Gemcitabine Hydrochloride and Alvocidib in Treating Patients With Solid Tumors

A Phase I Trial of Gemcitabine Followed by a Short Infusion of Flavopiridol in Patients With Solid Tumors

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

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: alvocidib; Other: pharmacological study; Drug: gemcitabine hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; 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 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.

Drug: alvocidib; Given IV; Other Names: FLAVO; flavopiridol; HMR 1275; L-868275; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; gemcitabine; dFdC; difluorodeoxycytidine hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose-limiting toxicity (DLT) graded by National Cancer Institute (NCI) Common Toxicity Criteria	28 days
Maximum tolerated dose, defined as one dose level below the dose that induces DLT in more than 1/6 patients	28 days

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Geoffrey Shapiro, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start: September 1, 2003
• Primary Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: November 4, 2003
• First Submitted That Met QC Criteria: November 5, 2003
• First Posted (Estimate): November 6, 2003

Study Record Updates

• Last Update Posted (Estimate): July 2, 2013
• Last Update Submitted That Met QC Criteria: July 1, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Gemcitabine; Alvocidib
• Other Study ID Numbers: NCI-2009-00038; U01CA062490 (U.S. NIH Grant/Contract); P30CA006516 (U.S. NIH Grant/Contract); 6051; CDR0000339727 (Registry Identifier: PDQ (Physician Data Query))