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Lenalidomide and Alvocidib in Treating Patients With Relapsed or Refractory B-cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00735930
Recruitment Status : Completed
First Posted : August 15, 2008
Last Update Posted : April 2, 2015
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of lenalidomide when given together with alvocidib in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Lenalidomide may stop the growth of leukemia or lymphoma by blocking blood flow to the cancer. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide together with alvocidib may kill more cancer cells.

Condition or disease Intervention/treatment Phase
Anemia Chronic Lymphocytic Leukemia Prolymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Thrombocytopenia Drug: Alvocidib Hydrochloride Drug: Lenalidomide Other: Pharmacological Study Other: Laboratory Biomarker Analysis Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of flavopiridol (alvocidib) in combination with lenalidomide in patients with relapsed or refractory B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of flavopiridol in combination with lenalidomide in the treatment of patients with relapsed or refractory CLL/SLL.

SECONDARY OBJECTIVES:

I. To assess preliminary efficacy of flavopiridol combined with lenalidomide in patients with relapsed/refractory CLL/SLL to justify future, rigorous phase II studies of the combination in CLL.

II. To determine the pharmacokinetics of flavopiridol and lenalidomide alone and in combination in patients with CLL/SLL.

III. To correlate select pre-treatment prognostic markers, including interphase cytogenetics with minimal residual disease, progression-free survival, response, and toxicity following combination therapy with flavopiridol and lenalidomide.

IV. To determine patient cytokine expression profiles immediately pre-treatment, after flavopiridol dosing, and after combination flavopiridol and lenalidomide therapy to assess the impact of lenalidomide on flavopiridol induced cytokine release (interleukin [IL]-6).

V. To assess if pre-treatment ex vivo and in vivo (day 1 and day 3 of lenalidomide) immune (B-cell, natural killer [NK] cell, and T-cell) activation correlates with response and toxicity of lenalidomide therapy.

VI. To assess the in vivo effect of lenalidomide on flavopiridol on the modulation of selected intracellular pharmacodynamic targets including signal transducer and activator of transcription 3 (acute-phase response factor) (STAT3), myeloid cell leukemia sequence 1 (BCL2-related) (Mcl-1), and other downstream IL-6 targets.

OUTLINE: This is a dose-escalation study of lenalidomide.

Patients receive alvocidib intravenously (IV) over 4.5 hours on days 1, 8, and 15 in course 1 followed by a week of rest. Beginning in course 2 and all subsequent courses, patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Trial of Flavopiridol in Combination With Lenalidomide in Patients With Relapsed or Refractory B-Cell CLL/SLL
Study Start Date : August 2008
Actual Primary Completion Date : March 2013
Actual Study Completion Date : November 2014


Arm Intervention/treatment
Experimental: Treatment (alvocidib, lenalidomide)
Patients receive alvocidib IV over 4.5 hours on days 1, 8, and 15 in course 1 followed by a week of rest. Beginning in course 2 and all subsequent courses, patients receive lenalidomide PO QD on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
Drug: Alvocidib Hydrochloride
Given IV
Other Names:
  • FLAVO
  • HL-275
  • HMR 1275

Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • IMiD-1

Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. MTD of lenalidomide when combined with alvocidib, defined as the maximum dose level with fewer than 2 of 6 patients experiencing dose limiting toxicity (DLT) [ Time Frame: Up to day 70 ]
  2. Incidence of DLT in patients treated with alvocidib and lenalidomide graded according to NCI CTCAE version 4.0 [ Time Frame: Up to day 70 ]
    Toxicities classified as DLT during course 1 will not be considered DLT for the combination of lenalidomide and flavopiridol, but will result in patient removal from the study.


Secondary Outcome Measures :
  1. Pharmacokinetic parameters of alvocidib and lenalidomide alone and in combination in plasma samples [ Time Frame: Baseline, day 1 of course 1, and on days 2-3 of course 2 ]
    Samples will be analyzed in batches to assess plasma drug concentrations, the plasma drug concentration-time profile (AUC), volume of distribution (Vss), clearance (CL), and half-life. Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  2. Plasma IL-6 and selected cytokine levels [ Time Frame: Up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  3. B-cell activation as assessed by surface antigen (CD40, CD80, CD86, HLA-DR, and CD95) expression [ Time Frame: Up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  4. Intracellular pharmacodynamic targets including STAT3, Mcl-1, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [ Time Frame: Up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  5. Response assessed by National Cancer Institute-Sponsored Working Group guidelines [ Time Frame: Up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  6. Progression-free survival (PFS) [ Time Frame: Time from start of treatment to time of progression, assessed up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  7. Toxicity graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.

  8. Presence of minimal residual disease [ Time Frame: Up to 5 years ]
    Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed B-cell CLL/SLL according to World Health Organization (WHO) criteria, or B-cell prolymphocytic leukemia (B-PLL) arising from CLL with at least one of the following indications for treatment:

    • Progressive disease or marked splenomegaly and/or lymphadenopathy
    • Anemia (hemoglobin < 11 mg/dL) or thrombocytopenia (platelets < 100,000/mm^3)
    • Unexplained weight loss exceeding 10% of body weight over the preceding 6 months
    • National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4.0) grade 2 or 3 fatigue
    • Fevers > 100.5 or night sweats for greater than 2 weeks without evidence of infection
    • Progressive lymphocytosis, with an increase exceeding 50% over a 2 month period or a doubling time of less than 6 months
  • Must have at least one prior therapy that includes either fludarabine (or equivalent nucleoside analogue) or an alternative regimen if a contra-indication to fludarabine exists (i.e., autoimmune hemolytic anemia); prior therapy with flavopiridol is not permitted; prior lenalidomide is permitted provided that it has been > 6 months since the last lenalidomide dose
  • Eastern Cooperative Oncology Group (ECOG) performance status =< (Karnofsky >= 60%)
  • White blood cell count =< 150,000/mm^3
  • Absolute neutrophil count >= 1,000/mm^3
  • Platelets >= 30,000/mm^3
  • Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 X institutional ULN
  • Creatinine =< 1.5 mg/dL OR creatinine clearance >= 60 ml/min
  • Recovery to =< grade 1 from all toxicities associated with prior therapy
  • Not pregnant or breast-feeding; woman of child bearing potential should have a negative pregnancy test (serum beta-human chorionic gonadotropin [HCG]) within 7-14 days of starting cycle 1 of treatment; woman of child bearing potential should have a negative pregnancy test (serum beta-HCG) within 10-14 days of starting cycle 2, the start of lenalidomide treatment (i.e. days 14-18 of cycle 1), and an additional test within 24 hours of starting cycle 2 treatment
  • Patient must agree to use adequate contraception for 4 weeks prior to the start of lenalidomide and up to 28 days following the last dose of lenalidomide to avoid risk of pregnancy

    • Women of child-bearing potential will be required to use two methods of birth control; one "highly effective method" and one "additional effective method" as defined below:

      • Highly effective methods

        • Intrauterine device
        • Hormonal (oral contraceptive, implants)
        • Tubal ligation
        • Partner's vasectomy
        • Abstinence
      • Alternative effective methods

        • Latex condoms
        • Diaphragm
        • Cervical cap
    • Men must agree to use latex condoms
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy; all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
  • Patients must agree not to donate blood, semen, sperm/ova during the course of taking lenalidomide and for 28 days after stopping lenalidomide treatment
  • Patients must have the ability to understand and the willingness to sign a written informed consent document
  • Patients who are glucose-6-phosphate dehydrogenase (G6PD) deficient are not eligible for this study
  • Only human immunodeficiency virus (HIV)-positive patients meeting all of the following criteria may be enrolled on this trial:

    • Cluster of differentiation (CD) 4 count > 500/mm^3
    • Not receiving highly active anti-retroviral therapy (HAART) or anti-HIV viral therapy
    • HIV viral load < 10,000 HIV messenger ribonucleic acid (mRNA) copies/mm^3
    • No history of acquired immune deficiency syndrome (AIDS)-defining illness

Exclusion Criteria:

  • Patients may not be receiving any other investigational agents
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated on this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00735930


Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kristie Blum Ohio State University Comprehensive Cancer Center
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00735930    
Other Study ID Numbers: NCI-2009-00269
NCI-2009-00269 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
OSU-08056
2008C0033
CDR0000738866
OSU 08056 ( Other Identifier: Ohio State University Comprehensive Cancer Center )
8046 ( Other Identifier: CTEP )
P30CA016058 ( U.S. NIH Grant/Contract )
U01CA076576 ( U.S. NIH Grant/Contract )
First Posted: August 15, 2008    Key Record Dates
Last Update Posted: April 2, 2015
Last Verified: February 2015
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Prolymphocytic
Thrombocytopenia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes
Blood Platelet Disorders
Hematologic Diseases
Lenalidomide
Alvocidib
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action