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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00058240
• Collaborator: (none)
• Enrollment: 52
• Location: 1
• Arm: 1
• Actual Duration (Months): 70.1
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
B-cell Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Waldenström Macroglobulinemia	Drug: alvocidib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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.

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

SECONDARY OBJECTIVES:

1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Apr 1, 2003
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I 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.	Drug: alvocidib; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: John Byrd, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00058240
• Other Study ID Numbers: NCI-2012-01435; NCI-2012-01435; CDR0000287197; NCI-5746; OSU-0055; OSU 0055; 5746; R21CA112947; P30CA016058; U01CA076576
• First Posted: Apr 9, 2003
• Last Update Posted: Jul 2, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Waldenstrom Macroglobulinemia; Alvocidib

Study Results

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

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4
Arm/Group Description	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	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	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	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
Period Title: First Dose Level
STARTED	20	3	17	12
Treated	20	3	17	12
COMPLETED	20	3	17	12
NOT COMPLETED	0	0	0	0
Period Title: First Dose Level
STARTED	0	0	2	4
COMPLETED	0	0	2	4
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4	Total
Arm/Group Description	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	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.	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	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	Total of all reporting groups
Overall Participants	20	3	17	12	52
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61.5	52	55	60	60
Sex: Female, Male (Count of Participants)
Female	6 30%	2 66.7%	3 17.6%	3 25%	14 26.9%
Male	14 70%	1 33.3%	14 82.4%	9 75%	38 73.1%
Region of Enrollment (patients) [Number]
United States	20	3	17	12	52

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Dose Limiting Toxicities (DLTs)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1	Dose Level 2	Dose Level 3	Dose Level 4
Arm/Group Description	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	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	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	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
Measure Participants	20	3	19	16
Number [patients]	2	2	4	3

2. Primary Outcome

Title	Recommended Dose Level of Flavopiridol
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 4
Arm/Group Description	Flavopiridol was escalated to 30mg/m2 bolus followed by 50 mg/m2 4 hour beginning Dose Level 2 Cycle 1 for 6 Cycles.
Measure Participants	16
Cycle 1 dose 1	30
Cycle 1 dose 2 thru Cycle 6	50

3. Secondary Outcome

Title	Overall Response Rate (CR + PR) of Flavopiridol in Patients Evaluated Utilizing the Revised National Cancer Institute-sponsored Working Group Guidelines
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1, 2, 3, 4
Arm/Group Description	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 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. 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 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
Measure Participants	52
Number [patients]	21

Adverse Events

Time Frame	Patients were assessed for toxicities from Day 1 of each Flavopiridol Treatment to Post-Treatment Follow-up. Follow up was performed every 3 months for 2 years.
Adverse Event Reporting Description	Adverse events were reported for 40 unique patients treated at dose levels 1-3 and 16 patients treated at Dose level 4
Arm/Group Title	Dose Levels 1-3		Dose Level 4
Arm/Group Description	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 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 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		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
All Cause Mortality
	Dose Levels 1-3		Dose Level 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Levels 1-3		Dose Level 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/42 (26.2%)		1/16 (6.3%)
Metabolism and nutrition disorders
Hyperacute Tumor Lysis	11/42 (26.2%)	11	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	Dose Levels 1-3		Dose Level 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		16/16 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	4/40 (10%)	4	4/16 (25%)	4
Gastrointestinal disorders
Diarrhea	16/40 (40%)	16	12/16 (75%)	12
Abdominal pain/cramping	2/40 (5%)	2	1/16 (6.3%)	1
General disorders
Fatigue	8/40 (20%)	8	2/16 (12.5%)	2
Infections and infestations
Infection w/neutropenia	7/40 (17.5%)	7	6/16 (37.5%)	6
Investigations
Absolute Neutrophil Count	30/40 (75%)	30	16/16 (100%)	16
WBC	0/40 (0%)	0	11/16 (68.8%)	11
Platelets	15/40 (37.5%)	15	7/16 (43.8%)	7
AST SGOT(serum glutamic oxaloacetic transaminase) or ALT, SGPT (serum glutamic pyruvic transaminase)	13/40 (32.5%)	13	3/16 (18.8%)	3
Bilirubin	3/40 (7.5%)	3	1/16 (6.3%)	1
Metabolism and nutrition disorders
Biochemical tumor lysis	23/40 (57.5%)	23	7/16 (43.8%)	7
Musculoskeletal and connective tissue disorders
Pain	1/40 (2.5%)	1	1/16 (6.3%)	1
Renal and urinary disorders
Renal Failture	1/40 (2.5%)	1	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	6/40 (15%)	6	3/16 (18.8%)	3
Skin and subcutaneous tissue disorders
Pruritus	1/40 (2.5%)	1	1/16 (6.3%)	1
Vascular disorders
Hemorhage	3/40 (7.5%)	3	1/16 (6.3%)	1
Hypotension	4/40 (10%)	4	1/16 (6.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.