- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00070239
Alvocidib in Treating Patients With Metastatic or Unresectable Refractory Solid Tumors or Hematologic Malignancies
A Phase I Clinical, Pharmacokinetic and Pharmacodynamic Study of Flavopiridol in Patients With Refractory Solid Tumors and Hematologic Malignancies
Study Overview
Status
Detailed Description
PRIMARY OBJECTIVE:
I. Determine the maximum tolerated dose of flavopiridol in patients with metastatic or unresectable refractory solid tumors or hematologic malignancies. (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04)
SECONDARY OBJECTIVES:
I. Determine the safety profile and toxic effects of this drug in these patients.
II. Determine the pharmacokinetics of this drug in these patients. III. Determine, by pharmacodynamic assays, the ability of this drug to inhibit cyclin-dependent kinase activity in tumor tissue, normal proliferating tissues, circulating tumor cells, and in plasma in these patients.
IV. Determine, preliminarily, the antitumor activity of this drug in these patients.
OUTLINE: This is a 2-part, dose-escalation, multicenter study.
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of alvocidib until the maximum tolerated dose (MTD)* is determined.
PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD.
NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients are followed at 1 month and then every 2 months thereafter.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
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Massachusetts
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Boston, Massachusetts, United States, 02115
- Dana-Farber Cancer Institute
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Histologically confirmed malignancy, including the following types:
- Hematologic malignancy, including any of the following: (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04)
- Mantle cell lymphoma
- Morphologically confirmed disease
- CD20 and CD5 positive
- Any other refractory lymphoma
- Chronic lymphocytic leukemia
Rai stage III or IV and meeting at least 1 of the following criteria for active disease:
- Weight loss > 10% in the last 6 months
- Fatigue
- Fever or night sweats with no evidence of infection
- Progressive anemia or thrombocytopenia
- Progressive lymphocytosis with a lymphocyte doubling time of < 6 months
- Marked hypogammaglobulinemia or paraproteinemia
- Progressive splenomegaly and/or lymphadenopathy
- Multiple myeloma
- Disease confirmed by bone marrow aspirate and/or biopsy
- Relapsed or refractory disease after the most recent treatment regimen
- Quantifiable monoclonal immunoglobulin in serum and/or urine
Solid tumor, including but not limited to any of the following:
- Breast cancer
- Histologically or cytologically confirmed stage IV invasive disease
- HER-2 positivity not required for study enrollment
- Tumor overexpressing HER-2 should be confirmed by immunohistochemistry OR fluorescence in situ hybridization
- Small cell lung cancer
- Extensive stage or limited stage disease in relapse
- Extrapulmonary small cell carcinoma allowed
- Squamous cell carcinoma of the head and neck
- Metastatic, recurrent, or refractory disease
- Renal cell carcinoma
- Mesothelioma
- Pleural or peritoneal disease of epithelial, sarcomatoid, or mixed subtype
- Melanoma
- Kaposi's sarcoma
- Metastatic or unresectable disease for which standard therapy does not exist or is no longer effective
- Measurable or nonmeasurable disease (solid tumor patients)
- Measurable disease defined as at least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or 10 mm by spiral CT scan
Nonmeasurable disease includes any of the following:
- All other lesions, including lesions < 20 mm by conventional techniques or 10 mm by spiral CT scan
- Bone lesions
- Cytologically positive pleural or peritoneal disease
- Elevated tumor marker (e.g., CEA, CA 125, CA 19-9, or other tumor marker)
- Multinodular or confluent nonmeasurable pulmonary, hepatic, adrenal, intra-abdominal, or skin metastases
- Previously treated with at least 1 chemotherapy regimen*
- Prior therapy may have included combined modality treatment (e.g., full-dose chemotherapy and radiotherapy with radiosensitizing chemotherapy)
- Prior therapy with flavopiridol allowed provided the patient was enrolled in a flavopiridol clinical trial employing a different schedule NOTE: *Except in cases where chemotherapy is not known to be effective (e.g., renal cell carcinoma, chondrosarcoma, or gastrointestinal stromal tumor)
- No active CNS metastases
History of CNS metastases allowed provided all of the following criteria are met:
- Previously treated and stable and asymptomatic for at least 4 weeks since the completion of treatment
- Image documentation required
- Off steroids or on a stable dose of steroids for at least 1 week
Hormone receptor status:
- Not specified
Age
- 18 and over
Sex
- Male or female
Menopausal status
- Not specified
Performance status
- ECOG 0-1 OR
- Karnofsky 70-100%
Life expectancy
- More than 12 weeks
Hematopoietic
- Absolute neutrophil count > 1,000/mm^3*
- Platelet count > 75,000/mm^3 (50,000 for hematologic malignancies)* (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04) NOTE: *Unless abnormality is caused by tumor burden and not cumulative prior chemotherapy
Hepatic
- Bilirubin normal
- AST/ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
Renal
- Creatinine ≤ 2.0 mg/dL OR
- Creatinine clearance ≥ 60 mL/min
Cardiovascular
- No myocardial infarction within the past 6 months
- No unstable angina within the past 6 months
- No transient ischemic attack or cerebrovascular accident within the past 6 months
- No history of arterial vascular events
- No new cardiac arrhythmias likely to be related to cardiac ischemia within the past 6 months
- No symptomatic congestive heart failure
Pulmonary
- No history of pulmonary embolism within the past 6 months
Gastrointestinal
- No chronic diarrheal disease within the past 6 months
- No severe malnutrition
- No intractable emesis
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective hormonal or barrier contraception
- No ongoing or active infection
- No other concurrent uncontrolled illness
- No psychiatric illness or social situation that would preclude study compliance
- At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
- At least 3 weeks since prior radiotherapy No prior radiotherapy to 50% or more of bone marrow
- Recovered from all prior therapy No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating doses of alvocidib until the MTD* is determined. PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD. NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
Given IV
Other Names:
Correlative studies
Other Names:
Correlative studies
Other Names:
Correlative studies
Other Names:
Correlative studies
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Dose-limiting toxicity (DLT)
Time Frame: 28 days
|
28 days
|
MTD (or recommended phase II dose), defined as one dose level below that which produces two instances of DLT during the first 28-day course and the level at which no more than one of six patients experiences DLT during course 1
Time Frame: 28 days
|
28 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacokinetic parameters, including maximum concentration (Cmax), half-life, area under the curve (AUC), clearance, and volume of distribution
Time Frame: 24 hours, 48 hours, 72 hours, and 8 weeks
|
Determined by nonlinear regression analysis of geometric mean plasma profile.
Cmax in patients w/stable disease or response at 8 weeks compared to those who progressed using Mann-Whitney test.
Wilcoxon signed-rank test to compare concentration and metabolic ratios directly following infusion and 24, 48, 72 hrs later.
Concentration and metabolic ratios compared in patients w/ and w/o toxicities of diarrhea, neutropenia, and asthenia using Mann- Whitney test.
Fisher's exact test to assess association of flavopiridol systemic metabolism (low vs. high metabolic ratio) w/development of toxicity.
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24 hours, 48 hours, 72 hours, and 8 weeks
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Potency of alvocidib in plasma based on change in proliferation of stimulated peripheral blood mononuclear cells (PBMCs)
Time Frame: Baseline to up to 72 hours of day 1 course 1
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Baseline to up to 72 hours of day 1 course 1
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Change in tumor metabolism and proliferation assessed by fludeoxyglucose F 18 (FDG) and fluorine F 18 fluorothymidine (FLT) positron emission tomography (PET)
Time Frame: Baseline to up to day 19 of course 2
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Each type of pre- and post-treatment scans may be analyzed as paired data.
The FDG and FLT data will be correlated to explore the relationship between tumor metabolism and tumor proliferation, for example, using Pearson or Spearman correlation coefficient.
|
Baseline to up to day 19 of course 2
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Geoffrey Shapiro, Dana-Farber Cancer Institute
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms
- Neoplasms by Site
- Hematologic Diseases
- Hematologic Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Growth Substances
- Growth Inhibitors
- Radiopharmaceuticals
- Protein Kinase Inhibitors
- Fluorodeoxyglucose F18
- Alvocidib
Other Study ID Numbers
- NCI-2009-00039 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- 03-082 (Dana-Farber Cancer Institute)
- P 6052
- CDR0000331689
- 6052 (CTEP)
- U01CA062490 (U.S. NIH Grant/Contract)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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