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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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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

Intervention / Treatment
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* Drug: alvocidib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (alvocidib)<br>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<br>* Given IV<br>* Other names: L-868275;|

What is the study measuring?
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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) | 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) | 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) | 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 | 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 | 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 | 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) |  | Up to 30 days after completion of study treatment | 
| Induced Response in Patients Independent of p53 Mutational Status | 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). | The correlation of the pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs) | Day 1 | 
| Pharmacokinetics (Cmax) of Flavopiridol | 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 |