Combination Chemotherapy in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00042874

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

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. This phase I trial is studying the side effects and best dose of combination chemotherapy in treating patients with locally advanced or metastatic solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: alvocidib Drug: irinotecan hydrochloride Drug: fluorouracil Drug: leucovorin calcium Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

Determine the maximum tolerated dose of flavopiridol (alvocidib) when administered with irinotecan hydrochloride, fluorouracil, and leucovorin calcium in patients with locally advanced or metastatic solid tumors.
Determine the clinical pharmacokinetics of fluorouracil when administered in this regimen in these patients.
Determine, preliminarily, the therapeutic activity of this regimen in these patients.Correlate the role of p21 and Drg1 with apoptosis and treatment response in patients receiving this regimen.

OUTLINE: This is a dose-escalation study of alvocidib and fluorouracil (5-FU).

Patients receive irinotecan hydrochloride IV over 90 minutes followed 5 hours later by leucovorin calcium IV over 2 hours and alvocidib IV over 1 hour immediately followed by 5-FU IV continuously over 48 hours beginning on day 1 of weeks 1, 3, and 5. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of alvocidib and 5-FU 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. Ten additional patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 27-77 patients will be accrued for this study within 11-38 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

77 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Labeled, Non-Randomized Phase I Study of Alvocidib (Flavopiridol) Administered With Irinotecan (CPT-11) and Fluorouracil/Leucovorin in Patients With Advanced Solid Tumors

Study Start Date :

May 1, 2002

Actual Primary Completion Date :

Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (combination chemotherapy) Patients receive irinotecan hydrochloride IV over 90 minutes followed 5 hours later by leucovorin calcium IV over 2 hours and alvocidib IV over 1 hour immediately followed by 5-FU IV continuously over 48 hours beginning on day 1 of weeks 1, 3, and 5. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of alvocidib and 5-FU 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. Ten additional patients are treated at the MTD.	Drug: alvocidib Given IV Other Names: FLAVO flavopiridol HMR 1275 L-868275 Drug: irinotecan hydrochloride Given IV Other Names: Campto Camptosar CPT-11 irinotecan U-101440E Drug: fluorouracil Given IV Other Names: 5-fluorouracil 5-Fluracil 5-FU Drug: leucovorin calcium Given IV Other Names: CF CFR LV Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (combination chemotherapy)

Drug: alvocidib

Given IV

Other Names:

FLAVO

flavopiridol

HMR 1275

L-868275

Drug: irinotecan hydrochloride

Given IV

Other Names:

Campto

Camptosar

CPT-11

irinotecan

U-101440E

Drug: fluorouracil

Given IV

Other Names:

5-fluorouracil

5-Fluracil

5-FU

Drug: leucovorin calcium

Given IV

Other Names:

CFR

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

MTD of biweekly flavopiridol when given in conjunction with irinotecan hydrochloride, fluorouracil, and leucovorin [8 weeks]

Secondary Outcome Measures

Clinical pharmacokinetics of the regimen under investigation [Day 1, prior to flavopiridol infusion (t=3:30hr), post flavopiridol infusion (t=4:30hr), prior to flavopiridol infusion (t=3:30hr), post 30 minute flavopiridol bolus (t=4:00), post 4 hour flavopiridol infusion (t=8:00hr)]
Therapeutic activity of flavopiridol in combination with irinotecan hydrochloride in patients with advanced solid tumors [Up to 7 years]
Change in molecular marker expression [Baseline to 2 weeks post-treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed locally advanced or metastatic solid tumor
Refractory to standard therapy or for which there is no standard therapy
Preference given to colorectal cancer, upper gastrointestinal cancer, or neuroendocrine tumors
Evaluable disease
No CNS metastases or primary CNS malignancy
Performance status - Karnofsky 60-100%
WBC at least 3,500/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Bilirubin no greater than 1.5 mg/dL
AST and ALT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
Creatinine no greater than 1.5 mg/dL
No history of cardiac arrhythmia
No congestive heart failure
No myocardial infarction within the past 6 months
No prior grade 3 or 4 diarrhea secondary to irinotecan, despite optimal antidiarrheal prophylaxis
HIV negative
No serious or uncontrolled infection
No other medical condition or reason that would preclude study participation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for at least 2 months after study participation
At least 2 weeks since prior immunotherapy
No more than 2 prior chemotherapy regimens unless there is no evidence of significant myelotoxicity as determined by the primary investigator
At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin)
Prior irinotecan and fluorouracil allowed
At least 2 weeks since prior radiotherapy
Recovered from all prior therapy
No other concurrent investigational medications
No concurrent vitamins, antioxidants, or herbal preparations or supplements except a single daily multivitamin