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

Neoplasm Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00001341
• Other study ID #: 930210
• Secondary ID: 93-C-0210
• Status: Completed
• Phase: Phase 1
• First received: November 3, 1999
• Last updated: March 3, 2008
• Start date: September 1993
• Est. completion date: June 2001

Study information

• Verified date: August 2000
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: June 2001
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Endpoint Classification: Safety Study, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neoplasm
• Neoplasms

Intervention

Drug:
• ZD1694 (TOMUDEX)

Locations

Country	Name	City	State
United States	National Cancer Institute (NCI)	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation