Clinical trial NCT00112723: Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2005-06-03
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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:

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 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 (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

Primary outcomes:
measure: 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)
timeFrame: 28 days
measure: Maximum Tolerated Dose (MTD)
timeFrame: 28 days
measure: Complete and Partial Response Rate (Phase II)
timeFrame: Up to 2 years
measure: Qualitative and Quantitative Toxicities in Regard to Organ Specificity
timeFrame: Up to 30 days after completion of study treatment
measure: Lymphoid/Plasma Cell Malignancies
timeFrame: Up to 2 years
Secondary outcomes:
measure: Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol
timeFrame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1
measure: Number of Patients Reporting Acute Infusion Toxicity (e.g., Fever, Hypotension, Tumor Pain, and Dyspnea)
timeFrame: Up to 30 days after completion of study treatment
measure: Induced Response in Patients Independent of p53 Mutational Status
timeFrame: Up to 2 years
measure: Pharmacodynamic Effects of Flavopiridol on Normal Peripheral Blood Mononuclear Cells (PBMCs).
timeFrame: Day 1
measure: Pharmacokinetics (Cmax) of Flavopiridol
timeFrame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: Jeffrey Jones
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hofmeister CC, Poi M, Bowers MA, Zhao W, Phelps MA, Benson DM, Kraut EH, Farag S, Efebera YA, Sexton J, Lin TS, Grever M, Byrd JC. A phase I trial of flavopiridol in relapsed multiple myeloma. Cancer Chemother Pharmacol. 2014 Feb;73(2):249-57. doi: 10.1007/s00280-013-2347-y. Epub 2013 Nov 16.