Expired Study
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Bethesda, Maryland 20892


Purpose:

Thymidylate synthase (TS), an enzyme which acts by utilizing 5,10-CH(2)FH(4) in the reductive methylation of deoxyuridylate (dUMP), is required for the de novo synthesis of thymidylate and is a potential chemotherapeutic target. ZD1694 is a new quinazolone folate analog that directly inhibits TS. This phase I trial and pharmacokinetic study will describe and define the toxicities, determine the MTD, and describe the plasma pharmacokinetics of ZD1694 in pediatric patients with refractory cancer. The starting dose for this trial will be 2.0 mg/m(2) administered as a 15 minute IV infusion every 21 days.


Study summary:

Thymidylate synthase (TS), an enzyme which acts by utilizing 5,10-CH(2)FH(4) in the reductive methylation of deoxyuridylate (dUMP), is required for the de novo synthesis of thymidylate and is a potential chemotherapeutic target. ZD1694 is a new quinazolone folate analog that directly inhibits TS. This phase I trial and pharmacokinetic study will describe and define the toxicities, determine the MTD, and describe the plasma pharmacokinetics of ZD1694 in pediatric patients with refractory cancer. The starting dose for this trial will be 2.0 mg/m(2) administered as a 15 minute IV infusion every 21 days.


Criteria:

DISEASE CHARACTERISTICS: Histologically proven malignancy considered refractory to standard therapy. Objective evidence of progression on prior therapy required. No leukemia. Bone marrow involvement by tumor acceptable. Marrow biopsy required if there is a history of involvement or peripheral counts are inadequate. PRIOR/CONCURRENT THERAPY: Biologic Therapy: Recovery from toxic effects of prior immunotherapy required. Chemotherapy: No more than 2 prior chemotherapy regimens and recovered. At least 2 weeks since myelosuppressive therapy (6 weeks since nitrosoureas). Endocrine Therapy: Not specified. Radiotherapy: No prior central axis irradiation (i.e., skull, spine, ribs, pelvis). Recovery from toxic effects of prior radiotherapy required. Surgery: Not specified. Other: No prior bone marrow transplantation. PATIENT CHARACTERISTICS: Age: 21 and under. Performance status: ECOG 0-2. Life expectancy: At least 8 weeks. Hematopoietic: (unless histologic evidence of bone marrow involvement by tumor). AGC at least 1,500/mm3. Platelet count at least 100,000/mm3. Hemoglobin at least 8.0 g/dL. Prior transfusion acceptable. Hepatic: Bilirubin no greater than 2 times normal. ALT no greater than 2 times normal. Renal: Creatinine less than 1.5 mg/dL OR Creatinine clearance greater than 60 mL/min/1.73 sqm. Cardiovascular: Not specified. Pulmonary: Not specified. OTHER: No significant accumulation of third space fluid. No significant systemic illness (e.g., infection). No pregnant or nursing women. Pregnancy test required in fertile women. All patients or their guardians must sign an informed consent.


Study is Available At:


Original ID:

930210


NCT ID:

NCT00001341


Secondary ID:

93-C-0210


Study Acronym:


Brief Title:

A Phase I Trial of ZD1694 (TOMUDEX), an Inhibitor of Thymidylate Synthase, in Pediatric Patients With Advanced Neoplastic Disease


Official Title:

A Phase I Trial of ZD1694 (TOMUDEX® (Registered Trademark)), an Inhibitor of Thymidylate Synthase, in Pediatric Patients With Advanced Neoplastic Disease


Overall Status:

Completed


Study Phase:

Phase 1


Genders:

Both


Minimum Age:

N/A


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Institutes of Health Clinical Center (CC)


Oversight Authority:

United States: Federal Government


Reasons Why Stopped:


Study Type:

Interventional


Study Design:

Endpoint Classification: Safety Study, Primary Pu


Number of Arms:

0


Number of Groups:

0


Total Enrollment:

60


Enrollment Type:


Study Dates

Start Date:September 1993
Completion Date:June 2001
Verification Date:August 2000
Last Changed Date:March 3, 2008
First Received Date:November 3, 1999

Study Outcomes

There are no available Study Outcomes

Study Interventions

Intervention Type:Drug
Name:ZD1694 (TOMUDEX)

Study Arms

There are no available Study Arms

Study Agencies

Agency Class:NIH
Agency Type:Lead Sponsor
Agency Name:National Cancer Institute (NCI)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Reference
Citation:Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR, Hughes LR. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res. 1991 Oct 15;51(20):5579-86.
PMID:1913676
Reference Type:Reference
Citation:Jackman AL, Marsham PR, Moran RG, Kimbell R, O'Connor BM, Hughes LR, Calvert AH. Thymidylate synthase inhibitors: the in vitro activity of a series of heterocyclic benzoyl ring modified 2-desamino-2-methyl-N10-substituted-5,8-dideazafolates. Adv Enzyme Regul. 1991;31:13-27. Review.
PMID:1877386
Reference Type:Reference
Citation:Cunningham D, Zalcberg JR, Rath U, Olver I, Van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G, et al. 'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group. Eur J Cancer. 1995 Nov;31A(12):1945-54.
PMID:8562146

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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