Trial record 1 of 1 for:    NCT01959698
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Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Roswell Park Cancer Institute
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:
NCT01959698
First received: October 8, 2013
Last updated: May 13, 2014
Last verified: May 2014
  Purpose

This phase I/II 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 relapsed or refractory diffuse large B-cell lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. 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 or by stopping them from dividing. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be an effective treatment for diffuse large B-cell lymphoma.


Condition Intervention Phase
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Stage I Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Drug: carfilzomib
Biological: rituximab
Drug: etoposide
Drug: carboplatin
Drug: ifosfamide
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II 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)

Resource links provided by NLM:


Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:
  • MTD defined as the dose of carfilzomib added to standard R-ICE chemotherapy which, if exceeded, would put the patient at an undesirable risk of medically unacceptable dose-limiting toxicities (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Best overall response rate (PR + CR) (Phase II) [ 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Complete response rate according to the International Working Group Response criteria as reported by the revised Cheson criteria [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Toxicity of the addition of carfilzomib to R-ICE at the MTD, assessed by the CTEP 4ersion 4.0 of the NCI CTCAE [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    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.

  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Progression-free survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • 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 cycle 1, day 1, then at 24 hours post cycle 1 infusion on cycle 1, day 2 (prior to day 2 infusion) ] [ Designated as safety issue: No ]
    The physiologic PK/PD models explored will be described by the estimation of mean structural model parameters (e.g. plasma volumes of distribution and clearances), the magnitude of inter-animal variability in these parameters and the magnitude of residual variability. For each model, the fit will be assessed by examination of several diagnostics. For comparisons of hierarchical models, the change in the minimum value of the objective function, a statistic that is proportional to minus twice the log likelihood of the data, will be examined.


Other Outcome Measures:
  • Functional activity of patients peripheral blood mononuclear "effector" cells [ Time Frame: Day of 1 of course 1 and day 2 of course 2 ] [ Designated as safety issue: No ]
  • Ex vivo analysis of sensitivity of primary tumor cells to various combinations of carfilzomib versus bortezomib +/- rituximab [ Time Frame: Day of 1 of course 1 and day 2 of course 2 ] [ Designated as safety issue: No ]
  • Degree of proteasome inhibition determined by enzymatic assay for chymotrypsin-like activity [ Time Frame: Days 1-3 of course 1 ] [ Designated as safety issue: No ]

Estimated Enrollment: 73
Study Start Date: April 2014
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (carfilzomib, rituximab, chemotherapy)
Patients 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.
Drug: carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Drug: ifosfamide
Given IV
Other Names:
  • Cyfos
  • Holoxan
  • IFF
  • IFX
  • IPP
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

    • A tissue block or unstained slides will be submitted to the Roswell Park Cancer Institute (RPCI) Pathology Department for central pathology review; in addition immunohistochemistry (IHC) for CD20, antigen identified by monoclonal antibody Ki-67 (Ki67), CD10, B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2), Bcl-6, and melanoma associated antigen (mutated) 1 (MUM-1) staining will be performed
    • Cell of origin will be determined according to the Han's algorithm
    • A fresh tumor biopsy for correlative studies is required as part of participation in this study
  • 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.)
  • Patients may have received other monoclonal immunotherapy, radiation therapy, or bortezomib
  • >= 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
  • Serum direct bilirubin =< 2 mg/dL (34 umol/L) in the absence of a history of Gilbert's disease (or pattern consistent with Gilbert's), 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01959698

Locations
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724    ASKRPCI@roswellpark.org   
Principal Investigator: Myron S. Czuczman         
Sponsors and Collaborators
Roswell Park Cancer Institute
Investigators
Principal Investigator: Myron Czuczman Roswell Park Cancer Institute
  More Information

No publications provided

Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT01959698     History of Changes
Other Study ID Numbers: I 240813, NCI-2013-01784, I 240813, P30CA016056, R01CA136907
Study First Received: October 8, 2013
Last Updated: May 13, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Non-Hodgkin
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Etoposide phosphate
Isophosphamide mustard
Carboplatin
Etoposide
Ifosfamide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on September 16, 2014