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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 1

Conditions: Unspecified Adult Solid Tumor, Protocol Specific

Treatments: Drug: leucovorin calcium; Other: laboratory biomarker analysis; Drug: alvocidib; Drug: fluorouracil; Drug: irinotecan hydrochloride

Study type: Interventional

Funder types: NIH

Identifiers

NCT00042874

CDR0000069479

NCI-2012-01410

U01CA069856 (U.S. NIH Grant/Contract)

MSKCC-02024

5757

NCI-5757

Details and patient eligibility

About

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.

Full description

PRIMARY OBJECTIVES:

I. 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.

II. Determine the clinical pharmacokinetics of fluorouracil when administered in this regimen in these patients.

III. 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.

Enrollment: 77 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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77 participants in 1 patient group

Treatment (combination chemotherapy)

Experimental group

Description:

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.

Treatment:

Drug: irinotecan hydrochloride

Drug: fluorouracil

Drug: alvocidib

Other: laboratory biomarker analysis

Drug: leucovorin calcium