Clinical trial NCT00001341: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasm
Keywords: Antifolate
Inhibitor
Pharmacokinetics
Thymidylate Synthetase
Toxicity
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2002-12-10
Enrollment: 60
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Cancer Institute (NCI)
state: Maryland
Study officials:
References:
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.
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. doi: 10.1016/0065-2571(91)90006-8.
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. doi: 10.1016/0959-8049(95)00502-1.