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Everolimus and Bortezomib in Treating Patients With Relapsed or Refractory Mantle Cell or Other Indolent Non-Hodgkin Lymphoma
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), June 2009
First Received: May 2, 2008   Last Updated: June 9, 2009   History of Changes
Sponsors and Collaborators: Case Comprehensive Cancer Center
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00671112
  Purpose

RATIONALE: Everolimus and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with bortezomib in treating patients with relapsed or refractory mantle cell or other indolent non-Hodgkin lymphoma.


Condition Intervention Phase
Leukemia
Lymphoma
Drug: bortezomib
Drug: everolimus
Other: immunohistochemistry staining method
Other: laboratory biomarker analysis
Other: pharmacological study
Phase I

Study Type: Interventional
Study Design: Treatment
Official Title: A Phase 1 Trial of the Combination of Everolimus (RAD001) and Bortezomib (VELCADE) for Relapsed or Refractory Indolent and Mantle Cell Non-Hodgkin's Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of everolimus in combination with bortezomib [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Toxicities [ Designated as safety issue: Yes ]
  • Pharmacodynamics and pharmacokinetics [ Designated as safety issue: No ]
  • Response rate [ Designated as safety issue: No ]
  • 6-month progression-free survival [ Designated as safety issue: No ]
  • Correlation of tumor characteristics with response to treatment [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: May 2008
Estimated Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose of everolimus in combination with bortezomib in patients with relapsed or refractory mantle cell or other indolent non-Hodgkin lymphoma.

Secondary

  • Evaluate the toxicity of this treatment regimen.
  • Assess the pharmacodynamics and pharmacokinetics of this treatment regimen.
  • Assess the response rate and 6-month progression-free survival of these patients.
  • Obtain preliminary data to assess associations between tumor characteristics and response to treatment.

OUTLINE: This is a dose-escalation study.

Patients receive bortezomib IV on days 1, 4, 8, and 11. Patients also receive oral everolimus once daily or once every other day on days 4-21 in course 1 and on days 1-21 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for pharmacodynamic and pharmacokinetic studies. Baseline tumor expression of mTOR and NFkB -related proteins (i.e., pS6K, pAKT, and cREL) and FOXP3 is assessed by immunohistochemistry.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed indolent non-Hodgkin lymphoma, according to the World Health Organization (WHO)/Revised European-American Lymphoma Classification, including any of the following subtypes:

    • Mantle cell lymphoma
    • Hairy cell leukemia
    • Grade I, II, or III follicular lymphoma
    • Marginal zone B-cell lymphoma
    • Small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (SLL/CLL)
    • Lymphoplasmacytic lymphoma (with or without Waldenstrom macroglobulinemia)
  • History of transformed lymphoma allowed as long as screening evaluation and current biopsy show no evidence of aggressive lymphoma, as deemed by the Investigator
  • Refractory to or relapsed after receiving ≥ 1 prior treatment regimen for lymphoma (which may have included prior autologous stem cell transplantation) AND demonstrates evidence of progressive disease by clinical and/or radiographic characteristics
  • Measurable disease by radiographic criteria (≥ 2 cm by CT scan)

    • Patients with leukemic forms of SLL/CLL must have an absolute lymphocytosis > 5 times 10^9/L with a B-cell phenotype and > 30% bone marrow lymphocytes
  • No plasma cell myeloma
  • No uncontrolled brain or leptomeningeal metastases, including ongoing requirement for glucocorticoids for brain or leptomeningeal metastases

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless attributed to active hemolysis or ineffective erythropoiesis)
  • AST or ALT ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement by lymphoma)
  • ANC ≥ 1,500/μL
  • WBC ≥ 3,000/μL
  • Platelet count ≥ 100,000/μL
  • Hemoglobin ≥ 9.0 g/dL
  • Creatinine ≤ 1.5 times ULN
  • Fasting cholesterol ≤ 300 mg/dL (or ≤ 7.75 mmol/L)
  • Fasting triglycerides ≤ 2.5 times ULN
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able and willing to undergo a tissue biopsy (i.e., excisional biopsy, bone marrow aspirate and biopsy, or needle biopsy) for histologic verification of diagnosis and correlative study analysis
  • No other malignancies within the past 3 years, except for adequately treated carcinoma of the cervix, basal cell or squamous cell carcinoma of the skin, or curatively treated low-risk prostate cancer
  • No severe and/or uncontrolled medical condition that would preclude study participation, including the following:

    • Unstable angina pectoris
    • New York Heart Association class III or IV symptomatic congestive heart failure
    • Myocardial infarction within the past 6 months
    • Serious uncontrolled cardiac arrhythmia
    • Severely impaired lung function
    • Any active (acute or chronic) or uncontrolled infection and/or disorder
    • Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis)
    • Known history of HIV seropositivity
    • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, or malabsorption syndrome)
    • Non-malignant medical illness that is uncontrolled or whose control may be jeopardized by study therapy
  • None of the following diabetic conditions:

    • Diabetes mellitus currently requiring insulin therapy
    • Preexisting poorly controlled diabetes mellitus (e.g., hemoglobin A1c value > 9% within the past 4 weeks)
    • Uncontrolled diabetes, defined by fasting serum glucose > 1.5 times ULN (off medications)
  • No preexisting peripheral neuropathy ≥ grade 2
  • No active bleeding diathesis
  • No known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients, or to bortezomib, boron, or mannitol
  • No history of noncompliance to medical regimens
  • No personal, medical, or psychiatric reason that would preclude compliance with study requirements

PRIOR CONCURRENT THERAPY:

  • More than 4 weeks since prior chemotherapy or investigational drug
  • More than 3 months since prior monoclonal antibody
  • More than 1 week since prior and no concurrent strong CY3PA4 inhibitors
  • No prior allogeneic stem cell transplantation
  • No prior treatment with an mToR inhibitor or bortezomib
  • No prior small bowel resection that may significantly alter the absorption of everolimus
  • No concurrent immunization with attenuated live vaccine
  • No concurrent chronic treatment with systemic steroids or other immunosuppressive agents
  • No other concurrent investigational or anticancer agents
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00671112

Locations
United States, Ohio
Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44106-5065
Contact: Clinical Trials Office - Case Comprehensive Cancer Center     800-641-2422        
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Stephen D. Smith, MD The Cleveland Clinic
  More Information

Additional Information:
No publications provided

Study ID Numbers: CDR0000594429, CASE-2407
Study First Received: May 2, 2008
Last Updated: June 9, 2009
ClinicalTrials.gov Identifier: NCT00671112     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
Waldenstrom macroglobulinemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
refractory hairy cell leukemia
B-cell chronic lymphocytic leukemia
refractory chronic lymphocytic leukemia

Study placed in the following topic categories:
Leukemia, Lymphoid
Immunologic Factors
Lymphoma, Mantle-Cell
Lymphoma, Follicular
Lymphoma, B-Cell, Marginal Zone
Mantle Cell Lymphoma
Follicular Lymphoma
Lymphoma, B-Cell
Lymphoma, Small Cleaved-cell, Diffuse
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-cell, Chronic
Lymphoma
Everolimus
Immunoproliferative Disorders
Hairy Cell Leukemia
Bortezomib
Immunosuppressive Agents
Recurrence
Protease Inhibitors
Lymphatic Diseases
Leukemia, Hairy Cell
Waldenstrom Macroglobulinemia
Chronic Lymphocytic Leukemia
B-cell Lymphomas
Lymphoproliferative Disorders
Lymphoma, Non-Hodgkin

Additional relevant MeSH terms:
Everolimus
Neoplasms by Histologic Type
Immunoproliferative Disorders
Molecular Mechanisms of Pharmacological Action
Immune System Diseases
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Bortezomib
Enzyme Inhibitors
Immunosuppressive Agents
Pharmacologic Actions
Protease Inhibitors
Leukemia
Lymphatic Diseases
Neoplasms
Therapeutic Uses
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Lymphoma

ClinicalTrials.gov processed this record on September 03, 2009