Clinical trial NCT00058240: Flavopiridol in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia or Lymphocytic Lymphoma
Official title: A Dose-Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With Previously Treated B-Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: B-cell Chronic Lymphocytic Leukemia
Recurrent Small Lymphocytic Lymphoma
Refractory Chronic Lymphocytic Leukemia
Waldenström Macroglobulinemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-04-09
Enrollment: 52
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/II trial studies the side effects and best dose of flavopiridol in treating patients with previously treated chronic lymphocytic leukemia or lymphocytic lymphoma. Drugs used in chemotherapy such as flavopiridol work in different ways to stop cancer cells from dividing so they stop growing or die.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the toxicity profile, dose-limiting toxicity, and maximum tolerated dose of flavopiridol administered as a 30 minute loading dose followed by a 4-hour infusion once weekly for 4 consecutive weeks every 6 weeks.

II. To determine the safety and feasibility of performing dose escalation to 80 mg/m2 (30 mg/m2 30-minute IV bolus followed by 50 mg/m2 4-hour IV infusion) beginning dose 2 in patients who do not experience severe tumor lysis requiring hemodialysis during dose 1.

III. To determine the pharmacokinetics and cellular pharmacodynamics of flavopiridol administered in this schedule.

SECONDARY OBJECTIVES:

I. To determine the complete response (CR) and overall response rate (CR + PR) of flavopiridol in patients with previously-treated CLL administered as a 30 minute loading dose followed by a 4 hour infusion once weekly for 4 consecutive weeks every 6 weeks.

OUTLINE: This is a dose-escalation study.

Patients receive a loading dose of flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of unacceptable toxicity or disease progression.

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. After the MTD is determined, 12 additional patients are accrued and treated as above at the recommended phase II dose.

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

Eligibility criteria: Inclusion Criteria:

* Diagnosis of B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, including Waldenstrom's macroglobulinemia, as indicated by the following:

  * Massive or progressive splenomegaly and/or lymphadenopathy
  * Anemia (hemoglobin less than 11 g/dL) or thrombocytopenia (platelet count less than 100,000/mm\^3)
  * Weight loss of more than 10% within the past 6 months
  * Grade 2 or 3 fatigue
  * Fevers greater than 100.5º C or night sweats for more than 2 weeks with no evidence of infection
  * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or anticipated doubling time of less than 6 months
* Received at least 1 prior therapy for CLL
* Performance status - ECOG (Eastern Cooperative Oncology Group) 0-2
* See Disease Characteristics
* WBC (white blood count) less than 200,000/mm\^3
* Bilirubin no greater than 1.5 times normal (unless due to Gilbert's disease or any of the conditions stated below)\*
* AST (aspartate aminotransferase) no greater than 2 times normal\*
* Creatinine no greater than 2.0 mg/dL
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No other malignancy that would limit survival to less than 2 years
* No history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) unless inactive for more than 2 years
* No psychiatric condition that would preclude compliance with treatment or giving informed consent
* No other concurrent chemotherapy
* No concurrent chronic corticosteroids
* No concurrent hormonal therapy except steroids for new adrenal failure or hormonal agents for nondisease-related conditions (e.g., insulin for diabetes)
* No concurrent dexamethasone or other corticosteroid-based antiemetics
* No concurrent radiotherapy

Primary outcomes:
measure: Number of Patients With Dose Limiting Toxicities (DLTs)
timeFrame: up to 7 weeks
measure: Recommended Dose Level of Flavopiridol
timeFrame: Up to 6 weeks
Secondary outcomes:
measure: Overall Response Rate (CR + PR) of Flavopiridol in Patients Evaluated Utilizing the Revised National Cancer Institute-sponsored Working Group Guidelines
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: John Byrd
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ni W, Ji J, Dai Z, Papp A, Johnson AJ, Ahn S, Farley KL, Lin TS, Dalton JT, Li X, Jarjoura D, Byrd JC, Sadee W, Grever MR, Phelps MA. Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition. PLoS One. 2010 Nov 1;5(11):e13792. doi: 10.1371/journal.pone.0013792.
citation: Pierceall WE, Warner SL, Lena RJ, Doykan C, Blake N, Elashoff M, Hoff DV, Bearss DJ, Cardone MH, Andritsos L, Byrd JC, Lanasa MC, Grever MR, Johnson AJ. Mitochondrial priming of chronic lymphocytic leukemia patients associates Bcl-xL dependence with alvocidib response. Leukemia. 2014 Nov;28(11):2251-4. doi: 10.1038/leu.2014.206. Epub 2014 Jul 3. No abstract available.
citation: Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA, Blum KA, Flynn JM, Jones JA, Hu W, Moran ME, Mitchell SM, Smith LL, Wagner AJ, Raymond CA, Schaaf LJ, Phelps MA, Villalona-Calero MA, Grever MR, Byrd JC. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol. 2009 Dec 10;27(35):6012-8. doi: 10.1200/JCO.2009.22.6944. Epub 2009 Oct 13.
citation: Woyach JA, Lozanski G, Ruppert AS, Lozanski A, Blum KA, Jones JA, Flynn JM, Johnson AJ, Grever MR, Heerema NA, Byrd JC. Outcome of patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol: impact of genetic features. Leukemia. 2012 Jun;26(6):1442-4. doi: 10.1038/leu.2011.375. Epub 2012 Jan 13. No abstract available.