Trial Outcomes & Findings for Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma (NCT NCT00112723)

Last Updated: 2016-08-08

Results Overview

Dose limiting toxicity (DLT) for an individual disease group is defined as 1) any grade 3-4 non-hematologic toxicity (except leukopenia or neutropenia) that does not resolve or decrease to grade 1-2 within 2 weeks, or 2) any grade 4 hematologic toxicity that causes more than a 1 week delay in administration of therapy.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

46 participants

Primary outcome timeframe

28 days

Results posted on

2016-08-08

Participant Flow

Patients were accrued to the study between April 2006 and September 2010.

Patients with confirmed diagnosis of NHL (Non-Hodgkin's lymphoma) were accrued to one of the four cohorts defined by the World Health Organization criteria: indolent B-cell, mantle cell, intermediate-grade B-cell including transformed lymphoma and T-/NK-cell excluding primary cutaneous disease.

Participant milestones

Participant milestones
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Overall Study STARTED	13	19	14
Overall Study Patients Evaluable for Toxicity	11	12	12
Overall Study COMPLETED	11	12	12
Overall Study NOT COMPLETED	2	7	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment (Alvocidib) n=46 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 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. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I. alvocidib: Given IV
Age, Continuous	66 years n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants
Region of Enrollment United States	45 patients n=5 Participants
Region of Enrollment Canada	1 patients n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance status 0 (Fully active)	8 patients n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance status 1 (Restricted in physically strenuous activity)	34 patients n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance status 2 (Ambulatory capable of all selfcare)	4 patients n=5 Participants
Diagnosis Indolent B-cell	15 patients n=5 Participants
Diagnosis intermediate grade B-NHL	17 patients n=5 Participants
Diagnosis Mantle cell lymphoma	7 patients n=5 Participants
Diagnosis T/NK cell NHL	7 patients n=5 Participants

PRIMARY outcome

Timeframe: 28 days

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=11 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) n=19 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) n=14 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Disease-specific Dose-limiting Toxicity and Maximum Tolerated Dose of Flavopiridol Graded According to the CTCAE (Common Toxicity Criteria for Adverse Effects) Version 4.0 (Phase I)	0 patients	0 patients	0 patients

PRIMARY outcome

Timeframe: 28 days

The maximum tolerated dose (MTD) is defined as that dose level beneath the dose at which 2 or more of 6 patients experience DLT.

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=11 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) n=12 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) n=12 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Maximum Tolerated Dose (MTD)	60 mg/m2	80 mg/m2	100 mg/m2

PRIMARY outcome

Timeframe: Up to 2 years

Population: Includes patients enrolled with Indolent B-cell NHL, Intermediate Grade B NHL, Mantle cell NHL and T/NK-cell NHL

Patients were assessed for clinical response after two , four and six cycle with laboratory studies, physical exam, and CT scans. Response was evaluated using the modified NCI-sponsored Working Group Lymphoma Response Criteria.

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=12 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) n=17 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) n=14 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Complete and Partial Response Rate (Phase II) Complete Response	0 patients	0 patients	0 patients
Complete and Partial Response Rate (Phase II) Partial Response	2 patients	2 patients	2 patients

PRIMARY outcome

Timeframe: Up to 30 days after completion of study treatment

Population: Grade 3 and 4 toxicities.

The NCI Common Toxicity Criteria for Adverse Events (version 3.0) were used to define and grade toxicity for patients.

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=35 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Qualitative and Quantitative Toxicities in Regard to Organ Specificity Leukopenia	86 percentage of patients	—	—
Qualitative and Quantitative Toxicities in Regard to Organ Specificity Neutropenia	23 percentage of patients	—	—
Qualitative and Quantitative Toxicities in Regard to Organ Specificity Infection	20 percentage of patients	—	—
Qualitative and Quantitative Toxicities in Regard to Organ Specificity Diarrhea	51 percentage of patients	—	—
Qualitative and Quantitative Toxicities in Regard to Organ Specificity Fatigue	34 percentage of patients	—	—

PRIMARY outcome

Timeframe: Up to 2 years

Population: Response indicated for Indolent B-cell NHL, Mantle cell NHL and T-cell NHL

Identify subsets, based on levels of response (PR and SD), of lymphoid / plasma cell malignancies that are suitable for larger phase II studies designed to further evaluate the efficacy and toxicity of flavopiridol.

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=13 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) n=6 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) n=6 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Lymphoid/Plasma Cell Malignancies Partial Response	3 patients	2 patients	0 patients
Lymphoid/Plasma Cell Malignancies Stable Disease	0 patients	0 patients	3 patients

SECONDARY outcome

Timeframe: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1

Population: total of 71 PK (Pharmacokinetic) profiles comprising 484 plasma concentration were determined for 45 of 46 patients following treatment

Whole blood samples were collected for pharmacokinetics analysis during the first (Day 1) and fourth (Day 22) treatments during cycle 1. Samples were collected on both occasions prior to dosing and at 0.5, 1, 3, 4.5, 6, 8 and 24 hour after the start of the bolus infusion.

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=45 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol Day 1	10.404 hr×μM Standard Deviation 5.923	—	—
Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol Day 22	11.949 hr×μM Standard Deviation 5.109	—	—

SECONDARY outcome

Timeframe: Up to 30 days after completion of study treatment

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=35 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Number of Patients Reporting Acute Infusion Toxicity (e.g., Fever, Hypotension, Tumor Pain, and Dyspnea)	8 patients	—	—

SECONDARY outcome

Timeframe: Up to 2 years

Population: Data not available due to studies were not conducted by collaborating laboratory Investigator

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

Population: Data not available due to studies were not conducted by collaborating laboratory Investigator

The correlation of the pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1

Outcome measures

Outcome measures
Measure	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2) n=45 Participants PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2) PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I.
Pharmacokinetics (Cmax) of Flavopiridol Day 1	1.954 μM Standard Deviation 0.886	—	—
Pharmacokinetics (Cmax) of Flavopiridol Day 22	2.071 μM Standard Deviation 0.820	—	—

Adverse Events

Treatment (Alvocidib)

Serious events: 0 serious events

Other events: 34 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Treatment (Alvocidib) n=35 participants at risk PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 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. PHASE II: Patients receive flavopiridol\* as in phase I at the MTD determined in phase I. alvocidib: Given IV
Investigations Leukopenia	85.7% 30/35 • Number of events 30 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Investigations Neutropenia	97.1% 34/35 • Number of events 34 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Investigations Lymphopenia	71.4% 25/35 • Number of events 25 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Blood and lymphatic system disorders Anemia	62.9% 22/35 • Number of events 22 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Injury, poisoning and procedural complications Thrombocytopenia	37.1% 13/35 • Number of events 13 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Infections and infestations Infection	25.7% 9/35 • Number of events 9 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
General disorders Neutropenia fever	11.4% 4/35 • Number of events 4 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Investigations Increased ALT/AST	34.3% 12/35 • Number of events 12 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Investigations Hyperbilirubinemia	17.1% 6/35 • Number of events 6 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Gastrointestinal disorders Nausea	34.3% 12/35 • Number of events 12 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Gastrointestinal disorders Vomiting	28.6% 10/35 • Number of events 10 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Gastrointestinal disorders Anorexia	22.9% 8/35 • Number of events 8 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Gastrointestinal disorders Diarrhea	77.1% 27/35 • Number of events 27 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Metabolism and nutrition disorders Tumor Lysis Syndrome	22.9% 8/35 • Number of events 8 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Immune system disorders Cytokine Release Syndrome	22.9% 8/35 • Number of events 8 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
General disorders Fatigue	60.0% 21/35 • Number of events 21 • Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans. NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.

Additional Information

Jeffrey Jones, MD

The Ohio State University Comprehensive Cancer Center

Phone: 614-293-3507

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60