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

Recurrent Mantle Cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00112723
• Other study ID #: NCI-2011-01346
• Secondary ID: NCI-2011-01346OS
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: June 2, 2005
• Last updated: December 6, 2013
• Start date: December 2005

Study information

• Verified date: December 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 180
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• 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
• Hodgkin Disease
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, T-Cell
• Leukemia-Lymphoma, Adult T-Cell
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone
• Lymphoma, Extranodal NK-T-Cell
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Anaplastic
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Lymphomatoid Granulomatosis
• Multiple Myeloma
• Mycosis Fungoides
• Neoplasms, Plasma Cell
• 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
• Sezary Syndrome
• Splenic Marginal Zone Lymphoma
• Stage I Multiple Myeloma
• Stage II Multiple Myeloma
• Stage III Multiple Myeloma
• Waldenstrom Macroglobulinemia
• Waldenström Macroglobulinemia

Intervention

Drug:
• alvocidib
Given IV

Locations

Country	Name	City	State
United States	Ohio State University Medical Center	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-specific dose-limiting toxicity and maximum tolerated dose of flavopiridol graded according to the CTCAE version 4.0 (Phase I)	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.	28 days	Yes
Primary	Complete and partial response rate (Phase II)		Up to 2 years	No
Primary	Qualitative and quantitative toxicities in regard to organ specificity, time course, predictability, and reversibility as measured by CTCAE version 4.0		Up to 30 days after completion of study treatment	Yes
Primary	Lymphoid/plasma cell malignancies		Up to 2 years	No
Secondary	Pharmacokinetics of flavopiridol		Days 1 and 22	No
Secondary	Acute infusion toxicity (e.g., fever, hypotension, tumor pain, and dyspnea)		Up to 30 days after completion of study treatment	Yes
Secondary	Induced response in patients independent of p53 mutational status		Up to 2 years	No
Secondary	Pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs).		Day 1	No