Phase I pharmacokinetic and pharmacodynamic study of SJG-136, a novel DNA sequence selective minor groove cross-linking agent, in advanced solid tumors.

PURPOSE: This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer. EXPERIMENTAL DESIGN: In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 µg/m(2)) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 µg/m(2)). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care. RESULTS: Schedule A-dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3-4). PK analysis revealed dose-dependent increases in AUC and C(max). Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B-the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2. CONCLUSIONS: The MTD of SJG-136 in this study was 30 µg/m(2) administered on a daily 3× basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer.

A phase I trial of irinotecan alternating with epirubicin in patients with advanced malignancies.

OBJECTIVES: This phase I study was conducted to evaluate the combination of irinotecan, a topoisomerase I inhibitor, with epirubicin, a topoisomerase II inhibitor, when administered sequentially on a once-every-three week basis. METHODS: Irinotecan was administered at doses ranging from 100 to 150 mg/m(2) intravenously over 90 minutes, 24 hours before epirubicin, in doses from 30 to 60 mg/m(2), every 3 weeks. Toxicity assessments were performed weekly. Tumor evaluation by radiographic and physical examination was performed after every 3 cycles using Response Evaluation Criteria in Solid Tumors. RESULTS: Eighteen patients with metastatic solid tumors were enrolled in this study. The maximum tolerated dose and recommended phase II dose was irinotecan 150 mg/m(2) and epirubicin 30 mg/m(2). Dose-limiting toxicities were primarily neutropenia. Other toxicities at this dose level were mild. Three patients with colon cancer, 1 patient with renal cell cancer and 1 patient with adenosquamous cell carcinoma of the ethmoid sinus had stable disease. No objective responses were observed. CONCLUSIONS: The maximum tolerated dose and recommended phase II dose for irinotecan and epirubicin administered 24 hours apart every 3 weeks was 150 mg/m(2) and 30 mg/m(2), respectively. Higher doses were limited by significant hematologic toxicity and fatigue.