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

This study is currently recruiting participants.
Verified August 2017 by Northwestern University
Sponsor:
ClinicalTrials.gov Identifier:
NCT02481310
First Posted: June 25, 2015
Last Update Posted: August 15, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Cancer Institute (NCI)
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Northwestern University
  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.

Condition Intervention Phase
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 Drug: Cyclophosphamide Drug: Cytarabine Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Ixazomib Citrate Other: Laboratory Biomarker Analysis Drug: Methotrexate Drug: Prednisone Biological: Rituximab Drug: Therapeutic Hydrocortisone Drug: Vincristine Sulfate Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • 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 ]
    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

  • For phase II of the study, 12-month PFS (Progression Free Survival) of ixazomib given with DA-EPOCH-R will be measured [ Time Frame: Time elapsed between treatment initiation and tumor progression or death from any cause, assessed at 12 months ]
    Excluding patients who are lost to follow-up, the 12-month PFS will be defined as the percentage of patients alive and progression free 12 months from start of therapy.


Secondary Outcome Measures:
  • Frequency of toxicity [ Time Frame: Up to 1 year ]
    Adverse events will be defined as those included in CTCAE v 4.0. The occurrence of each will be recorded.

  • Severity of toxicity [ Time Frame: Up to 1 year ]
    Adverse events will be defined as those included in CTCAE v 4.0. The severity of each will be recorded.

  • Response rate and OS (Overall Survival) [ Time Frame: At 3 weeks and at 6 weeks ]
    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.

  • Assess the predictive value of FDG-PET/CT scans on PFS [ Time Frame: Up to 1 year after treatment stopped ]
    Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of treatment imaging.


Other Outcome Measures:
  • Determine the impact of cell of origin (COO) upon response rate, PFS, and OS [ Time Frame: Up to 1 year ]
    Impact of COO defined as germinal center B-cell (GCB) and non-GCB via the Hans algorithm upon response rate, PFS, and OS (applicable only to patients with DLBCL).

  • Consolidation SCT (Stem cell transplant) [ Time Frame: Up to 1 year ]
    Feasibility and outcomes of consolidation SCT will be assessed. Patients will be grouped by whether consolidative SCT was performed in first remission, with PFS compared across groups (SCT vs. non-SCT).


Estimated Enrollment: 55
Study Start Date: September 2015
Estimated Study Completion Date: July 2020
Estimated Primary Completion Date: July 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (combination chemotherapy, rituximab, ixazomib)

INDUCTION:

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.

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: Cytarabine
Given IT or intraventricularly
Other Names:
  • .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-28453
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
Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213
Drug: Ixazomib Citrate
Given PO
Other Names:
  • MLN-9708
  • MLN9708
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Methotrexate
Given IT or intraventricularly
Other Names:
  • 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
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:
  • BI 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
  • RTXM83
Drug: Therapeutic Hydrocortisone
Given IT or intraventricularly
Other Names:
  • Aeroseb-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
  • Rectoid
Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

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.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02481310


Contacts
Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Adam M. Petrich, MD    312-695-4537    apetrich@nmff.org   
Principal Investigator: Adam M. Petrich, MD         
United States, Massachusetts
Tufts University Recruiting
Medford, Massachusetts, United States, 02155
Contact: Andrew M. Evens, MD    617-636-8077    AEvens@tuftsmedicalcenter.org   
Principal Investigator: Andrew M. Evens, MD         
Sponsors and Collaborators
Northwestern University
National Cancer Institute (NCI)
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Adam Petrich, MD Northwestern University
  More Information

Responsible Party: Northwestern University
ClinicalTrials.gov Identifier: NCT02481310     History of Changes
Other Study ID Numbers: NU 14H09
NCI-2015-00400 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
X16042
STU00200596
NU 14H09 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
First Submitted: May 26, 2015
First Posted: June 25, 2015
Last Update Posted: August 15, 2017
Last Verified: August 2017

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Burkitt Lymphoma
Lymphoma, Large B-Cell, Diffuse
Plasmablastic Lymphoma
Lymphoma, Large-Cell, Immunoblastic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Cyclophosphamide
Methotrexate
Cytarabine
Rituximab
Liposomal doxorubicin
Etoposide phosphate
Ixazomib
Doxorubicin
Prednisone
Etoposide
Vincristine
Podophyllotoxin