Study of ZD1839 Combined With Irinotecan and Vincristine in Pediatric Patients With Refractory Solid Tumors

A Phase I Study of ZD1839 (Iressa) in Combination With Irinotecan (Camptosar or CPT-11) and Vincristine in Pediatric Patients With Refractory Solid Tumors

The purpose of this protocol is to estimate the maximum tolerated dose of gefitinib in combination with fixed dose of irinotecan and vincristine in patients with refractory solid tumors.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Irinotecan, ZD1839, Vincristine, Cefixime, Cefpodoxime.

Detailed Description

Objectives of this study are:

• To determine the dose-limiting toxicities (DLT) of the combination of irinotecan and ZD1839 when given on this schedule.
• To characterize the pharmacokinetics and pharmacodynamics of gefitinib alone and in combination with irinotecan and vincristine.
• To estimate the maximum tolerated dose (MTD) of gefitinib in combination with escalating intravenous irinotecan by using selective intestinal decontamination with oral cefixime or cefpodoxime to prevent diarrhea.
• To estimate the MTD of vincristine (MTD) in combination with gefitinib and irinotecan.

Details of Treatment Interventions

First Cohort:

Standard dose escalation, starting at ZD1839 150 mg/m2/day for 21 days in combination with irinotecan 15mg/m2/day on a daily x 5 for two consecutive week schedule. Dose-limiting diarrhea was seen in this cohort. ZD scheduled was reduced to 12 days. The first dose level (1a) consisted of ZD1839 112.5mg/m2/day for 12 days + irinotecan 15mg/m2/day daily x 5 x 2 and was found to be the MTD in this cohort.

Second Cohort:

Cefixime then added at 4 additional subjects were enrolled at dose level 1c, consisting of ZD1839 at 112mg/m2/day + irinotecan 20mg/m2/day + cefixime 8 mg/kg/day administered once daily, beginning on day -1, and continued to day 14.

Third Cohort:

Irinotecan/ZD1839/Vincristine/Cefixime- Cefixime 8 mg/kg/day administered once daily, beginning on day -1, and continued to day 14, with a maximum dose of 400 mg daily + gefitinib 112.5 mg/m2 orally, daily for 12 days and irinotecan at 15 mg/m2 daily x 5 x 2 +1 mg/m2 (maximum 2mg/dose) on days 1 and 8 with escalating dose of VCR as tolerated.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Younger than 22 years of age.
• Histologic verification of solid tumor malignancy at original diagnosis.
• Has disease considered refractory to conventional therapy or no conventional therapy exists.
• Adequate performance status, bone marrow, liver and kidney function.
• Patients must not have had any previous allergic reactions to penicillin or cephalosporins

Exclusion Criteria:

• Known severe hypersensitivity to ZD1839 or any of the excipients of this product
• Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or St John's Wort, and CYP3A4 inhibitors
• Treatment with a non-approved or investigational drug within 30 days before Day 1 of trial treatment.
• Incomplete healing from previous oncologic or other major surgery
• Pregnant or breast-feeding
• Patients who have an uncontrolled infection
• Any evidence of clinically active interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded).
• As judged by the investigator, any evidence of uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease).
• Evidence of any other significant clinical disorder or laboratory finding that makes is undesirable for the subject to participate in the trial.

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
Other: 1	Drug: Irinotecan, ZD1839, Vincristine, Cefixime, Cefpodoxime.; See Detailed Description section for details of treatment interventions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose limiting toxicities	Within the first 30 days of completion of first cycle

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: AstraZeneca; National Institutes of Health (NIH)
• Investigators: Principal Investigator: Wayne Furman, M.D., St. Jude Children's Research Hospital

Publications and helpful links

General Publications

• A Phase I Study of Gefitinib and irinotecan (IRN) in pediatric patients with refractory solid tumors. WL Furman et al. Vol 22, No 14S (July 15 Supplement), 2004: 8521
• Effect of Gefitinib on the bioavailability of oral irinotecan in children with refractory solid tumors. K.R. Crews, W.L. Furman, J.C. Panetta, B.B. Freeman, L.C. Iacono, P.J. Houghton, C.F. Stewart. Proceeding of ASCO. Vol 22, No 14S, 2004:2012.
• Effect of gefitinib on the systemic dispositon of intravenous irinotecan (IRN) in pediatric patients with refractory solid tumors. L.C. Iacono, W.L. Furman, K.R. Crews, J.C. Panetta, B.B. Freeman, N.C. Daw, C.F. Stewart. Proceedings of ASCO. Vol 22, No 14S, 2004:2011.

Helpful Links

• St. Jude Children's Research Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2003
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): April 26, 2017
• Last Update Submitted That Met QC Criteria: April 24, 2017
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: Refractory Childhood Solid Tumors
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Topoisomerase I Inhibitors; Gefitinib; Irinotecan; Vincristine; Cefpodoxime; Cefpodoxime proxetil; Cefixime
• Other Study ID Numbers: ZD1839

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No