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

Phase 1

Terminated

Conditions: Adult Lymphocyte Predominant Hodgkin Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult T-cell Leukemia/Lymphoma
Recurrent Cutaneous T-cell Non-Hodgkin 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

Interventions: Drug: alvocidib

Registration Number: NCT00112723

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 46

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (alvocidib)	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.

Primary Outcome Measures

Name	Time	Method
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)	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.
Maximum Tolerated Dose (MTD)	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.
Complete and Partial Response Rate (Phase II)	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.
Qualitative and Quantitative Toxicities in Regard to Organ Specificity	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.
Lymphoid/Plasma Cell Malignancies	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.

Secondary Outcome Measures

Name	Time	Method
Induced Response in Patients Independent of p53 Mutational Status	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.
Pharmacodynamic Effects of Flavopiridol on Normal Peripheral Blood Mononuclear Cells (PBMCs).	Day 1	The correlation of the pharmacodynamic effects of flavopiridol on normal peripheral blood mononuclear cells (PBMCs)
Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol	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.
Number of Patients Reporting Acute Infusion Toxicity (e.g., Fever, Hypotension, Tumor Pain, and Dyspnea)	Up to 30 days after completion of study treatment
Pharmacokinetics (Cmax) of Flavopiridol	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.