligible
  • Absence of history of acquired immune deficiency syndrome (AIDS)-related conditions (other than the presenting DLBCL) or post-transplant lymphoproliferative disorder (PTLD) in immunocompromised patients; patients with human immunodeficiency virus (HIV) on antiretroviral therapy other than zidovudine (AZT) and/or stavudine and without prior AIDS defining conditions and adequate CD4 count (> 400) are eligible
  • No other active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy; exceptions to this are as follows: localized non-melanotic skin cancer and any cancer that in the judgment of the investigator has been treated with curative intent and will not interfere with the study treatment plan and response assessment
  • No history of radiation therapy to >= 25% of the bone marrow for other diseases or history of anthracycline therapy
  • Patients must not be receiving erythroid stimulating agents (erythropoietin [EPO]: Procrit, Aranesp)
  • RANDOMIZATION (STEP 1)
  • Patient meets the eligibility criteria outlined above
  • Site has received notification from Mayo Clinic - Rochester Division of Hematopathology of the central confirmation of diagnosis and tissue adequacy for mandatory research studies
  • Patients must have measurable disease (at least 1 lesion of >= 1.5 cm in one diameter) as detected by computed tomography (CT) or the CT images of the positron emission tomography (PET)/CT
  • International Prognostic Index (IPI) of 2 or greater
  • Ejection fraction of >= 45% by either multi-gated acquisition (MUGA) scan or echocardiogram (ECHO)
  • Absence of co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Absolute neutrophil count (ANC) >= 1500
  • Platelets (PLT) >= 100,000
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN, the direct bilirubin must be normal
  • Alkaline (Alk.) phosphatase =< 3 x ULN unless evidence of the direct liver involvement by lymphoma - then =< 5 x ULN
  • Aspartate aminotransferase (AST) =< 3 x ULN unless evidence of the direct liver involvement by lymphoma - then =< 5 x ULN
  • Creatinine =< 2 x ULN or creatinine clearance (CrCl) > 30 ml/min
  • Women must not be pregnant or breast-feeding
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Men must agree to use a latex condom during sexual contact with a FCBP 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01856192

  Show 482 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Grzegorz Nowakowski ECOG-ACRIN Cancer Research Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01856192     History of Changes
Other Study ID Numbers: NCI-2013-00959  NCI-2013-00959  ECOG-E1412  E1412  E1412  U10CA180820  U10CA021115 
Study First Received: May 14, 2013
Last Updated: August 25, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Thalidomide
Rituximab
Liposomal doxorubicin
Lenalidomide
Doxorubicin
Prednisone
Vincristine
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Cortisone acetate
Cortisone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 25, 2016