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

Phase 1

Completed

• Conditions: Recurrent Small Lymphocytic Lymphoma; B-cell Chronic Lymphocytic Leukemia; Hematopoietic/Lymphoid Cancer; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia
• Interventions: Drug: carfilzomib; Other: Cytokine Assessment; Other: Pharmacodynamic Studies; Other: Proteosome Inhibition Assessment; Other: Pharmacogenomic Studies

• Registration Number: NCT01212380
• Lead Sponsor: Ohio State University Comprehensive Cancer Center

Brief 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.

Study Timeline

• Study First Submitted: 2010-09-10
• Study First Submitted QC: 2010-09-29
• Study First Posted: 2010-09-30
• Study Start: 2010-10
• Primary Completion: 2014-07
• Study Completion: 2015-09
• Status Verified: 2016-05
• Last Update Submitted: 2016-05-06
• Last Update Posted: 2016-05-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• Previously treated patients with a diagnosis of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or prolymphocytic leukemia (PLL) by NCI Criteria with intermediate or high risk B-Cell chronic lymphocytic leukemia (CLL)(Modified Rai stage) satisfying at least one of the criteria for active disease requiring treatment;patients with a history of Richter's transformation are eligible if they now have evidence of chronic lymphocytic leukemia (CLL) only, with < 10% large cells in the bone marrow
• Massive or progressive splenomegaly and/or lymphadenopathy; or need for cytoreduction for stem cell transplant
• Anemia (hemoglobin < 11 g/dl) or thrombocytopenia (platelets < 100 x 10^9/L)
• Presence of weight loss > 10% over the preceding 6 month period
• NCI grade 2 or 3 fatigue
• Fevers > 100.5 °C or night sweats for greater than 2 weeks without evidence of infection
• Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months
• Creatinine Clearance (CrCl) > 15mL/min
• Alanine aminotransferase (ALT) < 3X upper limit of normal (ULN)
• Bilirubin =< 2 times the upper limit of normal, unless disease related
• Platelets >= 20 x 10^9/L and absence of active bleeding
• Patients must have an ECOG (Eastern Cooperative Oncology Group) performance status =< 2
• Patients must not have secondary cancers that result in a life expectancy of <2 years or that would confound assessment of toxicity in this study
• Patients of all racial/ethnic groups are eligible for the study if they meet eligibility criteria outlined-
• Patients must provide written informed consent

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Exclusion Criteria

• Absence of previously treated chronic lymphocytic leukemia (CLL)
• Female subject that is pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception prior to study entry, duration of study participation,and 30 days following study completion; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately;confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
• Patients with congestive heart failure (CHF)in whom pre-treatment hydration would be prohibitive;New York Heart Association (NYHA) Class III/IV CHF is excluded
• Patients who have had treatment for chronic lymphocytic leukemia (CLL) within 2 weeks, although palliative steroids are acceptable
• Patient unable to give written informed consent
• Failure to recover from toxicity of previous radiotherapy or chemotherapy to grade 1
• Patients with active infections requiring intravenous (IV) antibiotic/antiviral therapy are not eligible for entry onto the study until resolution of the infection; patients on prophylactic antibiotics or antivirals are acceptable
• Patients who have previously taken bortezomib

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1	Cytokine Assessment	Patients receive carfilzomib 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.Performance of pharmacology, pharmacodynamic and pharmacogenomic studies allow assessment of carfilzomib mechanism of action and also to understand how the variability of these different features correlate with clinical benefit/response and also toxicity.
Arm 1	Pharmacodynamic Studies	Patients receive carfilzomib 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.Performance of pharmacology, pharmacodynamic and pharmacogenomic studies allow assessment of carfilzomib mechanism of action and also to understand how the variability of these different features correlate with clinical benefit/response and also toxicity.
Arm 1	Proteosome Inhibition Assessment	Patients receive carfilzomib 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.Performance of pharmacology, pharmacodynamic and pharmacogenomic studies allow assessment of carfilzomib mechanism of action and also to understand how the variability of these different features correlate with clinical benefit/response and also toxicity.
Arm 1	Pharmacogenomic Studies	Patients receive carfilzomib 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.Performance of pharmacology, pharmacodynamic and pharmacogenomic studies allow assessment of carfilzomib mechanism of action and also to understand how the variability of these different features correlate with clinical benefit/response and also toxicity.
Arm 1	carfilzomib	Patients receive carfilzomib 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.Performance of pharmacology, pharmacodynamic and pharmacogenomic studies allow assessment of carfilzomib mechanism of action and also to understand how the variability of these different features correlate with clinical benefit/response and also toxicity.

Primary Outcome Measures

Name	Time	Method
Determine safety of carfilzomib by evaluating the toxicity profile.	Up to 24 months	The safe use of carfilzomib will be assessed by: * Determining the dose limiting toxicity and maximal tolerated dose of carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) and prolymphocytic leukemia (PLL); * To evaluating the toxicity profile of carfilzomib in relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) and prolymphocytic leukemia (PLL)

Secondary Outcome Measures

Name	Time	Method
To evaluate the efficacy of Carfilzomib therapy in relapsed or refractory chromic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL)	Up to 24 months	Efficacy of this therapy is evaluated by: * Determining the degree and duration of cellular proteosome inhibition and relationship to pharmacodynamic (PD), response and toxicity.; * Determining the pharmacokinetics(plasma and cellular)of carfilzomib and relationship to proteosome inhibition, PD, response and toxicity.; * Examining the effect of carfilzomib on PD parameters, changes in downstream targets including NFkB (p50/p65 binding;IkB level, P-IkB level, select target genes), p53 (p53 nuclear levels, p53 nuclear binding, and select target genes), ER stress proteins, and p73

Trial Locations

Locations (1)

Ohio State University Medical Center; 🇺🇸 Columbus, Ohio, United States