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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00112723
• Collaborator: (none)
• Enrollment: 46
• Location: 1
• Arm: 1
• Duration (Months): 119
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This phase I/II trial is studying the side effects and best dose of flavopiridol and to see how well it works in treating patients with lymphoma or multiple myeloma. Drugs used in chemotherapy, such as flavopiridol, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Condition or Disease	Intervention/Treatment	Phase
Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Waldenström Macroglobulinemia	Drug: alvocidib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the disease-specific dose-limiting toxicity and maximum tolerated dose of flavopiridol in patients with relapsed or refractory lymphoma or multiple myeloma.

2. Determine the complete and partial response rate in patients with selected non-Hodgkin's lymphoma (e.g., indolent B-cell, mantle cell, intermediate grade B-cell, and T/NK-cell), Hodgkin's lymphoma, or multiple myeloma treated with this drug.

3. Determine the qualitative and quantitative toxic effects or this drug, in terms of organ specificity, time course, predictability, and reversibility in these patients.

4. Determine subsets of lymphoid/plasma cell malignancies that are suitable for larger phase II studies designed to further evaluate the efficacy and toxicity of this drug in these patients.

SECONDARY OBJECTIVES:

1. Determine the pharmacokinetics of this drug in these patients. II. Determine the effect of this drug on innate immunity (including T-, B-, and NK-cell subsets) and quantitative immunoglobulin levels in these patients.

2. Determine whether acute infusion toxicity (e.g., fever, hypotension, tumor pain, and dyspnea) observed with other flavopiridol treatment schedules is related to a cytokine-release syndrome in these patients.

3. Determine whether this drug induces response (independent of p53 mutational status) in these patients.

OUTLINE: This is a phase I, dose-escalation study followed by a multicenter, phase II, pilot study. Patients enrolled in the phase II portion of the study are stratified according to diagnosis.

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.

NOTE: The phase II treatment dose and schedule for hairy cell leukemia patients will be adapted from that developed in previous phase II studies of flavopiridol for the treatment of chronic lymphocytic leukemia.

After completion of study therapy, patients are followed every 3 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Flavopiridol Administered as a 30-Minute Bolus Followed by a 4-Hour Infusion in Lymphomas and Multiple Myeloma
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (alvocidib) 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.

Drug: alvocidib; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275

Outcome Measures

Primary Outcome Measures

1. 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) [28 days]

   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.

2. Maximum Tolerated Dose (MTD) [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.

3. Complete and Partial Response Rate (Phase II) [Up to 2 years]

   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.

4. Qualitative and Quantitative Toxicities in Regard to Organ Specificity [Up to 30 days after completion of study treatment]

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

5. Lymphoid/Plasma Cell Malignancies [Up to 2 years]

   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.

Secondary Outcome Measures

1. Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol [0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1]

   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.

2. Number of Patients Reporting Acute Infusion Toxicity (e.g., Fever, Hypotension, Tumor Pain, and Dyspnea) [Up to 30 days after completion of study treatment]

3. Induced Response in Patients Independent of p53 Mutational Status [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.

4. Pharmacodynamic Effects of Flavopiridol on Normal Peripheral Blood Mononuclear Cells (PBMCs). [Day 1]

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

5. Pharmacokinetics (Cmax) of Flavopiridol [0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of 1 of the following hematologic malignancies:

• Hodgkin's lymphoma

• Non-Hodgkin's lymphoma (NHL)

• Multiple myeloma

• Patients in the phase II portion of the study are enrolled in 1 of the following strata according to diagnosis*

• Stratum 1: Indolent B-cell NHL (non-Hodgkin's lymphoma), follicle center B-cell NHL (grade 1, 2, or 3), marginal zone lymphoma, Waldenstrom's macroglobulinemia, or small lymphocytic lymphoma (without blood lymphocytosis at any point in the disease process)

• Must have progressive lymphadenopathy, worsening cytopenias, or progressive symptoms attributed to lymphoma

• Must require therapy, as determined by progressive anemia, thrombocytopenia, symptoms (e.g., fever, night sweats, weight loss, or fatigue), or progressive lymphadenopathy that causes discomfort

• Received ≥ 2 prior therapies, including rituximab

• Stratum 1a: Hairy cell leukemia

• Must require therapy, as determined by progressive cytopenias or symptoms (fever, night sweats, weight loss, or fatigue)

• Must have received ≥ 2 therapies

• Stratum 2: Mantle cell lymphoma, as determined by the presence of cyclin D1 staining OR t(11;14)

• Stratum 3: Intermediate grade B-cell NHL, including diffuse large B-cell NHL and T-cell rich B-cell NHL

• Diffuse large B-cell NHL arising from an indolent NHL (i.e., transformed lymphoma) allowed

• Ineligible for potentially curative autologous stem cell transplantation

• Stratum 4: T-cell and natural killer-cell NHL, including anaplastic large cell lymphoma and peripheral T-cell NHL

• Primary cutaneous lymphoma or Sezary syndrome allowed provided criteria for measurable disease are met

• Received ≥ 1 prior systemic therapy

• Stratum 5: Hodgkin's lymphoma

• Any of the following subtypes are allowed:

• Nodular sclerosing

• Mixed cellularity

• Lymphocyte predominant

• Lymphocyte depleted

• Ineligible for potentially curative autologous stem cell transplantation

• Stratum 6: Progressive stage I or stage II or IIIA multiple myeloma meeting ≥ 1 major and 1 minor criterion OR ≥ 3 minor criteria as follows:

• Major criteria

• Plasmacytoma on tissue biopsy

• Bone marrow plasmacytosis ≥ 30% of marrow cellularity

• Monoclonal paraprotein ≥ 3,500 mg/dL (IgG), or ≥ 2,000 mg/dL (IgA), OR monoclonal protein (Bence-Jones protein) ≥ 1,000 mg by 24-hour urine collection

• Minor criteria

• Bone marrow plasmacytosis 10-29% of marrow cellularity

• Monoclonal paraprotein < 3,500 mg/dL (IgG) or < 2,000 mg/dL (IgA)

• Lytic bone lesions by x-ray or CT scan

• Decrease in normal IgM (< 50 mg/dL), IgA (< 100 mg/dL), or IgG (< 600 mg/dL)

• Relapsed or refractory disease

• Measurable disease, defined by 1 of the following:

• At least 1 node > 2 cm by CT scan

• Measurable disease in a lymphoid structure (i.e., spleen) by CT scan

• Bone marrow involvement (> 20% of marrow cellularity)

• Patients with multiple myeloma must have detectable serum or urinary paraprotein

• Patients with only cutaneous or subcutaneous disease (i.e., no measurable lymph node or bone marrow disease) are eligible if the extent of rash or skin involvement OR the size of the nodules are measurable

• Must have received ≥ 1 prior therapy

• Steroids alone are not considered prior therapy for patients with NHL or Hodgkin's lymphoma

• High-dose dexamethasone is considered 1 prior therapy for patients with multiple myeloma

• No standard effective therapy exists

• No HIV-associated lymphoma

• No nonsecretory multiple myeloma

• Performance status - ECOG (Eastern Cooperative Oncology Group) 0-2

• No concurrent hormonal therapy except steroids for new adrenal failure or hormones administered for non-disease-related conditions (e.g., insulin for diabetes)

• Hemoglobin ≥ 9.0 g/dL*

• Absolute neutrophil count ≥ 1,500/mm^3*

• Platelet count ≥ 50,000/mm^3*

• AST (aspartate aminotransferase) ≤ 3 times upper limit of normal (ULN)

• Bilirubin ≤ 2 times ULN

• No major renal dysfunction that would preclude study compliance or participation

• Phase I:

• Creatinine ≤ 1.5 mg/dL

• Creatinine clearance ≥ 70 mL/min

• Phase II:

• Creatinine ≤ 2.0 mg/dL

• Creatinine clearance ≥ 50 mL/min

• No cardiac or vascular dysfunction that would preclude central venous access, vigorous hydration, or hemodialysis

• No other major cardiac dysfunction that would preclude study compliance or participation

• No major pulmonary dysfunction that would preclude study compliance or participation

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No chronic gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) that would preclude study compliance or participation

• No other major organ system (including neurological or psychiatric) dysfunction that would preclude study compliance or participation

• Prior radiotherapy, including radioimmunotherapy, allowed

• No concurrent radiotherapy

• Prior idiotype vaccination or stem cell transplantation allowed

• More than 6 weeks since prior mitomycin or nitrosoureas

• No other concurrent chemotherapy

• More than 4 weeks since other prior therapy

• Prior systemic steroids allowed

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: Jeffrey Jones, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00112723
• Other Study ID Numbers: NCI-2011-01346; NCI-2011-01346; OSU-04100; CDR0000429577; OSU-2005C0006; NCI-7002; OSU 04100; 7002; U01CA076576; N01CM00070; P30CA016058
• First Posted: Jun 3, 2005
• Last Update Posted: Aug 8, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Mycoses; Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Hodgkin Disease; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, T-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mycosis Fungoides; Sezary Syndrome; Leukemia, T-Cell; Lymphoma, T-Cell, Cutaneous; Leukemia-Lymphoma, Adult T-Cell; Waldenstrom Macroglobulinemia; Lymphoma, Large-Cell, Anaplastic; Lymphomatoid Granulomatosis; Immunoblastic Lymphadenopathy; Recurrence; Alvocidib

Study Results

Participant Flow

Recruitment Details	Patients were accrued to the study between April 2006 and September 2010.
Pre-assignment Detail	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.

Arm/Group Title	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2)	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2)	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2)
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	13	19	14
Patients Evaluable for Toxicity	11	12	12
COMPLETED	11	12	12
NOT COMPLETED	2	7	2

Baseline Characteristics

Arm/Group Title	Treatment (Alvocidib)
Arm/Group Description	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
Overall Participants	46
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66
Sex: Female, Male (Count of Participants)
Female	20 43.5%
Male	26 56.5%
Region of Enrollment (patients) [Number]
United States	45
Canada	1
Eastern Cooperative Oncology Group (ECOG) Performance status (patients) [Number]
0 (Fully active)	8
1 (Restricted in physically strenuous activity)	34
2 (Ambulatory capable of all selfcare)	4
Diagnosis (patients) [Number]
Indolent B-cell	15
intermediate grade B-NHL	17
Mantle cell lymphoma	7
T/NK cell NHL	7

Outcome Measures

1. Primary Outcome

Title	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)
Description	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.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2)	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2)	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2)
Arm/Group Description	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.	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.	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.
Measure Participants	11	19	14
Number [patients]	0	0	0

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	The maximum tolerated dose (MTD) is defined as that dose level beneath the dose at which 2 or more of 6 patients experience DLT.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 (30+30)	Level 2 (30+50)	Level 3 (50+50)
Arm/Group Description	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. alvocidib: Given IV	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.	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.
Measure Participants	11	12	12
Number [mg/m2]	60	80	100

3. Primary Outcome

Title	Complete and Partial Response Rate (Phase II)
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2)	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2)	Dose Level 3 Dose (Flavopiridol 50 mg/m2 + 50 mg/m2)
Arm/Group Description	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.	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.	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.
Measure Participants	12	17	14
Complete Response	0	0	0
Partial Response	2	2	2

4. Primary Outcome

Title	Qualitative and Quantitative Toxicities in Regard to Organ Specificity
Description	The NCI Common Toxicity Criteria for Adverse Events (version 3.0) were used to define and grade toxicity for patients.
Time Frame	Up to 30 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

Grade 3 and 4 toxicities.

Arm/Group Title	Dose Levels 1, 2, 3
Arm/Group Description	Dose Level 1 (30 mg/m2 + 30 mg/m2), Dose Level 2 (30 mg/m2 + 50 mg/m2), Dose Level 3 (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. alvocidib: Given IV
Measure Participants	35
Leukopenia	86
Neutropenia	23
Infection	20
Diarrhea	51
Fatigue	34

5. Primary Outcome

Title	Lymphoid/Plasma Cell Malignancies
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1	Cohort 2	Cohort 4
Arm/Group Description	Patients diagnosed with Indolent B-cell NHL	Patients diagnosed with Mantle Cell NHL	Patients diagnosed with T Cell NHL
Measure Participants	13	6	6
Partial Response	3	2	0
Stable Disease	0	0	3

6. Secondary Outcome

Title	Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol
Description	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.
Time Frame	0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	All Dose Levels of Alvocidib
Arm/Group Description	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. alvocidib: Given IV
Measure Participants	45
Day 1	10.404 (5.923)
Day 22	11.949 (5.109)

7. Secondary Outcome

Title	Number of Patients Reporting Acute Infusion Toxicity (e.g., Fever, Hypotension, Tumor Pain, and Dyspnea)
Time Frame	Up to 30 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Dose Levels of Alvocidib
Arm/Group Description	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
Measure Participants	35
Number [patients]	8

8. Secondary Outcome

Title	Induced Response in Patients Independent of p53 Mutational Status
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

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

Arm/Group Title	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2)	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2)	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2)
Arm/Group Description	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.	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.	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.
Measure Participants	0	0	0

9. Secondary Outcome

Title	Pharmacodynamic Effects of Flavopiridol on Normal Peripheral Blood Mononuclear Cells (PBMCs).
Description	The correlation of the pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs)
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dose Level 1 (Flavopiridol 30 mg/m2 + 30 mg/m2)	Dose Level 2 (Flavopiridol 30 mg/m2 + 50 mg/m2)	Dose Level 3 (Flavopiridol 50 mg/m2 + 50 mg/m2)
Arm/Group Description	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.	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.	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.
Measure Participants	0	0	0

10. Secondary Outcome

Title	Pharmacokinetics (Cmax) of Flavopiridol
Description	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.
Time Frame	0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Dose Levels of Alvocidib
Arm/Group Description	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. alvocidib: Given IV
Measure Participants	45
Day 1	1.954 (0.886)
Day 22	2.071 (0.820)

Adverse Events

Time Frame	Patients were assessed for clinical response after two, four and six cycles with laboratory studies, physical exam, and CT scans.
Adverse Event Reporting Description	NCI Common Toxicity Criteria for Adverse Events (version 3.0) was used to define and grade toxicity.
Arm/Group Title	Treatment (Alvocidib)
Arm/Group Description	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
All Cause Mortality
	Treatment (Alvocidib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Alvocidib)
	Affected / at Risk (%)	# Events
Total	0/35 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Alvocidib)
	Affected / at Risk (%)	# Events
Total	34/35 (97.1%)
Blood and lymphatic system disorders
Anemia	22/35 (62.9%)	22
Gastrointestinal disorders
Nausea	12/35 (34.3%)	12
Vomiting	10/35 (28.6%)	10
Anorexia	8/35 (22.9%)	8
Diarrhea	27/35 (77.1%)	27
General disorders
Neutropenia fever	4/35 (11.4%)	4
Fatigue	21/35 (60%)	21
Immune system disorders
Cytokine Release Syndrome	8/35 (22.9%)	8
Infections and infestations
Infection	9/35 (25.7%)	9
Injury, poisoning and procedural complications
Thrombocytopenia	13/35 (37.1%)	13
Investigations
Leukopenia	30/35 (85.7%)	30
Neutropenia	34/35 (97.1%)	34
Lymphopenia	25/35 (71.4%)	25
Increased ALT/AST	12/35 (34.3%)	12
Hyperbilirubinemia	6/35 (17.1%)	6
Metabolism and nutrition disorders
Tumor Lysis Syndrome	8/35 (22.9%)	8

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.