Clinical Trials /

Combination Chemotherapy, Rituximab, and Ixazomib Citrate in Treating Patients With Non-Hodgkin Lymphoma

NCT02481310

Description:

The purpose of this study is to evaluate the effects, good and bad of a new drug called ixazomib (also called MLN9708), when it is given along with a common treatment combination, called Dose-Adjusted EPOCH-R (DA-EPOCH-R, for short). This is a type of study called a phase I/II trial. In the phase I part, the dose of the study drug (ixazomib) will be adjusted (either up or down) to find the maximum (highest) dose that does not cause excessive (too many) harmful side effects. In the phase II part, this dose of ixazomib will be given at the maximum safe dose found in phase I. In both phase I and II, DA-EPOCH-R will be adjusted between cycles depending on how blood cell levels are affected between cycles. Ixazomib is considered investigational because it is not approved by the U.S. Food and Drug Administration (FDA). DA-EPOCH-R is a combination chemotherapy treatment developed over the last 14-15 years, and each of the drugs in this regimen is FDA-approved and considered part of the standard of care.

Related Conditions:
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • B-Cell Non-Hodgkin Lymphoma
  • Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy, Rituximab, and Ixazomib Citrate in Treating Patients With Non-Hodgkin Lymphoma
  • Official Title: A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib as Frontline Therapy for Patients With MYC-aberrant Lymphoid Malignancies: The DACIPHOR Regimen

Clinical Trial IDs

  • ORG STUDY ID: NU 14H09
  • SECONDARY ID: NCI-2015-00400
  • SECONDARY ID: X16042
  • SECONDARY ID: STU00200596
  • SECONDARY ID: NU 14H09
  • SECONDARY ID: P30CA060553
  • NCT ID: NCT02481310

Conditions

  • Adult Burkitt Lymphoma
  • B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • MYC Gene Mutation
  • Plasmablastic 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- 138719Treatment (combination chemotherapy, rituximab, ixazomib)
Cytarabine.beta.-Cytosine arabinoside, 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-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (combination chemotherapy, rituximab, ixazomib)
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, RubexTreatment (combination chemotherapy, rituximab, ixazomib)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (combination chemotherapy, rituximab, ixazomib)
Ixazomib CitrateMLN-9708, MLN9708Treatment (combination chemotherapy, rituximab, ixazomib)
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-19039Treatment (combination chemotherapy, rituximab, ixazomib)
Prednisone.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-PrednisoneTreatment (combination chemotherapy, rituximab, ixazomib)
RituximabBI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar BI 695500, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, RTXM83Treatment (combination chemotherapy, rituximab, ixazomib)
Therapeutic HydrocortisoneAeroseb-HC, Barseb HC, Barseb-HC, Cetacort, Cort-Dome, Cortef, Cortenema, Cortifan, Cortisol, Cortispray, Cortril, Dermacort, Domolene, Eldecort, Hautosone, Heb-Cort, HYDROCORTISONE, Hydrocortone, Hytone, Komed-HC, Nutracort, Proctocort, RectoidTreatment (combination chemotherapy, rituximab, ixazomib)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (combination chemotherapy, rituximab, ixazomib)

Purpose

The purpose of this study is to evaluate the effects, good and bad of a new drug called ixazomib (also called MLN9708), when it is given along with a common treatment combination, called Dose-Adjusted EPOCH-R (DA-EPOCH-R, for short). This is a type of study called a phase I/II trial. In the phase I part, the dose of the study drug (ixazomib) will be adjusted (either up or down) to find the maximum (highest) dose that does not cause excessive (too many) harmful side effects. In the phase II part, this dose of ixazomib will be given at the maximum safe dose found in phase I. In both phase I and II, DA-EPOCH-R will be adjusted between cycles depending on how blood cell levels are affected between cycles. Ixazomib is considered investigational because it is not approved by the U.S. Food and Drug Administration (FDA). DA-EPOCH-R is a combination chemotherapy treatment developed over the last 14-15 years, and each of the drugs in this regimen is FDA-approved and considered part of the standard of care.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety of ixazomib (ixazomib citrate) given with dose-adjusted etoposide,
      prednisone, vincristine (vincristine sulfate), cyclophosphamide, doxorubicin (doxorubicin
      hydrochloride), and rituximab (DA-EPOCH-R) in patients with aggressive, v-myc avian
      myelocytomatosis viral oncogene homolog (MYC)-aberrant lymphoid malignancies, and to
      determine the recommended phase II dose (RP2D) of the combination. (Phase I) II. To evaluate
      the efficacy, as measured by 12-month progression free survival (PFS), of ixazomib given with
      DA-EPOCH-R in patients with aggressive, MYC-aberrant lymphoid malignancies. (Phase II)

      SECONDARY OBJECTIVES:

      I. Further evaluate the frequency and severity of toxicity. II. Further evaluate the clinical
      efficacy, as measured by response rate and overall survival (OS).

      III. Assess the predictive value of fludeoxyglucose F-18 (FDG)-positron emission tomography
      (PET)/computed tomography (CT) scans on PFS.

      TERTIARY OBJECTIVES:

      I. Determine the impact of cell of origin (COO) upon response rate, PFS, and OS.

      II. Assess the feasibility and outcomes of consolidation stem cell transplant (SCT).

      OUTLINE: This is a phase I, dose-escalation study of ixazomib citrate followed by a phase II
      study.

      INDUCTION:

      Patients receive ixazomib citrate orally (PO) on day 1 and day 8 or 15; etoposide
      intravenously (IV), vincristine sulfate IV, and doxorubicin hydrochloride IV continuously
      over 96 hours on days 1-4; prednisone PO twice daily (BID) on days 1-5; rituximab IV should
      be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum
      rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5.

      CENTRAL NERVOUS SYSTEM (CNS) PROPHYLAXIS:

      Patients with a negative lumbar puncture (LP) receive methotrexate intrathecally (IT) once
      per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR
      cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT
      or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly.

      MAINTENANCE:

      Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8,
      and 15. Treatment repeats every 28 days for up to one year (or as long as deriving benefit)
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (combination chemotherapy, rituximab, ixazomib)ExperimentalINDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Cytarabine
  • Doxorubicin Hydrochloride
  • Etoposide
  • Ixazomib Citrate
  • Methotrexate
  • Prednisone
  • Rituximab
  • Therapeutic Hydrocortisone
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a histological diagnosis of any of the following (all stages
             allowed):

               -  Diffuse large b-cell lymphoma (DLBCL) (including transformation from a previously
                  indolent non-Hodgkin lymphoma [NHL], so long as no prior systemic treatment was
                  given for the indolent NHL)

               -  B-cell lymphoma, unclassifiable, with features intermediate between diffuse large
                  B-cell lymphoma

               -  Burkitt lymphoma

               -  MYC+ plasmablastic lymphoma by histology

          -  Patients must have measurable disease (defined as >= 1.5 cm in diameter)

          -  Patients must have MYC-rearrangement, as determined by fluorescent in-situ
             hybridization (FISH) (does not require central review)

          -  The following results must be available or pending at time of registration, though
             results will not affect enrollment/treatment:

               -  B-cell chronic lymphocytic leukemia (CLL)/lymphoma (BCL)-2 rearrangement by FISH

               -  BCL-6 rearrangement by FISH NOTE: although not required, it is encouraged that
                  MYC and BCL-2 be measured by immunohistochemistry (IHC) and clearly documented

          -  Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
             of 0-3

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3

          -  Platelets >= 75,000/mm^3

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN); NOTE: exceptions can be granted
             from principal investigator (PI) for instances of Gilbert's disease, and/or primarily
             indirect bilirubinemia, if due to recent transfusion and/or hemolysis

          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SPGT]) =<
             3 X institutional ULN

          -  Calculated creatinine clearance >= 30 mL/min

          -  NOTE: platelet transfusions to help patients meet eligibility criteria are not allowed
             within 3 days before registration; these requirements do not apply to those with
             marrow involvement of lymphoma (any extent)

          -  Female patients must meet one of the following criteria:

               -  Postmenopausal for at least 1 year prior to registration

               -  Surgically sterile

               -  Of childbearing potential and agree to practice 2 effective methods of
                  contraception, at the same time, from the time of signing the informed consent
                  form through 90 days after the last dose of study drug

               -  Of childbearing potential and agree to practice true abstinence when this is in
                  line with the preferred and usual lifestyle of the subject NOTE: periodic
                  abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and
                  withdrawal are not acceptable methods of contraception

          -  Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
             to one of the following:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 90 days after the last dose of study drug

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject NOTE: periodic abstinence (eg, calendar,
                  ovulation, symptothermal, post-ovulation methods) and withdrawal are not
                  acceptable methods of contraception

          -  Females of child-bearing potential (FOCBP) must have a negative pregnancy test within
             # days prior to registration on study

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent prior to registration on study

        Exclusion Criteria:

          -  Patients who have had more than one cycle of prior chemoimmunotherapy for diagnosis of
             NHL are not eligible; NOTE: such patients must have fully recovered (ie, =< grade 1
             toxicity) from the reversible effects of prior chemotherapy before starting treatment
             on the current protocol

          -  Patients who have had major surgery within 4 weeks prior to registration are not
             eligible

          -  Patients who have had radiotherapy within 14 days before registration are not
             eligible; NOTE: If the involved field is small, 7 days will be considered a sufficient
             interval between treatment and administration of the ixazomib

          -  Patients who have an infection requiring systemic antibiotic therapy or other serious
             infection within 14 days before study enrollment are not eligible

          -  Patients who have evidence of current uncontrolled cardiovascular conditions,
             including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic
             congestive heart failure, unstable angina, or myocardial infarction within the past 6
             months are not eligible

          -  Patients who have undergone systemic treatment, within 14 days prior to registration,
             with strong inhibitors of cytochrome P450 superfamily (CYP)1A2 (fluvoxamine, enoxacin,
             ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin,
             itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A
             inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital),
             or use of Ginkgo biloba or St. John's wort are not eligible

          -  Patients who have a clinically active hepatitis B or C virus infection are not
             eligible; NOTE: those with evidence of exposure to hepatitis B virus (HBV) may enroll
             so long as HBV viral load is negative AND subject is willing/able to take appropriate
             antiviral prophylaxis to prevent reactivation

          -  Patients with any serious medical or psychiatric illness that could, in the
             investigator's opinion, potentially interfere with the completion of treatment
             according to this protocol are not eligible

          -  Patients who have a known allergy to any of the study medications, their analogues, or
             excipients in the various formulations of any agent are not eligible

          -  Patients who have a known gastrointestinal (GI) disease or GI procedure that could
             interfere with the oral absorption or tolerance of ixazomib including difficulty
             swallowing are not eligible

          -  Patients who have been diagnosed or treated for another malignancy within 2 years
             before study enrollment or previously diagnosed with another malignancy and have any
             evidence of residual disease are not eligible; NOTE: Patients with nonmelanoma skin
             cancer or carcinoma in situ of any type are not excluded if they have undergone
             complete resection

          -  Patients who have >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical
             examination during the screening period are not eligible

          -  Patients who are participating in other clinical trials, including those with other
             investigational agents not included in this trial, within 30 days of registration and
             throughout the duration of this trial are not eligible

          -  Female patients who are nursing or have a positive pregnancy test during screening are
             not eligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:For phase I of the study, the dose-limiting toxicity of ixazomib given with DA-EPOCH-R will be evaluated
Time Frame:The first 21 days
Safety Issue:
Description:The dose-limiting toxicity (DLT), defined as the occurrence of ≥ Grade 3 toxicity experienced during the first cycle (3 weeks or 21 days) of study treatment, will be determined, except for cytopenias. The Maximum Tolerated Dose (MTD) will constitute the RP2D

Secondary Outcome Measures

Measure:Frequency of toxicity
Time Frame:Up to 1 year
Safety Issue:
Description:Adverse events will be defined as those included in CTCAE v 4.0. The occurrence of each will be recorded.
Measure:Severity of toxicity
Time Frame:Up to 1 year
Safety Issue:
Description:Adverse events will be defined as those included in CTCAE v 4.0. The severity of each will be recorded.
Measure:Response rate and OS (Overall Survival)
Time Frame:At 3 weeks and at 6 weeks
Safety Issue:
Description:Anti-tumor activity will be defined as the detection of SD (Stable Disease), Partial Response (PR), or CR (Complete Response) by CT or PET/CT scan, and/or resolution of marrow-only involvement. CR and PR will each be assessed according to the Revised Response Criteria for Malignant Lymphoma. Assessments will be performed after cycles 2 and 6, then at the discretion of the treating investigator. OS will be defined as freedom from death by any cause.
Measure:Assess the predictive value of FDG-PET/CT scans on PFS
Time Frame:Up to 1 year after treatment stopped
Safety Issue:
Description:Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of treatment imaging.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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