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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00112723
First received: June 2, 2005
Last updated: December 6, 2013
Last verified: December 2013
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Disease-specific dose-limiting toxicity and maximum tolerated dose of flavopiridol graded according to the CTCAE version 4.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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. The maximum tolerated dose (MTD) is defined as that dose level beneath the dose at which 2 or more of 6 patients experience DLT.

  • Complete and partial response rate (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Qualitative and quantitative toxicities in regard to organ specificity, time course, predictability, and reversibility as measured by CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  • Lymphoid/plasma cell malignancies [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetics of flavopiridol [ Time Frame: Days 1 and 22 ] [ Designated as safety issue: No ]
  • Acute infusion toxicity (e.g., fever, hypotension, tumor pain, and dyspnea) [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  • Induced response in patients independent of p53 mutational status [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs). [ Time Frame: Day 1 ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: December 2005
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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, 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 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 ≤ 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00112723

Locations
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: Jeffrey Jones Ohio State University
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00112723     History of Changes
Other Study ID Numbers: NCI-2011-01346, NCI-2011-01346, OSU-04100, CDR0000429577, OSU-2005C0006, NCI-7002, OSU 04100, 7002, N01CM00070, U01CA076576
Study First Received: June 2, 2005
Last Updated: December 6, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hodgkin Disease
Immunoblastic Lymphadenopathy
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphomatoid Granulomatosis
Waldenstrom Macroglobulinemia
Multiple Myeloma
Neoplasms, Plasma Cell
Mycoses
Mycosis Fungoides
Sclerosis
Sezary Syndrome
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Lymphoma, Large-Cell, Anaplastic
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Extranodal NK-T-Cell
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders

ClinicalTrials.gov processed this record on July 20, 2014