Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Flavopiridol in Treating Patients With Metastatic or Unresectable Refractory Solid Tumors or Hematologic Malignancies

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Temporarily closed	18 and over	NCI	DFCI-03082 NCI-6052, NCT00070239, 6052

Objectives

Primary

1. 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

1. Determine the safety profile and toxic effects of this drug in these patients.
2. Determine the pharmacokinetics of this drug in these patients.
3. 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.
4. Determine, preliminarily, the antitumor activity of this drug in these patients.

Entry 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

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

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/mm³*
• Platelet count > 75,000/mm³ (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

Expected Enrollment

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

Outcomes

Maximum tolerated dose assessed every 28 days

Antitumor activity of flavopiridol as measured by CT, MRI, or positron-emission test (PET) scans at every other course

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.

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.

Trial Contact Information

Trial Lead Organizations

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Geoffrey Shapiro, MD, PhD, Principal investigator		Ph: 617-632-4942; 866-790-4500 Email: geoffrey_shapiro@dfci.harvard.edu

Registry Information
Official Title		A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Novel Flavopiridol in Patients With Refractory Solid Tumors and Hematologic Malignancies
Trial Start Date		2003-10-03
Trial Completion Date		2006-06-29 (estimated)
Registered in ClinicalTrials.gov		NCT00070239
Date Submitted to PDQ		2003-08-21
Information Last Verified		2008-06-01
NCI Grant/Contract Number		CA06516, CA62490

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