Clinical trial NCT00070239: Alvocidib in Treating Patients With Metastatic or Unresectable Refractory Solid Tumors or Hematologic Malignancies
Official title: A Phase I Clinical, Pharmacokinetic and Pharmacodynamic Study of Flavopiridol in Patients With Refractory Solid Tumors and Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hematopoietic/Lymphoid Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-10-07
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I trial is studying the side effects and best dose of alvocidib in treating patients with metastatic or unresectable refractory solid tumors or hematologic malignancies. Drugs used in chemotherapy, such as alvocidib, work in different ways to stop cancer cells from dividing so they stop growing or die.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Dose-limiting toxicity (DLT)
timeFrame: 28 days
measure: 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
timeFrame: 28 days
Secondary outcomes:
measure: Pharmacokinetic parameters, including maximum concentration (Cmax), half-life, area under the curve (AUC), clearance, and volume of distribution
timeFrame: 24 hours, 48 hours, 72 hours, and 8 weeks
measure: Potency of alvocidib in plasma based on change in proliferation of stimulated peripheral blood mononuclear cells (PBMCs)
timeFrame: Baseline to up to 72 hours of day 1 course 1
measure: Change in tumor metabolism and proliferation assessed by fludeoxyglucose F 18 (FDG) and fluorine F 18 fluorothymidine (FLT) positron emission tomography (PET)
timeFrame: Baseline to up to day 19 of course 2
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Geoffrey Shapiro
role: PRINCIPAL_INVESTIGATOR
References: