Carfilzomib, Rituximab, and Combination Chemotherapy in Treating Patients with Diffuse Large B-Cell Lymphoma

Status: Active

Description

This phase I / II trial studies the side effects and best dose of carfilzomib when given together with rituximab and combination chemotherapy and to see how well they work in treating patients with diffuse large B-cell lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, 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. It is not known if carfilzomib in combination with rituximab and combination chemotherapy is better or worse than combination chemotherapy alone in treating patients with diffuse large B-cell lymphoma.

Eligibility Criteria

Inclusion Criteria

  • Patients must have histologically confirmed diffuse large B-cell lymphoma (DLBCL); patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are eligible only if they have not previously been treated for indolent lymphoma
  • Diagnosis of high grade B-cell lymphoma of non-germinal center subtype by Hans algorithm
  • Patients must have radiographically measurable disease
  • Patients may have received brief (< 15 days) treatment with glucocorticoids and/or 1 cycle of chemotherapy such as R-CHOP [or some component(s) thereof] for the diagnosis of B-cell lymphoma provided they had all necessary staging tests performed prior to R-CHOP including computed tomography (CT) and/or positron emission tomography (PET)/CT scans, echocardiogram and bone marrow biopsy; treatment must occur within 60 days prior to enrollment
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2; performance status of 3 will be accepted if impairment is caused by DLBCL complications and improvement is expected once therapy is initiated
  • Hemoglobin >= 7.0 g/dl
  • Absolute neutrophil count >= 1,500/mcL
  • Platelet count >= 100,000/mcL
  • Total bilirubin within normal institutional limits unless due to Gilbert’s disease
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine clearance >= 45 mL/min calculated by Cockcroft-Gault or 24 hour collection
  • Adequate cardiac function left ventricular ejection fraction (LVEF) > 50% as assessed by echocardiogram or MUGA (multi gated acquisition scan)
  • Women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks prior to initiation of treatment, for the duration of study participation and for 3 months after completing treatment; should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately; men must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document
  • International Prognostic Index must be documented: * ECOG performance status >= 2 (1 point) * Age >= 60 (1 point) * >= 2 extranodal sites (1 point) * Lactate dehydrogenase (LDH) > upper limit of normal (1 point) * Ann Arbor stage III or IV (1 point) * Is there evidence of transformation from indolent lymphoma? (Yes/No)

Exclusion Criteria

  • Patients who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents
  • Known central nervous system (CNS) involvement by lymphoma; patients at high risk for secondary CNS involvement but without neurologic symptoms suspected to be due to lymphoma are allowed to be enrolled and receive intrathecal chemotherapy including but not limited to methotrexate, cytarabine and glucocorticoids; patients who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on study at the discretion of the principal investigator
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or other agents (R-CHOP) used in this study
  • Active congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within four months prior to enrollment
  • Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with carfilzomib
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or low-risk prostate cancer after curative therapy
  • Patients who have had major surgical procedures or significant traumatic injury within 28 days prior to study treatment
  • Patients who are reported to be of direct Asian-Pacific (China, Japan, Taiwan, Singapore, Republic of Korea, and Thailand) ancestry

Locations & Contacts

Florida

Weston
Cleveland Clinic-Weston
Status: Active
Contact: Anupama Doraiswamy
Phone: 954-659-5840

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: Temporarily closed to accrual
Contact: Christopher Robert Flowers
Phone: 404-778-1827
Email: crflowe@emory.edu

Ohio

Cleveland
Case Comprehensive Cancer Center
Status: Active
Contact: Brian Thomas Hill
Phone: 216-445-9451
Email: hillb2@ccf.org
University Hospitals Cleveland Medical Center
Status: Active
Contact: Paolo Fabrizio Caimi
Phone: 216-844-8220
Email: Paolo.Caimi@UHhospitals.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety of carfilzomib in combination with rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) (CR-CHOP) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and identify a recommended phase II dose (RP2D). (Phase I)

SECONDARY OBJECTIVES:

I. To determine if CR-CHOP improves the rates of 1-year progression free survival (PFS) and overall survival (OS) in non-germinal center (non-GC) DLBCL patients relative to historical controls treated with R-CHOP. (Phase II)

II. To determine response rates (complete and partial remission) in non-GC DLBCL patients treated with CR-CHOP and compare to historical controls treated with R-CHOP. (Phase II)

III. Compare the PFS, OS and response rates of the ABC subgroup of patients with DLBCL as determined by the gene expression profiling with those of the overall group of non-GC DLBCL. (Phase II)

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

Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1 and 2, rituximab IV over at least 90 minutes on day 2, cyclophosphamide IV over 30-60 minutes on day 3, doxorubicin hydrochloride IV over 3-5 minutes on day 3, vincristine sulfate IV over 1 minute on day 3, and prednisone orally (PO) on days 3-7. Patients also receive pegfilgrastim subcutaneously (SC) on day 4 or filgrastim IV or SC on days 1-10 and acyclovir PO twice daily (BID) starting day 1 of course 2. Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and at 6, 12, and 24 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Brian Hill

Trial IDs

Primary ID CASE3413
Secondary IDs NCI-2014-00249
Clinicaltrials.gov ID NCT02073097