P. Bhargava et al., A phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer, CLIN CANC R, 5(8), 1999, pp. 1989-1995
A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients
with advanced cancer. TNP-470 (25-235 mg/m(2)) was administered i.v. over
4 h once a week to patients who had solid tumors refractory to the best ava
ilable treatment or with a high risk of recurrence and who had normal renal
, hepatic, and hematological function and no evidence of coagulopathy. The
aims of the study were to determine the maximum tolerated dose, dose-limiti
ng toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-w
eekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an
Eastern Cooperative Oncology Group performance status of 0-2 were treated.
The number of patients at each dose level (mg/m(2)) were 6 (25), 3 (50), 3
(75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of
TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in conc
entration and short-term memory, confusion, anxiety, and depression, which
occurred at doses of 133, 177, and 235 mg/m(2). Two patients treated at 235
mg/m(2) experienced DLT in the form of grade In cerebellar neurotoxicity a
fter 6 weeks of treatment. Overall, these neurological symptoms were dose-r
elated, had an insidious onset, progressively worsened with treatment, and
resolved completely within 2 weeks of stopping the drug. One patient with m
alignant melanoma had stabilization of the previously growing disease for 2
7 weeks while on the treatment. Two patients, one with adenocarcinoma of th
e colon and the other with a soft tissue sarcoma, had no clinically detecta
ble disease but were at high risk for recurrence at the initiation of treat
ment and received 13 months and >3 years of treatment, respectively, with n
o evidence of disease recurrence. The remaining patients had progression of
their disease after 1-6 months of treatment. The mean plasma half-life (t(
1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely sho
rt (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no
drug detectable in the plasma by 60 min after the end of the infusion. MII
, an inactive metabolite, had a considerably longer t(1/2) of approximately
2.6 h. Mean peak TNP-470 concentrations were greater than or equal to 400
ng/ml at doses greater than or equal to 177 mg/m(2). On the basis of this s
tudy, the maximum tolerated dose of TNP-470 administered on a weekly schedu
le was 177 mg/m(2) given i.v over 4 h. The principal DLT was neurotoxicity,
which appeared to be dose-related and was completely reversible. On the ba
sis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v.
infusion schedule is warranted.