Phase I study of the DNA minor groove binding pyrrolobenzodiazepine dimer (SJG 136) administered every 21 days in patients with advanced solid tumours

Abstract

2566 Background: This phase I study was undertaken to define dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the pyrrolobenzodiazepine dimer SJG-136 in patients with advanced solid tumors. Methods: Good performance patients (PS ≤1) with refractory advanced solid tumors were assigned sequentially to escalating doses of SJG-136 (15 to 240 μg/m2) given as a 10-minute intravenous infusion once every 21 days. An accelerated dose-escalation strategy based on the Simon design was used. Results: 16 patients (11M, 5F) median age 70 years for M (range 41–79) and 56 for F (range 54–58) recruited. Cancer sites included biliary (2), colorectal (5), lung (1), oesophagogastric (2), pancreas (2), sarcoma (1), melanoma (3). Dose levels μg/m2) were 15 (1 pt), 30 (1 pt), 45 (7 pt), 60 (4 pt) 120 (2 pt), 240 (1 pt). 10 pts had grade 1–3 VLS (30–240 μg/m2) with Gr 3 occurring at the top doses at 120 and 240 in 2 pts. DLT were a delayed vascular leak syndrome (DVLS) seen in 4 of 5 pts treated at doses between 30 and 240 μg/m2. DVLS was characterized by hypoalbuminemia, oedema, and other features included pleural effusion, dyspnoea, weight gain and abdominal distension. The dose was reduced to 60 μg/m2 but 2/3 pts developed delayed, prolonged liver toxicity. 7 pts were recruited at a dose level of 45 μg/m2 in combination with dexamethasone, starting 24 hours before treatment to prevent DVLS. Other unexpected adverse events included elevated liver function tests and fatigue. 10 patients had stable disease for > 6 weeks, 2 patients for > 12 weeks. There was no evidence of crosslinking using the single cell gel electrophoresis (comet) assay. Evidence of DNA interstrand cross-linking in peripheral lymphocytes and tumour cells was demonstrated at all dose levels using a sensitive gamma-H2AX assay. SJG-136 demonstrated biphasic clearance and linear pharmacokinetics across the dose range tested. Conclusions: When given as a single injection every 21 days, the MTD for SJG-136 is 45 μg/m2 but a recommended dose for phase II testing was not identified. The major DLT was DVLS, but delayed liver toxicity was also observed. DNA damage was noted at all dose levels studied in circulating lymphocytes and tumour. Alternative clinical dosing strategies are now being evaluated. No significant financial relationships to disclose.