Flavopiridol in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia or Lymphocytic Lymphoma

Phase 1

Completed

• Conditions: Recurrent Small Lymphocytic Lymphoma; Waldenström Macroglobulinemia; B-cell Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia
• Interventions: Drug: alvocidib

• Registration Number: NCT00058240
• Lead Sponsor: National Cancer Institute (NCI)

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.

Study Timeline

• Study Start: 2003-04
• Study First Submitted: 2003-04-07
• Study First Submitted QC: 2003-04-08
• Study First Posted: 2003-04-09
• Primary Completion: 2009-02
• Study Completion: 2009-02
• Results First Submitted: 2015-04-07
• Results First Submitted QC: 2017-05-02
• Status Verified: 2017-06
• Results First Posted: 2017-06-02
• Last Update Submitted: 2017-06-02
• Last Update Posted: 2017-07-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 52

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

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	alvocidib	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.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Dose Limiting Toxicities (DLTs)	up to 7 weeks	DLTs were defined as non-hematologic toxicity of grade 3 or greater severity (excluding transient liver function abnormalities, transient electrolyte abnormalities that are not life threatening, fatigue, or diarrhea that resolve within 4 days), or in some case grade 2 toxicity (i.e. irreversible renal, chronic pulmonary, neurologic, or cardiac toxicity). Hematologic toxicity were evaluated by the modified NCI criteria and followed closely. Dose limiting only if grade 4 thrombocytopenia or neutropenia persists for 7 days or greater. Inability to continue with cycle 2 by 7 weeks for reasons other than progression of disease will also be considered a DLT.The National Cancer Institute Common Toxicity Criteria will be used to characterize toxicity.
Recommended Dose Level of Flavopiridol	Up to 6 weeks	Recommended dose determined by number of DLTs \[non-hematologic toxicity grade 3 or greater (excluding not life-threatening transient liver function or transient electrolyte abnormalities, fatigue, or diarrhea resolving within 4 days), some grade 2 toxicity (i.e. irreversible renal, chronic pulmonary, neurologic, or cardiac toxicity), hematologic toxicity of grade 4 thrombocytopenia/neutropenia persisting for 7 days or greater, or inability to continue cycle 2 by 7 weeks for reasons other than disease progression\] and consideration of number of patients with severe tumor lysis requiring hemodialysis with dose 1.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (CR + PR) of Flavopiridol in Patients Evaluated Utilizing the Revised National Cancer Institute-sponsored Working Group Guidelines	Up to 2 years	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Trial Locations

Locations (1)

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