Doselimiting Toxicities And Determination Of Maximumtolerated Dose

DLTs were reported for three of 32 prostate cancer patients, two of 21 cervical cancer patients, and five of 68 solid tumor patients. Excepting one report of hemoptysis (grade 1), which occurred in a patient with NSCLC with a history of similar episodes, all were neurological in nature. DLTs involving complaints of gait and coordination disturbances, memory impairment, increased anxiety, and emotional lability were observed in three prostate cancer patients at two dose levels, 70.6 (two patients) and 105.9 (one patient) mg/m2. In two cases, the DLTs presented within the first 3 wk of treatment; in one case they were delayed and reported after the 2-wk rest period. Two cervical cancer patients experienced DLTs following treatment at 71 mg/m2 for 4 wk; these consisted of gait disturbance as well as dizziness and nystagmus. In the solidtumor study administering TNP-470 every MWF, a single DLT (grade 1 unsteadiness) was reported in a patient with melanoma after 102 d of treatment at 32.4 mg/m2. The cohort was expanded, but no additional DLTs were reported at that dose level. However, at 76.5 mg/m2, two patients experienced DLTs. In one case, a prostate cancer patient had complaints of grade 3 gait disturbance and nystagmus after 40 d of treatment. The second patient had complaints of grade 1 hemoptysis. Finally, in the solidtumor study using a once weekly schedule, two patients experienced dizziness, grades 1 or 2, after 52, or 78 d of treatment at 235 mg/m2, respectively.

Patients experiencing DLTs were evaluated utilizing radiographic and neuropsycho-logic assessments. Findings were negative for CT scans and MRIs, but psychometric testing showed effects on cognitive function and affect. In most cases, resolution of the DLTs occurred within several weeks, and, in all cases, the DLTs were reversible.

MTDs were determined in each of the four phase I studies. Two studies (prostate and cervical cancer) used the same dosing regimen, i.e., 1-h infusion qod for 28 d, followed by a 14-d rest period, and these MTDs were 47.1 and 60.0 mg/m2, respectively. When TNP-470 was administered as a 1-h infusion every MWF in the absence of a rest period, the MTD was 57.4 mg/m2. Extending the infusion to 4 h, and administering TNP-470 once weekly, resulted in an MTD of 177 mg/m2.

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