Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

• ClinicalTrials.gov Identifier: NCT00377104
• Recruitment Status: Terminated
• First Posted: September 15, 2006
• Last Update Posted: July 2, 2013
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: September 13, 2006
• First Posted Date: September 15, 2006
• Last Update Posted Date: July 2, 2013
• Study Start Date: September 2006
• Actual Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 21, 2012)

• Toxicity profile of alvocidib administered as a 30 minute loading dose followed by a 4-hour infusion once weekly for 3 consecutive weeks every 5 weeks as consolidation therapy following cytoreduction chemotherapy [ Time Frame: Day 1, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment ]
  Assessed utilizing the NCI Common Terminology Criteria for Adverse Events version 3.0.
• Dose-limiting toxicity of alvocidib as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma [ Time Frame: Course 1 ]
  The National Cancer Institute Common Toxicity Criteria version 3.0 will be used to characterize toxicity. If no patients experience dose-limiting toxicity, dose escalation will occur. If 1 patient has a dose limiting toxicity, 3 additional patients will be enrolled at that dose. If fewer than 2 of 6 patients experiences dose limiting toxicity, then the next highest dose level will be used for the subsequent cohort of 3 patients. If at any dose level two or more of the six patients experience a dose limiting toxicity, 3 additional patients will be treated at the previous dose level.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: August 21, 2012)

• Pharmacokinetics and cellular pharmacodynamics of alvocidib administered in this schedule [ Time Frame: Baseline and day 1 ]
  Cytokine studies will be examined by standard ELISA assays to determine if increase IL-6 correlates with hypotension, hypoxemia, and tachycardia observed following treatment and to identify the source of production of this cytokine. We will examine interphase cytogenetics, p53 mutational status, p53/ATM functional assay, VH mutational status, and ZAP-70 over-expression.
• Complete response (CR) and overall response rate (CR and partial response) of alvocidib in patients with previously-treated CLL [ Time Frame: Baseline, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment ]
  Criteria for response will utilize the Revised National Cancer Institute-sponsored Working Group Guidelines.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
• Official Title: A Phase I Dose-Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With B-Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Following Cytoreduction With Chemotherapy
• Brief Summary: This phase I trial is studying the side effects and best dose of flavopiridol in treating patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as alvocidib, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the toxicity profile, dose-limiting toxicity, and maximum tolerated dose of flavopiridol (alvocidib) as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics and cellular pharmacodynamics of flavopiridol in these patients.

II. Determine the complete response (CR) and overall response rate (CR and partial response) of patients treated with flavopiridol.

OUTLINE: This is a dose-escalation study. Patients receive alvocidib intravenously (IV) over 30 minutes (loading dose), followed by alvocidib IV over 4 hours on days 1, 8, and 15.

Treatment repeats every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD (i.e., recommended phase II dose). Patients undergo blood collection at baseline and periodically during study for pharmacokinetic and cytokine studies (levels of tumor necrosis factor-alpha, interleukin [IL]-6, -11, and -16) by enzyme-linked immunosorbent assay (ELISA). Interphase cytogenetics, p53 mutational status, p53/ATM function, V_H mutational status, zeta-chain-associated protein kinase 70 (ZAP-70) overexpression, and single nucleotide polymorphisms are also examined.

After completion of study treatment, patients are followed at 2 months and then every 3 months for 5 years.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• B-cell Chronic Lymphocytic Leukemia
• Contiguous Stage II Small Lymphocytic Lymphoma
• Noncontiguous Stage II Small Lymphocytic Lymphoma
• Stage I Chronic Lymphocytic Leukemia
• Stage I Small Lymphocytic Lymphoma
• Stage II Chronic Lymphocytic Leukemia
• Stage III Chronic Lymphocytic Leukemia
• Stage III Small Lymphocytic Lymphoma
• Stage IV Chronic Lymphocytic Leukemia
• Stage IV Small Lymphocytic Lymphoma

Intervention

• Drug: alvocidib
  Given IV
  Other Names:

  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies
• Other: laboratory biomarker analysis
  Correlative studies

Study Arms

Experimental: Treatment (chemotherapy)

Patients receive alvocidib IV over 30 minutes (loading dose), followed by alvocidib IV over 4 hours on days 1, 8, and 15. Treatment repeats every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Interventions:

• Drug: alvocidib
• Other: pharmacological study
• Other: laboratory biomarker analysis

• Publications *: Awan FT, Jones JA, Maddocks K, Poi M, Grever MR, Johnson A, Byrd JC, Andritsos LA. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy. Ann Hematol. 2016 Jun;95(7):1137-43. doi: 10.1007/s00277-016-2683-1. Epub 2016 Apr 27.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 8, 2006): 24
• Original Enrollment: Not Provided
• Study Completion Date: Not Provided
• Actual Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of 1 of the following:

  • B-cell chronic lymphocytic leukemia (CLL)
  • Small lymphocytic lymphoma (SLL)

• Must have received 1-3 prior therapies for CLL

  • Completed therapy 2-12 months ago
  • Prior therapy must have led to a partial response or greater
  • No evidence of progressive disease
• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,000/mm³
• WBC ≤ 5,000/mm³
• Platelet count ≥ 50,000/mm³
• Cytopenia allowed
• Creatinine < 2.0 mg/dL
• Bilirubin ≤ 1.5 times normal (unless due to Gilbert's disease or hemolysis)
• AST ≤ 2 times normal (unless due to hemolysis)
• No secondary malignancy or other disease that would limit survival to < 2 years
• No history of inflammatory bowel disease unless inactive for > 2 years
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• See Disease Characteristics
• No other concurrent chemotherapy
• No concurrent radiotherapy
• No concurrent dexamethasone or other corticosteroid-based antiemetics
• No concurrent chronic corticosteroid therapy

• No other concurrent hormonal therapy except for the following:

  • Steroids for new adrenal failure
  • Hormones for nondisease-related conditions (e.g., insulin for diabetes)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00377104
• Other Study ID Numbers: NCI-2009-00161; OSU 05116; OSU-IRB-2006C0031; CDR0000501975; OSU-05116; U01CA076576 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Leslie Andritsos; Ohio State University

• PRS Account: National Cancer Institute (NCI)
• Verification Date: July 2013