Clinical trial NCT00377104: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-09-15
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: 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
timeFrame: Day 1, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment
measure: Dose-limiting toxicity of alvocidib as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma
timeFrame: Course 1
Secondary outcomes:
measure: Pharmacokinetics and cellular pharmacodynamics of alvocidib administered in this schedule
timeFrame: Baseline and day 1
measure: Complete response (CR) and overall response rate (CR and partial response) of alvocidib in patients with previously-treated CLL
timeFrame: Baseline, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: Leslie Andritsos
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.