Clinical Trials /

Ibrutinib, Rituximab, Venetoclax, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma

NCT03710772

Description:

This phase II trial studies how well ibrutinib and rituximab given together with venetoclax and combination chemotherapy work in treating patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of tumor 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, venetoclax, cyclophosphamide, vincristine, doxorubicin, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib, rituximab, and venetoclax together with combination chemotherapy may work better in treating patients with mantle cell lymphoma.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib, Rituximab, Venetoclax, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma
  • Official Title: A Phase II Study of Ibrutinib Plus Rituximab Followed by Venetoclax and Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma: Window II Protocol

Clinical Trial IDs

  • ORG STUDY ID: 2018-0447
  • SECONDARY ID: NCI-2018-02137
  • SECONDARY ID: 2018-0447
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03710772

Conditions

  • CD20 Positive
  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-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- 138719Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
Cytarabine.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-28453Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, VisumetazoneGroup I (ibrutinib, rituximab, venetoclax, chemotherapy)
Doxorubicin Hydrochloride5,12-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, RubexGroup I (ibrutinib, rituximab, venetoclax, chemotherapy)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
MethotrexateAbitrexate, 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-19039Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
RituximabABP 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 GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Group I (ibrutinib, rituximab, venetoclax, chemotherapy)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaGroup I (ibrutinib, rituximab, venetoclax, chemotherapy)
VincristineLEUROCRISTINE, VCR, VincrystineGroup I (ibrutinib, rituximab, venetoclax, chemotherapy)

Purpose

This phase II trial studies how well ibrutinib and rituximab given together with venetoclax and combination chemotherapy work in treating patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of tumor 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, venetoclax, cyclophosphamide, vincristine, doxorubicin, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib, rituximab, and venetoclax together with combination chemotherapy may work better in treating patients with mantle cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the complete response rate of the ibrutinib plus rituximab combination
      followed by venetoclax in newly diagnosed young mantle cell lymphoma (MCL) patients.

      SECONDARY OBJECTIVES:

      I. To determine the safety profile of the ibrutinib plus rituximab combination followed by
      venetoclax in newly diagnosed young MCL patients.

      II. To evaluate the progression-free survival and overall survival time of the ibrutinib plus
      rituximab combination followed by venetoclax and hyper-fractionated cyclophosphamide,
      vincristine, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in newly diagnosed
      young MCL patients.

      EXPLORATORY OBJECTIVES:

      I. Developing a novel minimal residual disease (MRD) assay using circulating tumor
      deoxyribonucleic acid (DNA) (ctDNA) from patients' plasma samples collected in this trial.

      OUTLINE:

      PART I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and receive
      rituximab intravenously (IV) over 4-8 hours on days 1, 8, 15, and 22 of course 1 and on day 1
      of courses 3-12. Patients also receive venetoclax PO QD on days 1-28 of courses 5-12.
      Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or
      unacceptable toxicity.

      PART II: Patients are assigned to 1 of 3 groups depending on risk status.

      GROUP I:

      COMBINATION CHEMOTHERAPY: 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, and
      doxorubicin hydrochloride IV over 24 hours and vincristine IV over 15-30 minutes on day 5 of
      odd-numbered courses (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 3-4 of
      even-numbered courses (2, 4, 6, and 8). Treatment repeats every 28 days for up to 8 courses
      in the absence of disease progression or unacceptable toxicity.

      MAINTENANCE THERAPY: Patients receive ibrutinib and venetoclax PO QD on days 1-28, and
      rituximab IV over 4-8 hours on day 1 of every other month. Courses repeat every 28 days for
      up to 24 months in the absence of disease progression or unacceptable toxicity.

      GROUP II: Patients receive combination chemotherapy as in group I. Treatment repeats every 28
      days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
      Patience also receive maintenance therapy as in group I.

      GROUP III: Patients receive maintenance therapy as in group I.

      After completion of study treatment, patients are followed up at 30 days, every 4 months for
      2 years, every 6 months for 2 years, and then annually for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (ibrutinib, rituximab, venetoclax, chemotherapy)ExperimentalPatients receive ibrutinib, rituximab, and venetoclax as described in part I. COMBINATION CHEMOTHERAPY: 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, and doxorubicin hydrochloride IV over 24 hours and vincristine IV over 15-30 minutes on day 5 of odd-numbered courses (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 3-4 of even-numbered courses (2, 4, 6, and 8). Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive ibrutinib and venetoclax PO QD on days 1-28, and rituximab IV over 4-8 hours on day 1 of every other month. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin Hydrochloride
  • Ibrutinib
  • Methotrexate
  • Venetoclax
  • Vincristine
Group II (ibrutinib, rituximab, venetoclax, chemotherapy)ExperimentalPatients receive ibrutinib, rituximab, and venetoclax as in part I. Patients receive combination chemotherapy as in group I. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patience also receive maintenance therapy as in group I.
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin Hydrochloride
  • Ibrutinib
  • Methotrexate
  • Venetoclax
  • Vincristine
Group III (ibrutinib, rituximab, venetoclax)ExperimentalPatients receive ibrutinib, rituximab, venetoclax as in part I. Patients then receive maintenance therapy as in group I.
  • Ibrutinib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy

          -  MCL must be symptomatic and need immediate therapy. Symptoms and nature of MCL include
             any of the following: a) B-symptoms, b) Mantle Cell Lymphoma International Prognostic
             Index (MIPI) larger than 3, c) Ki 67 larger than or equal to 30%, d) bulky tumors
             larger than 10cm or in case of larger than or equal to 2 tumors, each larger than or
             equal to 5cm in diameter, e) disease threatening organ function, f) elevated lactate
             dehydrogenase (LDH), g) peripheral blood (PB) white blood cell (WBC) larger than
             50,000, h) pancytopenia due to bone marrow MCL, i) patient's choice due to anxiety; j)
             pain due to lymphoma; k) somatic mutations in the TP53, c-MYC or NOTCH genes; l) size
             of spleen larger than or equal to 20 cm

          -  Newly diagnosed MCL with no prior therapy and consent to provide a new baseline
             (pretreatment) tumor biopsy (bone marrow biopsy and/or surgical biopsy)

          -  Sign (or their legally-acceptable representatives must sign) an informed consent
             document indicating that they understand the purpose of and procedures required for
             the study, including biomarkers, and are willing to participate in the study

          -  Bi-dimensional measurable disease using both computed tomography (CT) scan and/or
             positron emission tomography (PET)-CT gastrointestinal, bone marrow or spleen only
             patients are allowable

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

          -  Absolute neutrophil count (ANC) larger than or equal to 1000/mm^3 independent of
             growth factor support

          -  Platelets larger than or equal to 100,000/mm^3 or larger than or equal to 50,000/mm^3
             if bone marrow involvement without necessitating transfusion

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
             to 3 x upper limit of normal (ULN)

          -  Total bilirubin less than or equal to 1.5 x ULN unless bilirubin rise is due to
             Gilbert's syndrome or of non-hepatic origin

          -  Creatinine clearance (CLcr) larger than 50 mL/min

          -  Cardiac ejection fraction larger than or equal to 50% by echocardiogram (ECHO) or
             multigated acquisition (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 with life
             expectancy of larger than 3 years. Principal investigator (PI) can use clinical
             judgement in the best interest of patients

          -  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 during and after the study consistent with local
             regulations regarding the use of birth control methods for subjects participating in
             clinical trials. 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. Men
             must agree to not donate sperm during and after the study. For females, these
             restrictions apply for 1 month after the last dose of study drug. For males, these
             restrictions apply for 3 months after the last dose of study drug

        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, laboratory
             abnormality, or psychiatric illness that, in the investigators opinion, places the
             patient at unacceptable risk or would prevent the subject from signing the informed
             consent form.

          -  Pregnant or breast-feeding females

          -  Known human immunodeficiency virus (HIV) infection (HIV testing is not required)

          -  Evidence of other clinically significant uncontrolled condition(s) including, but not
             limited to: a. Uncontrolled and/or active systemic infection (viral, bacterial or
             fungal) b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
             Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B
             surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core
             (HBc) antibody negative) or positive anti-HBc antibody from intravenous
             immunoglobulins (IVIG) may participate

          -  Treatment with any of the following within 7 days prior to the first dose of study
             drug:

               -  Steroid therapy for anti-neoplastic intent

               -  Moderate or strong cytochrome P450 3A (CYP3A) inhibitors

               -  Moderate or strong CYP3A inducers

          -  Administration or consumption of any of the following within 3 days prior to the first
             dose of study drug:

               -  Grapefruit or grapefruit products

               -  Seville oranges (including marmalade containing Seville oranges)

               -  Star fruit

          -  Patients with active hepatitis B infection (not including patients with prior
             hepatitis B vaccination; or positive serum hepatitis B antibody). Known hepatitis C
             infection is allowed as long as there is no active disease and is cleared by
             gastrointestinal (GI) consultation

          -  Central nervous system with mantle cell lymphoma

          -  Significant neuropathy (grades 3 to 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 or a wound that has not fully
             healed within 4 weeks of randomization. Clearance letter from primary physician
             required

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonist

          -  Requires chronic treatment with strong CYP3A inhibitors

          -  Patients with New York Health Association (NYHA) Class III and IV heart failure,
             myocardial infarction in the preceding 6 months, and significant conduction
             abnormalities, including but not limited to left bundle branch block, 2nd degree
             atrioventricular (AV) block type II, 3rd degree block, QT prolongation (corrected QT
             [QTc] larger than 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic
             bradycardia (heart rate less than 50 bpm), hypotension, light headedness and syncope,
             persistent and uncontrolled atrial fibrillation

          -  Recent placement of 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 therapy

          -  Child-Pugh class B or C are excluded

          -  Vaccinated with live, attenuated vaccines within 4 weeks of randomization
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy of ibrutinib plus rituximab combination followed by venetoclax as determined by complete response (CR)
Time Frame:After 12, 28 day cycles
Safety Issue:
Description:The complete response after 4 cycles of venetoclax combined with ibrutinib plus rituximab and toxicity within first cycle of venetoclax combination will be monitored simultaneously using the Bayesian stopping boundaries calculated based on beta-binomial distributions. The prior probabilities of response and toxicity are modeled by beta distributions. Complete response and its 95% confidence interval will be calculated. Logistic regression will be utilized to assess the effect of patient prognostic factors on the CR rate and the toxicity rate.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame:Up to 5 years
Safety Issue:
Description:The safety is measured by toxicity which is defined as grade 3-4 non-hematologic toxicities within first cycle treatment of venetoclax combined with ibrutinib plus rituximab. Toxicity data by type and severity will be summarized by frequency tables. Logistic regression will be utilized to assess the effect of patient prognostic factors on the CR rate and the toxicity rate.
Measure:Progression-free survival (PFS)
Time Frame:Up to 5 years
Safety Issue:
Description:The distribution of PFS will be estimated using the method of Kaplan and Meier. Comparison of PFS by important subgroups will be made using the log-rank test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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