Ibrutinib, Rituximab, and Consolidation Chemotherapy in Treating Young Patients With Newly Diagnosed Mantle Cell Lymphoma

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2

Total Enrollment

131 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-06-03

Study Completion Date

2027-06-30

Brief Summary

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This phase II trial studies how well ibrutinib, rituximab, and consolidation chemotherapy consisting of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine work in treating young patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine, 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving ibrutinib together with rituximab and consolidation chemotherapy may be a better treatment for mantle cell lymphoma.

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Detailed Description

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PRIMARY OBJECTIVES:

I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival of ibrutinib plus rituximab with rituximab - cyclophosphamide, vincristine (vincristine sulfate), doxorubicin (doxorubicin hydrochloride), and dexamethasone (hyper-CVAD) consolidation in newly diagnosed MCL patients and in high-risk patients.

II. To further evaluate the toxicity profile of the ibrutinib/rituximab combination and consolidation therapy.

III. To estimate the rate of complete response (CR) prior to and following consolidation therapy.

IV. To estimate the response duration and overall survival. V. To analyze progression free survival in a subgroup of patients presenting with high risk features after receiving an additional 2 years of maintenance therapy with rituximab and ibrutinib at doses used in part 1 of the study, starting after part 2 of the study ends.

OUTLINE:

PART I (IBRUTINIB PLUS RITUXIMAB): Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and rituximab intravenously (IV) over 6-8 hours on days 1, 8, 15, and 22 of cycle 1 and then over 4 hours on day 1 of cycles 3-12. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or until patients achieve complete response.

PART II (CONSOLIDATION THERAPY): Patients receive rituximab IV over 6 hours on day 1; dexamethasone PO or IV on days 1-4; cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4; doxorubicin hydrochloride IV over 15-30 minutes on day 5; and vincristine sulfate IV over 15-30 minutes on day 5 of cycles 1, 3, 5, and 7. Patients also receive rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours BID on days 3 and 4 of cycles 2, 4, 6, and 8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Conditions

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Blastoid Variant Mantle Cell Lymphoma Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Treatment (ibrutinib, rituximab, consolidation chemotherapy)

PART I (IBRUTINIB PLUS RITUXIMAB): Patients receive ibrutinib PO QD on days 1-28 and rituximab IV over 6-8 hours on days 1, 8, 15, and 22 of cycle 1 and then over 4 hours on day 1 of cycles 3-12. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity or until patients achieve complete response.

PART II (CONSOLIDATION THERAPY): Patients receive rituximab IV over 6 hours on day 1; dexamethasone PO or IV on days 1-4; cyclophosphamide IV over 3 hours BID on days 2-4; doxorubicin hydrochloride IV over 15-30 minutes on day 5; and vincristine sulfate IV over 15-30 minutes on day 5 of cycles 1, 3, 5, and 7. Patients also receive rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours BID on days 3 and 4 of cycles 2, 4, 6, and 8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Cyclophosphamide

Intervention Type DRUG

Given IV

Cytarabine

Intervention Type DRUG

Given IV

Dexamethasone

Intervention Type DRUG

Given PO or IV

Doxorubicin

Intervention Type DRUG

Given IV

Doxorubicin Hydrochloride

Intervention Type DRUG

Given IV

Ibrutinib

Intervention Type DRUG

Given PO

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Methotrexate

Intervention Type DRUG

Given IV

Rituximab

Intervention Type BIOLOGICAL

Given IV

Vincristine

Intervention Type DRUG

Given IV

Vincristine Sulfate

Intervention Type DRUG

Given IV

Interventions

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Cyclophosphamide

Given IV

Intervention Type DRUG

Cytarabine

Given IV

Intervention Type DRUG

Dexamethasone

Given PO or IV

Intervention Type DRUG

Doxorubicin

Given IV

Intervention Type DRUG

Doxorubicin Hydrochloride

Given IV

Intervention Type DRUG

Ibrutinib

Given PO

Intervention Type DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type OTHER

Methotrexate

Given IV

Intervention Type DRUG

Rituximab

Given IV

Intervention Type BIOLOGICAL

Vincristine

Given IV

Intervention Type DRUG

Vincristine Sulfate

Given IV

Intervention Type DRUG

Other Intervention Names

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(-)-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 Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 .beta.-Cytosine arabinoside 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-.beta.-D-Arabinofuranosylcytosine 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-Beta-D-arabinofuranosylcytosine 1.beta.-D-Arabinofuranosylcytosine 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl- 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl- Alexan Ara-C ARA-cell Arabine Arabinofuranosylcytosine Arabinosylcytosine Aracytidine Aracytin Aracytine Beta-Cytosine Arabinoside CHX-3311 Cytarabinum Cytarbel Cytosar Cytosine Arabinoside Cytosine-.beta.-arabinoside Cytosine-beta-arabinoside Erpalfa Starasid Tarabine PFS U 19920 U-19920 Udicil WR-28453 Aacidexam Adexone Aknichthol Dexa Alba-Dex Alin Alin Depot Alin Oftalmico Amplidermis Anemul mono Auricularum Auxiloson Baycadron Baycuten Baycuten N Cortidexason Cortisumman Decacort Decadrol Decadron Decadron DP Decalix Decameth Decasone R.p. Dectancyl Dekacort Deltafluorene Deronil Desamethasone Desameton Dexa-Mamallet Dexa-Rhinosan Dexa-Scheroson Dexa-sine Dexacortal Dexacortin Dexafarma Dexafluorene Dexalocal Dexamecortin Dexameth Dexamethasone Intensol Dexamethasonum Dexamonozon Dexapos Dexinoral Dexone Dinormon Dxevo Fluorodelta Fortecortin Gammacorten Hemady Hexadecadrol Hexadrol Lokalison-F Loverine Methylfluorprednisolone Millicorten Mymethasone Orgadrone Spersadex TaperDex Visumetazone ZoDex Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin 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 Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex BTK Inhibitor PCI-32765 CRA-032765 Imbruvica PCI-32765 Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 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 Riabni Rituxan Rituximab ABBS Rituximab ARRX Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 Rituximab PVVR rituximab-abbs Rituximab-arrx Rituximab-pvvr RTXM83 Ruxience Truxima Leurocristine VCR Vincrystine Kyocristine Leurocristine Sulfate Leurocristine, sulfate Oncovin Vincasar Vincosid Vincrex Vincristine, sulfate

Eligibility Criteria

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Inclusion Criteria

* Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy
* Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following:

* Blastoid variant
* Pleomorphic variant
* B symptoms
* Mantle Cell International Prognostic Score (MIPI) \> 3
* Ki-67 \>= 30%
* Bulky tumors \> 7 cm or in case of \>= 2 tumors, each \>= 5 cm in diameter
* Disease threatening organ function
* Elevated lactate dehydrogenase (LDH)
* Peripheral blood white blood cell (PB WBC) \> 50,000
* Pancytopenia due to bone marrow MCL
* Patient's choice due to anxiety
* Pain due to lymphoma
* Somatic mutations in the TP53, c-MYC or NOTCH genes
* Size of spleen \>= 20 cm
* Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol:

* Blastoid or pleomorphic histology
* Ki-67 index larger than 30%
* Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter
* Somatic mutations in the TP53, c-MYC or NOTCH genes
* Size of spleen \>= 20 cm
* Patient has newly diagnosed disease with no prior therapy
* Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form
* Age =\< 65 years at the time of signing the informed consent
* Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography \[CT\] scan defined as at least 1 lesion that measures \>= 1.5 cm in single dimension)
* Gastrointestinal or bone marrow or spleen only patients are allowable
* Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
* An absolute neutrophil count (ANC) \> 1,000/mm\^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is \>= 500/mm\^3 \[growth factor allowed\]; these patients should be discussed with either the principal investigator \[PI\] or Co-PI of the study for final approval)
* Platelet count \> 100,000/mm\^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or \> than 20,000/mm\^3; these patients should be discussed with either the PI or Co-PI of the study for final approval)
* Serum bilirubin \< 1.5 mg/dl
* Creatinine (Cr) clearance \>= 30 mL/min
* Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) \< 2 x upper limit of normal or \< 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed
* Cardiac ejection fraction \>= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
* Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated
* Females of childbearing potential (FCBP)\* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy

* A female of childbearing potential is a sexually mature woman who: 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)

Exclusion Criteria

* Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form
* Pregnant or breast feeding females
* Known human immunodeficiency virus (HIV) infection
* Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C
* All patients with central nervous system lymphoma
* Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment
* Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib
* Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required
* Requires anticoagulation with warfarin or equivalent vitamin K antagonist
* Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors
* Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT \[QTc\] \> 500 millisecond \[msec\]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate \< 50 beats per minute \[bpm\]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist
* Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No