The efficacy criteria that are commonly applied to oncology clinical trials may not be appropriate for antiangiogenesis agents such as TNP-470. This is because response criteria assume that the result of a chemotherapeutic intervention will be tumor regression. Under these conditions, positive outcomes are limited to either a partial (PR) or complete response (CR), and exclude stable disease. However, TNP-470 may be tumoristatic, not cytotoxic. Treatment resulting in a slowing of tumor growth could present as disease stabilization, which has traditionally been regarded as treatment failure.

The phase I experience with TNP-470, described in detail in Section 8., reflects this situation. Seven patients experienced disease stabilization of at least 5 mo duration, and one cervical cancer patient had a CR (48-50). TNP-470 was administered under the same schedule (1-h infusion qod for 28 d, followed by a 14-d rest period) to prostate and cervical cancer patients. One prostate cancer patient with bone metastases was treated for 9 mo at 9.3 mg/m2 prior to disease progression. Two cervical cancer patients were treated for 5 and 6.5 mo, respectively, before their disease progressed. These patients were permitted intrapatient dose escalations (14 ^ 47.5 and 31.5 ^ 47.5 ^ 71 mg/m2, respectively). A third cervical cancer patient has been treated for more than 18 mo, and continues on treatment at 60 mg/m2, with serial assessments of stable disease. When TNP-470 was administered as a 4-h infusion once weekly, three patients experienced disease stabilization. A patient with metastatic melanoma remained on treatment at 25 mg/m2 for 6 mo prior to disease progression. At 50 mg/m2, a patient experienced stabilization of a fibrous histiocytoma from May 1995 until March 1997, at which time he discontinued treatment, but had not progressed. Finally, a patient with metastatic colon cancer received

TNP-470, 235 ^ 177 mg/m2, for 13 mo. At study discontinuation, the patient's disease remained stable.

The CR occurred in a patient with cervical cancer metastatic to the lungs (histologically documented), who was treated at 71 mg/m2. Tumor regression (PR) was first noted after treatment for 3 mo, and this was followed by documentation of a CR. The patient was treated from February 1995 until January 1997. As of May 1997, the CR was maintained.

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