Clinical trial NCT00072436: Gemcitabine Hydrochloride and Alvocidib in Treating Patients With Solid Tumors
Official title: A Phase I Trial of Gemcitabine Followed by a Short Infusion of Flavopiridol in Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-11-06
Enrollment: 58
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 gemcitabine hydrochloride and alvocidib in treating patients with solid tumors. Drugs used in chemotherapy, such as gemcitabine hydrochloride and alvocidib, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells

Detailed description: PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of gemcitabine and flavopiridol in patients with solid tumors.

SECONDARY OBJECTIVES:

I. Determine the safety profile and toxic effects of this regimen in these patients.

II. Determine the pharmacokinetics of flavopiridol with and without gemcitabine in these patients.

III. Determine, using pharmacodynamic assays, the activity of flavopiridol as a cdk inhibitor in these patients.

IV. Determine, using pharmacodynamic assays, the markers of this regimen in these patients.

OUTLINE: This is a dose-escalation, multicenter study.

Some patients receive an initial dose of alvocidib IV over 1-7 hours on day 1 (course 0). Beginning 1 week later and for all subsequent courses, all patients receive gemcitabine hydrochloride IV over 60-150 minutes on days 1 and 15 and alvocidib IV over 1-7 hours on days 2 and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gemcitabine hydrochloride and alvocidib 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. Once the MTD is determined, up to 10 additional patients receive treatment at that dose.

Patients are followed at 30 days after study completion.

Eligibility criteria: Inclusion Criteria:

* Negative pregnancy test
* Fertile patients must use effective contraception
* No active infection
* No severe malnutrition
* No more than 2 prior chemotherapy regimens:

  * Prior combined modality therapy (e.g., full-dose chemotherapy with radiosensitizing chemotherapy and radiotherapy) is considered 1 prior regimen if all therapy was delivered as part of 1 comprehensive treatment plan
* More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
* No other concurrent chemotherapy
* At least 6 months since prior radiotherapy to the lung parenchyma or mediastinum and no evidence of radiation pneumonitis on chest CT scan
* At least 4 weeks since other prior radiotherapy and recovered
* No prior radiotherapy to more than 50% of marrow volume
* No concurrent radiotherapy
* Histologically confirmed solid tumor for which gemcitabine is a treatment option OR for which no efficacious therapy exists
* Must meet criteria for 1 of the following:

  * Measurable disease:

    * At least 1 unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
  * Nonmeasurable disease, including any of the following:

    * Small lesions (less than 20 mm by conventional techniques OR less than 10 mm by spiral CT scan)
    * Bone lesions
    * Cytologically positive pleural or peritoneal disease
    * Elevated tumor markers (e.g., carcinoembryonic antigen, CA 125, CA 19-9, or other tumor marker)
    * Multinodular or confluent nonmeasurable pulmonary, hepatic, adrenal, intra-abdominal, or skin metastases
    * No active CNS metastases
    * Previously treated CNS metastases must be stable with no symptoms for 4 weeks after completion of treatment AND patient must be off steroid therapy or on a stable dose for at least the past 2 weeks
    * No known leptomeningeal metastases
* Performance status:

  * ECOG 0-1
* Hematopoietic:

  * Absolute neutrophil count at least 1,500/mm3;
  * Platelet count at least 100,000/mm3
* Hepatic:

  * Bilirubin no greater than 1.5 mg/dL;
  * SGOT no greater than 2.5 times upper limit of normal
* Renal:

  * Creatinine no greater than 1.5 mg/dL OR
  * Creatinine clearance at least 50 mL/min
* Cardiovascular:

  * None of the following within the past 6 months:

    * Myocardial infarction;
    * Unstable angina;
    * Transient ischemic attack;
    * Cerebrovascular accident

      * No new cardiac arrhythmia possibly related to cardiac ischemia;
      * No large and potentially symptomatic pericardial effusion;
      * No cardiac disease that would preclude study participation
* Pulmonary:

  * No pulmonary embolism within the past 6 months;
  * No large and potentially symptomatic pleural effusion;
  * No pulmonary disease that would preclude study participation
* Gastrointestinal:

  * No intractable emesis;
  * No grade 2 or greater chronic diarrheal disease within the past 6 months
* Not pregnant or nursing

Primary outcomes:
measure: Dose-limiting toxicity (DLT) graded by National Cancer Institute (NCI) Common Toxicity Criteria
timeFrame: 28 days
measure: Maximum tolerated dose, defined as one dose level below the dose that induces DLT in more than 1/6 patients
timeFrame: 28 days
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Geoffrey Shapiro
role: PRINCIPAL_INVESTIGATOR
References: