Details

Details

Title A Phase I/II Study of Carfilzomib in Combination with R-CHOP (CR-CHOP) for Patients with Diffuse Large B -Cell Lymphoma.

IRB CASE3413

CC 14-256

Hospital Florida Weston, Hillcrest, Main Campus, North Coast Cancer

Stage Stage 3, Stage 4

Phase Phase 1, Phase 2

Disease Lymphoma

Drug Carfilzomib , CHOP, Rituximab

Description

Description

Primary Objective (Phase I)
  • To determine the safety of carfilzomib in combination with R-CHOP (CR-CHOP) in patients with newly diagnosed DLBCL and identify a recommended phase II dose (RP2D).
Secondary Objectives (Phase II)
  • 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
  • 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.
  • Because a proportion (~10%) of patients classified as non-GC by IHC algorithms may not have the ABC subtyped of DLBCL, an exploratory secondary objective will compare the PFS, OS and response rates of the ABC subgroup of patients with DLBCL as determined by the MODAPLEX® system; with those of the overall group of non-GC DLBCL.
Inclusion Criteria

Inclusion Criteria

  1. 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. For the Phase II study, patients must have non-GC DLBCL as determined by Hans Algorithm as outlined in Section 10.1.1.3.1.
  2. Patients must have radiographically measurable disease
  3. Patients must not have been previously treated with chemotherapy or radiation for diagnosis of lymphoma. Brief (<15 days) treatment with glucocorticoids is acceptable.
  4. Age >18 years. Because no dosing or adverse event data are currently available on the use of Carfilzomib in patients <18 years of age, children are excluded from this study.
  5. 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. [See Appendix A].
  6. Patient must have adequate hematologic, hepatic, and renal function as defined below:
    • 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
    • AST (SGOT) < 2.5 X institutional upper limit of normal
    • ALT (SGPT) < 2.5 X institutional upper limit of normal
    • Creatinine clearance >60 mL/min calculated by Cockcroft-Gault
  7. Adequate cardiac function left ventricular ejection fraction (LVEF) > 50% as assessed by echocardiogram or MUGA (Multi Gated Acquisition Scan).
  8. The effects of Carfilzomib on the developing human fetus are unknown. For this reason and because chemotherapeutic agents used in this study are known to be teratogenic, 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.
  9. Subjects must have the ability to understand and the willingness to sign a written informed consent document.
  10. International Prognostic Index must be documented:
    • ECOG performance status ≥2
    • Age ≥60
    • ≥2 extranodal sites
    • LDH > upper limit of normal
    • Ann Arbor Stage III or IV
Exclusion Criteria

Exclusion Criteria

  1. Patients who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  2. Patients who are receiving any other investigational agents.
  3. Known 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.
  4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Carfilzomib or other agents (R-CHOP) used in this study.
  5. 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.
  6. 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.
  7. Pregnant or breastfeeding women are excluded from this study because Carfilzomib is a proteasome inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with Carfilzomib, breastfeeding should be discontinued if the mother is treated with Carfilzomib. These potential risks may also apply to other agents used in this study.
  8. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Carfilzomib. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  9. 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.
  10. Patients who have had major surgical procedures or significant traumatic injury within 28 days prior to study treatment.