Overview Of Clinical Trial Experience

Clinical trial experience with TNP-470 presently includes seven phase I and five phase II studies, in which more than 300 patients have been treated. All except one phase I study (pediatric malignancies) are for adult patient populations, including individual phase I studies in patients with hormone-refractory prostate cancer and cervical cancer, two in patients with solid tumors and two in AIDS-associated Kaposi's sarcoma (KS) patients. Three of these studies have concluded (prostate, cervical, and AIDS-associated KS), but the two solid tumor, one AIDS-associated KS and the pediatric study are ongoing. Phase II patient populations are limited to glioblastoma multiforme, locally advanced pancreatic cancer, and advanced breast, cervical, and renal cancer. Approximately two-thirds of the total number of patients exposed to TNP-470 derive from the phase I experience, and these are the data that will be discussed in this chapter. Findings in the pediatric phase I study are preliminary and will not be included, however. Nor will findings for the two phase I studies in AIDS-associated KS patients (47), since these data reside with the institutional sponsors, and at present are not included in the TNP-470 database.

The dosing regimens employed in the phase I studies varied in both the duration and frequency of administration of TNP-470. E ither a 1- or 4-h iv infusion was used. The latter was administered once weekly; the 1-h infusion was given once weekly or multiple times (either every other day [qod] or on a Monday, Wednesday, and Friday schedule [MWF]) per week. The final difference in dosing regimens is the inclusion of a rest period between treatment cycles. Maximum-tolerated doses (MTD) and dose-limiting toxicities (DLT) have been determined in all cases, with the exception of the 1-h once weekly schedule. The dosing regimen that has been taken into the initial phase II studies is 1-h, every MWF, and does not incorporate a rest period. The individual phase I study dosing regimens are summarized below:

Prostate cancer: 1-h, qod for 28 d, followed by a 14-d rest period Cervical cancer: 1-h, qod for 28 d, followed by a 14-d rest period Solid tumor: 1-hr, MWF, no rest period Pediatric cancer: 1-h, MWF, no rest period AIDS-associated KS: 1-h, qod, no rest period

AIDS-associated KS: 1-h, once weekly for 12 wk, followed by a 2-wk rest period Solid tumor: 4-h, once weekly, no rest period

The data presented in the remainder of this chapter derive from four adult patient phase I studies (prostate, cervical, and two solid tumor), and represent findings for a total of 121 patients.

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