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

June 27, 2016 updated by: National Cancer Institute (NCI)

A Phase I/II Study of Flavopiridol Administered as a 30-Minute Bolus Followed by a 4-Hour Infusion in Lymphomas and Multiple Myeloma

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

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

II. 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.

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

IV. 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:

I. 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.

III. 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.

IV. 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 Type

Interventional

Enrollment (Actual)

46

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
Time Frame: 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.
28 days
Maximum Tolerated Dose (MTD)
Time Frame: 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.
28 days
Complete and Partial Response Rate (Phase II)
Time Frame: 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.
Up to 2 years
Qualitative and Quantitative Toxicities in Regard to Organ Specificity
Time Frame: 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.
Up to 30 days after completion of study treatment
Lymphoid/Plasma Cell Malignancies
Time Frame: 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.
Up to 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol
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
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.
0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1
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
Up to 30 days after completion of study treatment
Induced Response in Patients Independent of p53 Mutational Status
Time Frame: 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.
Up to 2 years
Pharmacodynamic Effects of Flavopiridol on Normal Peripheral Blood Mononuclear Cells (PBMCs).
Time Frame: Day 1
The correlation of the pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs)
Day 1
Pharmacokinetics (Cmax) of Flavopiridol
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
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.
0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2005

Primary Completion (Actual)

February 1, 2011

Study Completion (Actual)

November 1, 2015

Study Registration Dates

First Submitted

June 2, 2005

First Submitted That Met QC Criteria

June 2, 2005

First Posted (Estimate)

June 3, 2005

Study Record Updates

Last Update Posted (Estimate)

August 8, 2016

Last Update Submitted That Met QC Criteria

June 27, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2011-01346 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • P30CA016058 (U.S. NIH Grant/Contract)
  • N01CM00070 (U.S. NIH Grant/Contract)
  • U01CA076576 (U.S. NIH Grant/Contract)
  • OSU-04100
  • CDR0000429577
  • OSU-2005C0006
  • NCI-7002
  • OSU 04100 (Other Identifier: Ohio State University Medical Center)
  • 7002 (CTEP)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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