B-cell Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Waldenström Macroglobulinemia
Conditions
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.
Interventions
DRUGalvocidib
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
Patients with relapsed, symptomatic Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) were enrolled and received treatment between May 2003 and February 2006
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Dose Level 1: Patients were administered Flavopiridol 30mg/m2 bolus followed by 30 mg/m2 4 hour infusion weekly for four weeks followed by two weeks without therapy for a total of 6 cycles | 20 |
| Dose Level 2 Dose Level 2: Patients were administered Flavopiridol 40mg/m2 bolus followed by 40 mg/m2 4 hour infusion weekly for four weeks followed by two weeks without therapy for a total of 6 cycles. | 3 |
| Dose Level 3 Dose Level 3: Patients were administered Flavopiridol dose level one scheduled for the first cycle. In absence of severe toxicity, dose level was escalated to 30mg/m2 bolus followed by 50 mg/m2 4 hour infusion for a total of 6 cycles | 17 |
| Dose Level 4 Dose Level 4: Patients were administered Flavopiridol dose level one scheduled for the first dose. In absence of severe toxicity, dose level was escalated to 30mg/m2 bolus followed by 50 mg/m2 4 hour infusion for a total of 6 cycles | 12 |
| Total | 52 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 3 | Dose Level 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61.5 years | 52 years | 55 years | 60 years | 60 years |
| Region of Enrollment United States | 20 patients | 3 patients | 17 patients | 12 patients | 52 patients |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 3 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 14 Participants | 1 Participants | 14 Participants | 9 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 40 | 16 / 16 |
| serious Total, serious adverse events | 11 / 42 | 1 / 16 |
Outcome results
Primary
Number of Patients With Dose Limiting Toxicities (DLTs)
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.
Time frame: up to 7 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLTs) | 2 patients |
| Dose Level 2 | Number of Patients With Dose Limiting Toxicities (DLTs) | 2 patients |
| Dose Level 3 | Number of Patients With Dose Limiting Toxicities (DLTs) | 4 patients |
| Dose Level 4 | Number of Patients With Dose Limiting Toxicities (DLTs) | 3 patients |
Primary
Recommended Dose Level of Flavopiridol
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.
Time frame: Up to 6 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level 1 | Recommended Dose Level of Flavopiridol | Cycle 1 dose 1 | 30 mg/m^2 |
| Dose Level 1 | Recommended Dose Level of Flavopiridol | Cycle 1 dose 2 thru Cycle 6 | 50 mg/m^2 |
Secondary
Overall Response Rate (CR + PR) of Flavopiridol in Patients Evaluated Utilizing the Revised National Cancer Institute-sponsored Working Group Guidelines
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
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 | Overall Response Rate (CR + PR) of Flavopiridol in Patients Evaluated Utilizing the Revised National Cancer Institute-sponsored Working Group Guidelines | 21 patients |