NCT01212380

Study of Carfilzomib in Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) or Prolymphocytic Leukemia (PLL)

A Phase I Study of Carfilzomib in Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)/Prolymphocytic Leukemia (PLL)

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 21 (actual)
• Sponsor: Ohio State University Comprehensive Cancer Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

RATIONALE: Carfilzomib 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 the best dose of carfilzomib in treating patients with relapsed or refractory chronic lymphocytic leukemia(CLL),small lymphocytic lymphoma(SLL), or prolymphocytic leukemia (PLL).

Detailed description

PRIMARY OBJECTIVES: I. To determine the dose limiting toxicity (DLT) and maximal tolerated dose (MTD) of carfilzomib in patients with relapsed or refractory Chronic Lymphocytic Leukemia(CLL) / Small Lymphocytic Lymphoma (SLL) and Prolymphocytic Leukemia (PLL). II. To evaluate the safety and toxicity profile of carfilzomib in relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL). SECONDARY OBJECTIVES: I. To evaluate efficacy of carfilzomib therapy in relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL) to justify future phase II studies. II. To determine the degree and duration of cellular proteosome inhibition induced by carfilzomib and relationship of this to pharmacodynamics, response and toxicity. III. To determine the pharmacokinetics (plasma and cellular) of carfilzomib and relationship of this to proteosome inhibition, pharmacodynamics, response, and toxicity.IV. To examine the effect of carfilzomib on pharmacodynamic parameters including cytokines, changes in downstream targets including NF-kappa B (p50/p65 binding; I-kappa B level, P-I-kappa B level,select target genes), p53 (p53 nuclear levels, p53 nuclear binding, and select target genes), ER stress proteins, and p73. OUTLINE: This is a dose-escalation study of carfilzomib.Patients receiving carfilzomib intra-venous(IV) over 30 minutes once daily, on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Conditions

• B-cell Chronic Lymphocytic Leukemia
• Hematopoietic/Lymphoid Cancer
• Prolymphocytic Leukemia
• Recurrent Small Lymphocytic Lymphoma
• Refractory Chronic Lymphocytic Leukemia

Interventions

Type	Name	Description
DRUG	carfilzomib	Given IV infusion lasting 30 minutes. Will be administered IV at a specified dose in mg/m2 QDx2 weekly for 3 weeks (days 1, 2, 8, 9, 15, and 16). The first and second dose will always be administered at 20 mg/m2.
OTHER	Cytokine Assessment	TNF-α,IFN-γ,IL-6,IL-8,IL-10,and IL-1β pre-dose, completion, 30 minutes, 2 hours, 6 hours, and approximately 24 hours from initiation of therapy on days 1 and 8 of treatment. These will be assessed utilizing standard ELISA or flow cytometry methodology. Other cytokines or soluble factors may be assessed that relate to drug toxicity or response. After 6 patients are examined in each group, the time points or number of cytokines examined may be changed to decrease time points examined. Cytokines will be examined by a multiplex flow cytometry assay or ELISA. Other cytokines, chemokines, or soluble factors may be assessed on residual material not used for these studies.
OTHER	Pharmacodynamic Studies	Based upon our preliminary data changes occuring in vivo during carfilzomib treatment will be determined and if their occurrence correlates with both clinical response and development of cytokine release. These studies will be performed from CD19 selected CLL cells at screening, pre-treatment, 4 hours, and 24 hours post-therapy on days 1 and 8 of treatment; end of therapy evaluation, and at time of relapse (in responding patients). These studies will include assessment of NF-κB (p50/p65 binding; I-κB level, P-I-κB level, select target genes), p53 (p53 nuclear levels, p53 nuclear binding, and select target genes), p73, and ER stress response. Standard Western Blot, EMSA, RT-PCR will be done to complete these studies.
OTHER	Proteosome Inhibition Assessment	Proteosome inhibition on CLL cells will be examined at screening, pre-treatment and post-treatment (immediately after completion of drug) days 1, pre-treatment day 2, day 3 (optional), day 5 (optional),pre and post-treatment days 8, pre and post-treatment days 9, day 10 (optional),day 12 (optional), and day 15 (optional).
OTHER	Pharmacogenomic Studies	Germ line DNA from a buccal swab and bone marrow fibroblasts will be obtained at baseline screening for possible examination of SNP polymorphisms that may correlate with response and toxicity to carfilzomib therapy. Tumor DNA will be derived from samples obtained at baseline for the p53 mutational studies. SNPs related to drug metabolism, response, or toxicity to therapy, cytokine release, and tumor biology may be examined. Other SNPs may be used in the future. Given the potential for contamination in the recipient, recipient DNA from a buccal swab and/or saliva will be obtained at baseline screening for examination of SNP polymorphisms that may correlate with response, toxicity, and pharmacokinetics.

Timeline

• Start date: 2010-10-01
• Primary completion: 2014-07-01
• Completion: 2015-09-01
• First posted: 2010-09-30
• Last updated: 2016-05-09

Locations

1 site across 1 country: United States