Combination Chemotherapy in Treating Patients With Advanced Cancer

Phase I Study of Flavopiridol in Combination With 5-Fluorouracil, Leucovorin and Irinotecan in Patients With Advanced Malignancies

Phase I trial to study the effectiveness of combining flavopiridol, fluorouracil, and leucovorin with or without irinotecan in treating patients who have advanced cancer. Drugs used in chemotherapy 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: leucovorin calcium; Drug: fluorouracil; Drug: alvocidib; Drug: irinotecan hydrochloride

Detailed Description

OBJECTIVES:

I. Determine the maximum tolerated dose of flavopiridol, fluorouracil, and leucovorin calcium with or without irinotecan in patients with advanced malignancy.

II. Assess the toxic effects of these regimens in these patients. III. Determine the clinical response in patients treated with these regimens.

OUTLINE: This a dose-escalation study of flavopiridol (FLAVO), fluorouracil (5-FU), and irinotecan. Patients are assigned to 1 of 2 groups. Groups I and II are conducted sequentially.

Group I: Patients receive FLAVO IV over 24 hours on day 1 and leucovorin calcium (CF) IV and 5-FU IV over 1.5 hours daily on days 2-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of FLAVO and 5-FU until the maximum tolerated doses (MTD) are determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

Group II: Once the MTDs for FLAVO and 5-FU are determined, patients receive FLAVO, CF, and 5-FU as in group I plus irinotecan IV over 1.5 hours on day 1. Courses repeat as in group I. Cohorts of 3-6 patients receive escalating doses of irinotecan until the MTD is determined. The MTD is defined as in group I.

Patients are followed at 3 months.

PROJECTED ACCRUAL: A maximum of 57-90 patients will be accrued for this study within 18 months.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

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:

• Histologically confirmed malignancy

  • Unresectable tumor
  • No known standard therapy with curative potential or capability of extending life expectancy
• No untreated CNS metastases
• Performance status - ECOG 0-2
• At least 12 weeks
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 8 g/dL
• Direct bilirubin no greater than upper limit of normal (ULN)
• AST no greater than 3 times ULN (5 times ULN if liver metastases present)
• Creatinine no greater than 1.5 times ULN
• No New York Heart Association class III or IV heart disease
• No seizure disorder
• No uncontrolled infection
• No baseline diarrhea, defined as at least 4 loose or liquid stools/day
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• More than 4 weeks since prior biologic therapy
• More than 4 weeks since prior immunotherapy
• No concurrent immunotherapy
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and fully recovered from acute reversible effects
• No other concurrent chemotherapy
• More than 4 weeks since prior radiotherapy
• No prior radiotherapy to more than 25% of bone marrow
• No concurrent radiotherapy
• No other concurrent ancillary investigational therapy

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 (alvocidib, combination chemotherapy); Group I: Patients receive FLAVO IV over 24 hours on day 1 and CF IV and 5-FU IV over 1.5 hours daily on days 2-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of FLAVO and 5-FU until the MTD are determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Once the MTDs for FLAVO and 5-FU are determined, patients receive FLAVO, CF, and 5-FU as in group I plus irinotecan IV over 1.5 hours on day 1. Courses repeat as in group I. Cohorts of 3-6 patients receive escalating doses of irinotecan until the MTD is determined. The MTD is defined as in group I.

Drug: leucovorin calcium; Given IV; Other Names: CF; CFR; LV; Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Drug: alvocidib; Given IV; Other Names: FLAVO; flavopiridol; HMR 1275; L-868275; Drug: irinotecan hydrochloride; Given IV; Other Names: irinotecan; Campto; Camptosar; U-101440E; CPT-11

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number and severity of toxicity incidents of alvocidib, 5-fluorouracil, leucovorin calcium with and without irinotecan hydrochloride, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of responses (complete response, partial response, stable disease, and progressive disease) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)	Summarized by simple descriptive summary statistics.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Keith Bible, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: May 1, 2001
• Primary Completion (Actual): April 1, 2006

Study Registration Dates

• First Submitted: July 11, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): December 11, 2013
• Last Update Submitted That Met QC Criteria: December 10, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Growth Substances; Growth Inhibitors; Micronutrients; Protein Kinase Inhibitors; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Alvocidib
• Other Study ID Numbers: NCI-2012-02389 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 2450 (Other Identifier: CTEP); CDR0000068745; MAYO-MC0014; NCI-2450; MC0014 (Other Identifier: Mayo Clinic)