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)
46
1
1
119
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.

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

    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)
    Description
    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.

    Results Point of Contact

    Name/Title Jeffrey Jones, MD
    Organization The Ohio State University Comprehensive Cancer Center
    Phone 614-293-3507
    Email Jeffrey.Jones@osumc.edu
    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