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

NCT00001341 | Completed Phase 1

• 2 other identifiers: 93021093-C-0210
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Neoplasm

Keywords

Antifolate; Inhibitor; Pharmacokinetics; Thymidylate Synthetase; Toxicity

Interventions

ZD1694 (TOMUDEX) DRUG

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Cancer Institute (NCI)

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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 BACKGROUND

• 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. doi: 10.1016/0065-2571(91)90006-8.

  PMID: 1877386 BACKGROUND

• 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. doi: 10.1016/0959-8049(95)00502-1.

  PMID: 8562146 BACKGROUND

MeSH Terms

Conditions

Neoplasms

Interventions

raltitrexed

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: December 10, 2002
• Study Start: September 1, 1993
• Study Completion: June 1, 2001
• Last Updated: March 4, 2008

Record last verified: 2000-08

Locations

US (1)