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Flavopiridol in Treating Patients With Metastatic or Unresectable Refractory Solid Tumors or Hematologic Malignancies
This study has been suspended.
First Received: October 3, 2003   Last Updated: January 28, 2009   History of Changes
Sponsor: Dana-Farber Cancer Institute
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00070239
  Purpose

RATIONALE: Drugs used in chemotherapy, such as flavopiridol, work in different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: This phase I trial is studying the side effects and best dose of flavopiridol in treating patients with metastatic or unresectable refractory solid tumors or hematologic malignancies.


Condition Intervention Phase
Breast Cancer
Head and Neck Cancer
Intraocular Melanoma
Kidney Cancer
Leukemia
Lung Cancer
Lymphoma
Malignant Mesothelioma
Melanoma (Skin)
Multiple Myeloma and Plasma Cell Neoplasm
Sarcoma
Small Intestine Cancer
Drug: alvocidib
Phase I

Study Type: Interventional
Study Design: Treatment
Official Title: A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Novel Flavopiridol in Patients With Refractory Solid Tumors and Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose assessed every 28 days [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Antitumor activity of flavopiridol as measured by CT, MRI, or positron-emission test (PET) scans at every other course [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: October 2003
Estimated Primary Completion Date: June 2006 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • 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

  • Determine the safety profile and toxic effects of this drug in these patients.
  • Determine the pharmacokinetics of this drug in these patients.
  • 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.
  • 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 flavopiridol IV over 1 hour on days 1, 8, and 15.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD)* is determined.

  • Part 2: Patients receive flavopiridol IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of flavopiridol IV over 1-6 hours on days 1, 8, and 15.

Cohorts of 3-6 patients receive escalating durations of the maintenance dose of flavopiridol until the MTD* is determined. An additional cohort of 10-20 patients receives flavopiridol 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.

PROJECTED ACCRUAL: Approximately 3-80 patients will be accrued for this study within 1-4 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • 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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Prior biologic therapy (e.g., monoclonal antibody therapy, immunologic therapies, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, or other investigational agents) allowed
  • At least 4 weeks since prior monoclonal antibody therapy

Chemotherapy

  • See Disease Characteristics
  • At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

Endocrine therapy

  • See Disease Characteristics

Radiotherapy

  • See Disease Characteristics
  • At least 3 weeks since prior radiotherapy
  • No prior radiotherapy to 50% or more of bone marrow

Surgery

  • Not specified

Other

  • Recovered from all prior therapy
  • No other concurrent investigational agents
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00070239

Locations
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Dana-Farber Cancer Institute
Investigators
Principal Investigator: Geoffrey Shapiro, MD, PhD Dana-Farber Cancer Institute
  More Information

Additional Information:
Publications:
Di Vizio D, O'Connell FP, Bhattacharya N, et al.: Pharmacodynamic assessment of the cyclin-dependent kinase inhibitor flavopiridol: modulation of cdk targets in clinical samples. [Abstract] Lab Invest 85 (Suppl 1): A-1375, 297A, 2005.
Di Vizio D, O'Connell FP, Bhattacharya N, et al.: Pharmacodynamic assessment of the cyclin-dependent kinase inhibitor flavopiridol: modulation of cdk targets in clinical samples. [Abstract] Mod Pathol 18 (Suppl 1): A-1375, 297A, 2005.

Study ID Numbers: CDR0000331689, DFCI-03082, NCI-6052
Study First Received: October 3, 2003
Last Updated: January 28, 2009
ClinicalTrials.gov Identifier: NCT00070239     History of Changes
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
stage IV mantle cell lymphoma
recurrent mantle cell lymphoma
recurrent breast cancer
stage IV breast cancer
extensive stage small cell lung cancer
limited stage small cell lung cancer
recurrent squamous cell carcinoma of the lip and oral cavity
stage IV squamous cell carcinoma of the lip and oral cavity
recurrent squamous cell carcinoma of the paranasal sinus and nasal cavity
stage IV squamous cell carcinoma of the paranasal sinus and nasal cavity
metastatic squamous neck cancer with occult primary squamous cell carcinoma
recurrent metastatic squamous neck cancer with occult primary
salivary gland squamous cell carcinoma
stage IV salivary gland cancer
recurrent salivary gland cancer
recurrent squamous cell carcinoma of the hypopharynx
stage IV squamous cell carcinoma of the hypopharynx
recurrent squamous cell carcinoma of the larynx
stage IV squamous cell carcinoma of the larynx
recurrent squamous cell carcinoma of the nasopharynx
recurrent squamous cell carcinoma of the oropharynx
stage IV squamous cell carcinoma of the nasopharynx
stage IV squamous cell carcinoma of the oropharynx
recurrent small cell lung cancer
refractory chronic lymphocytic leukemia
recurrent renal cell cancer
stage III renal cell cancer
stage IV renal cell cancer
epithelial mesothelioma
recurrent malignant mesothelioma

Additional relevant MeSH terms:
Thoracic Neoplasms
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urogenital Neoplasms
Urologic Neoplasms
Protein Kinase Inhibitors
Ileal Diseases
Duodenal Neoplasms
Neoplasms, Connective and Soft Tissue
Hemorrhagic Disorders
Neoplasms by Site
Lung Neoplasms
Therapeutic Uses
Cardiovascular Diseases
Kidney Diseases
Breast Diseases
Digestive System Neoplasms
Immunoproliferative Disorders
Eye Neoplasms
Immune System Diseases
Hematologic Diseases
Breast Neoplasms
Carcinoma
Multiple Myeloma
Neuroectodermal Tumors
Neoplasms
Lung Diseases
Sarcoma
Gastrointestinal Neoplasms
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on November 11, 2009