Combination Chemotherapy in Treating Patients With Advanced Solid Tumors

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

Phase I trial to study the effectiveness of combining alvocidib, irinotecan hydrochloride, and cisplatin in treating patients who have advanced solid tumors. 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: alvocidib; Drug: cisplatin; Drug: irinotecan hydrochloride

Detailed Description

OBJECTIVES:

I. Determine the maximum tolerated dose of flavopiridol (alvocidib), irinotecan (irinotecan hydrochloride), and cisplatin in patients with advanced solid tumors.

II. Determine the clinical pharmacokinetics of this regimen in these patients. III. Determine, preliminarily, the therapeutic activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients are stratified according to the number of prior treatment regimens (0 or 1 vs more than 1). Patients receive irinotecan hydrochloride intravenously (IV) over 30 minutes followed immediately by cisplatin IV over 30 minutes followed 7 hours later by alvocidib IV over 1-4.5 hours weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of cisplatin, alvocidib, and irinotecan hydrochloride until the maximum tolerated dose (MTD) of each is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 12 additional patients are treated at the recommended phase II dose.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • 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:

• Histologically confirmed locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists
• Evaluable disease
• No previously untreated CNS metastasis
• No primary CNS tumors
• Performance status - Karnofsky 60-100%
• Performance status - ECOG 0-2
• Not specified
• WBC at least 3,000/mm^3
• Neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Bilirubin no greater than 2.0 mg/dL
• AST and ALT no greater than 3 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance at least 60 mL/min
• No cardiac arrhythmia
• No congestive heart failure
• No myocardial infarction within the past 6 months
• HIV negative
• No neuropathy grade 2 or greater
• 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 4 weeks since prior immunotherapy
• At least 1 week since prior irinotecan and cisplatin alone
• At least 4 weeks since other prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• Not specified
• At least 4 weeks since prior radiotherapy
• Not specified
• Recovered from all prior therapy
• No concurrent vitamins, antioxidants, or herbal supplements except a daily multivitamin
• No other concurrent investigational drugs

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 (chemotherapy); Patients are stratified according to the number of prior treatment regimens (0 or 1 vs more than 1). Patients receive irinotecan hydrochloride IV over 30 minutes followed immediately by cisplatin IV over 30 minutes followed 7 hours later by alvocidib IV over 1-4.5 hours weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Drug: alvocidib; Given IV; Other Names: FLAVO; flavopiridol; HMR 1275; L-868275; Drug: cisplatin; Given IV; Other Names: CDDP; DDP; CACP; CPDD; Drug: irinotecan hydrochloride; Given IV; Other Names: irinotecan; Campto; Camptosar; U-101440E; CPT-11

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD alvocidib when administered in conjunction with irinotecan hydrochloride and cisplatin	Defined as the dose one level below the dose at which two or more of the patients in the initial cohort experience dose limiting toxicity (DLT) during the first treatment course. DLT is defined as the occurrence of Grade 4 hematologic toxicity, Grade 3 or 4 non-hematologic toxicity including diarrhea despite antidiarrheal prophylaxis, or any delay in treatment resulting in less than 2 treatments in 3 weeks.	Course 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pharmacokinetics of the regimen		Week 1 of courses 1 and 2
Therapeutic activity of alvocidib in combination with irinotecan hydrochloride in patients with advanced solid tumors	Evaluated using Response Evaluation Criteria In Solid Tumors (RECIST).	After 2 courses of treatment
Safety and tolerability	Evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. Tabulated individually, and summarized by body system, according to dosage of study medication.	Weekly

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Manish Shah, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: July 1, 2002
• Primary Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: October 3, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): February 24, 2014
• Last Update Submitted That Met QC Criteria: February 21, 2014
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Topoisomerase I Inhibitors; Irinotecan; Alvocidib
• Other Study ID Numbers: NCI-2009-00023 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA069856 (U.S. NIH Grant/Contract); P30CA008748 (U.S. NIH Grant/Contract); NCI-5700; CDR0000257034; MSKCC-02043; 02-043A (Other Identifier: Memorial Sloan-Kettering Cancer Center); 5700 (Other Identifier: CTEP); R01CA067819 (U.S. NIH Grant/Contract)