Clinical Trials /

Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

NCT01959698

Description:

This phase I/Ib trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also 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 carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma
  • Official Title: Phase I/Ib Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin Plus Etoposide (C-R-ICE) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: I 240813
  • SECONDARY ID: NCI-2013-01784
  • SECONDARY ID: I 240813
  • SECONDARY ID: P30CA016056
  • SECONDARY ID: R01CA136907
  • NCT ID: NCT01959698

Conditions

  • CD20 Positive
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Stage I Diffuse Large B-Cell Lymphoma
  • Stage II Diffuse Large B-Cell Lymphoma
  • Stage III Diffuse Large B-Cell Lymphoma
  • Stage IV Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (carfilzomib, rituximab, chemotherapy)
CarfilzomibKyprolis, PR-171Treatment (carfilzomib, rituximab, chemotherapy)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (carfilzomib, rituximab, chemotherapy)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Treatment (carfilzomib, rituximab, 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 PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Treatment (carfilzomib, rituximab, chemotherapy)

Purpose

This phase I/Ib trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also 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 carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

        -  I. To estimate the maximum tolerated dose (MTD) and examine the dose-limiting toxicities
           of carfilzomib when administered in combination with rituximab, ifosfamide, carboplatin,
           and etoposide (C-R-ICE) in patients with relapsed/refractory diffuse large B-cell
           lymphoma (DLBCL). (Phase I)

        -  II. To assess the toxicity of dose regimen using the Cancer Therapy Evaluation Program
           (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
           (CTCAE version 4.0). (Phase I)

        -  III. To evaluate the safety of carfilzomib (given at maximum tolerated dose [MTD] as
           determined in Phase I of this study) in combination with R-ICE salvage therapy in
           relapsed/refractory DLBCL patients. (Phase Ib)

        -  IV. To achieve an overall response rate (complete response [CR] and partial response
           [PR]) of 70% after 3 cycles of C-R-ICE in patients between the ages of 18 to 75 with
           relapsed/refractory cluster of differentiation (CD)20-positive DLBCL previously treated
           with rituximab-based immunochemotherapy (e.g., rituximab, cyclophosphamide, doxorubicin,
           vincristine [vincristine sulfate], and prednisone [R-CHOP], rituximab, etoposide,
           prednisone, vincristine, cyclophosphamide, and doxorubicin [REPOCH], rituximab,
           cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine
           [R-HyperCVAD], etc.) induction. (Phase Ib)

      SECONDARY OBJECTIVES:

        -  I. To determine the feasibility of successful mobilization of autologous stem cells
           (i.e., minimum of 2 x 10^6 CD34+ cells/kg should be collected) to be used for autologous
           stem cell transplant (ASCT)

        -  II. To determine toxicities associated with C-R-ICE salvage therapy

        -  III. To determine the time to progression (TTP), progression-free survival (PFS), and
           overall survival (OS) followed by ASCT; disease-free survival in CR patients.

        -  IV. To determine the pharmacokinetics/pharmacodynamics relationship between
           carfilzomib's degree of proteasome inhibition and response rate along with the time
           course of thrombocytopenia

        -  V. To study differences in clinical outcomes between germinal center B-cell-like (GCB)
           and non-GCB relapsed/refractory DLBCL following therapy with carfilzomib and R-ICE

        -  VI. Correlative translational research studies to include: phenotypic/genotypic analysis
           and functional activity (i.e., antibody-dependent cellular cytotoxicity [ADCC] and
           complement-mediated cytotoxicity [CMC]) of patient's peripheral blood mononuclear
           "effector" cells (PBMC), as well as ex vivo analysis of sensitivity of primary tumor
           cells to various combinations of carfilzomib versus bortezomib +/- rituximab; enzymatic
           assay for chymotrypsin-like activity to determine the degree of proteasome inhibition in
           primary DLBCL patient samples and patient PBMC specimens; explorative analysis to
           identify potential factors predictive of response to therapy will be performed.

      OUTLINE: This is a phase I, dose-escalation study of carfilzomib, followed by a phase Ib
      study.

      Patients receive carfilzomib intravenously (IV) over 10-30 minutes on days 1, 2, 8, and 9;
      rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV
      over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28
      days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 4 months for 1 year,
      every 6 months for 2 years, and then annually for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (carfilzomib, rituximab, chemotherapy)ExperimentalPatients receive carfilzomib IV over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Carfilzomib
  • Etoposide
  • Ifosfamide
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell
             lymphoma

          -  Ann Arbor stage I to stage IV DLBCL at the time of relapsed/refractory disease to be
             eligible

          -  Measurable or assessable disease is required; measurable tumor size (at least one node
             measuring 2.25 cm^2 in bidimensional measurement) per computed tomography (CT) scan,
             other radiological study, and/or physical exam

          -  Patients must have received at least 1 prior rituximab-based immunochemotherapy (e.g.,
             R-CHOP, R-EPOCH, etc.)

          -  >= 2 weeks since major surgery

          -  Patients must not have any significant toxicity associated with prior surgery,
             radiation therapy, chemotherapy, or immunotherapy, per principal investigator (PI)
             discretion

          -  Life expectancy >= 3 months

          -  Karnofsky score (KS) >= 50

          -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3.5 times the
             upper limit of normal within 14 days prior to starting therapy

          -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L within 14 days prior to starting
             therapy*

          -  Hemoglobin >= 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be
             receiving red blood cell [RBC] transfusions in accordance with institutional
             guidelines)*

          -  Platelet count >= 50 x 10^9/L (>= 20 x 10^9/L if lymphoma involvement in the
             pretreatment bone marrow is found) within 14 days prior to starting therapy*

          -  *Note: If patient has cytopenias due to bone marrow involvement, these requirements
             are not applicable

          -  Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL creatinine clearance must
             be > 60 mL/min within 7 days prior to treatment either measured or calculated using a
             standard Cockcroft and Gault formula

          -  Written informed consent in accordance with federal, local, and institutional
             guidelines

          -  Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and
             to practice contraception; should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately

          -  Male subjects must agree to practice contraception

          -  No known hypersensitivity to murine products

          -  Patients must have normal baseline cardiac function based upon echocardiogram or gated
             blood pool scan (multigated acquisition scan [MUGA]) with an ejection fraction >= 50%

          -  Patients who test positive for hepatitis C (HepC) antibodies (Ab) are eligible
             provided all of the following criteria are met: bilirubin =< 2 x upper limit of
             normal; ALT/AST =< 3 x upper limit of normal; and clinical evaluation to rule out
             cirrhosis

          -  Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL
             based on hepatitis B serological testing as follows:

               -  Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb)
                  negative, hepatitis B surface antibody (HBsAb) positive patients are eligible

               -  Patients who test positive for HBsAg are ineligible (regardless of other
                  hepatitis B serologies)

               -  Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status)
                  should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing done
                  and protocol eligibility determined as follows:

                    -  If HBV DNA is positive, the subject will be excluded from the study

                    -  If HBV DNA is negative, the subject may be included but must undergo at
                       least every 2 months HBV DNA polymerase chain reaction (PCR) testing from
                       the start of treatment throughout the duration the treatment course

        Exclusion Criteria:

          -  Patients with non-Hodgkin lymphoma (NHL) other than DLBCL; including "transformed"
             DLBCL

          -  Known to be seropositive for human immunodeficiency virus (HIV); an HIV test is not
             required for entry on this protocol, but is required if the patient is perceived to be
             at risk

          -  Positive serology for HBV defined as a positive test for HBsAg; in addition, if
             negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test
             will be performed and if positive the subject will be excluded

          -  Patients with symptomatic brain involvement

          -  Peripheral neuropathy of grade 2 or greater severity as defined by the National Cancer
             Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0;
             patients with grade 2 or higher (NCI-Common Toxicity Criteria [CTC]) neuropathy

          -  Myocardial infarct within 6 months before enrollment, New York Heart Association
             (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled
             ventricular arrhythmias, clinically significant pericardial disease, or
             electrocardiographic evidence of acute ischemia

          -  Uncontrolled intercurrent illness including, but not limited to, active infection,
             poorly controlled hypertension, diabetes mellitus or other serious medical or
             psychiatric conditions that could interfere with adherence to or completion of this
             study

          -  Pregnant or breastfeeding

          -  Patient has received other investigational drugs within 4 weeks before enrollment

          -  Chemotherapy within 3 weeks of the first scheduled study treatment

          -  Less than 2-years disease free from another primary malignancy (other than squamous or
             basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast,
             superficial bladder carcinoma, or previously treated localized prostate cancer with
             normal prostate-specific antigen [PSA] levels); patients are not considered to have a
             "currently active" malignancy if they have completed anti-cancer therapy, are
             considered by their physician to be at less than 30% risk of relapse and at least 2
             years have lapsed

          -  Major surgery, other than diagnostic surgery, within 2 weeks

          -  Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
             carfilzomib)

          -  Medical condition requiring chronic use of high dose systemic corticosteroids (i.e.,
             doses of prednisone higher than 10 mg/day or equivalent)

          -  Prior high-dose chemotherapy (HDC)-ASCT

          -  Active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma
             or known CNS parenchymal lymphoma; a lumbar puncture demonstrating DLBCL at the time
             of registration to this study is not exclusion for study enrollment
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response rate (PR + CR) (Phase Ib)
Time Frame:The time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented, assessed up to 12 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Complete response rate according to the International Working Group Response criteria as reported by the revised Cheson criteria
Time Frame:Up to 5 years
Safety Issue:
Description:Efficacy rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.
Measure:Overall survival
Time Frame:From the start of treatment until death for any reason, assessed up to 5 years
Safety Issue:
Description:The estimated distributions of overall survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.
Measure:Pharmacokinetics (PK)/pharmacodynamics (PD) of carfilzomib and standard R-ICE combination therapy in adult patients with relapsed/refractory diffuse large B-cell lymphoma
Time Frame:Pre-dose, just prior to the end of the infusion; and at 15 minutes, 30 minutes, 1, 2, 4, 6 hours post infusion on course 1, day 1, then at 24 hours post course 1 infusion on course 1, day 2 (prior to day 2 infusion)
Safety Issue:
Description:A population PK/PD structural model will be developed for carfilzomib based on degree of proteasome inhibition in relation to efficacy and toxicity endpoints in the proposed study using NONMEM. This model will describe the potential relationship between carfilzomib exposure in relation to proteasome inhibition to the time course of thrombocytopenia and neutropenia as indicators of pharmacodynamics response.
Measure:Progression-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:The estimated distributions of progression-free survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.
Measure:Toxicity of the addition of carfilzomib to R-ICE at the MTD, assessed by the CTEP version 4.0 of the NCI CTCAE
Time Frame:Up to 5 years
Safety Issue:
Description:Toxicity rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roswell Park Cancer Institute

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