Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors

Abstract

Purpose:This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. Experimental Design: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 Ag/m 2 ) given as a 10-minute i.v. infusion every 21days. The dose was subsequently reduced in incremental steps to 45 Ag/m 2 due to unexpected toxicity. Results:The maximum tolerated dose of SJG-136 was 45 Ag/m 2 .The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive g-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. Conclusions: SJG-136 was associated with dose-limitingVLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

“…For highly potent molecules, such as dolastatin-10, a tubulin-interacting agent, or adozelesin, a DNA alkylator, the MTD (3,5) in humans is about 33% of the mouse LD 10 . In contrast, the highly cytotoxic DNA cross-linking agents, bizelesin (a duocarmycin analog dimer) and SJG-136 (a PBD dimer) are poorly tolerated in humans compared with mice, with only about 3.5% of the mouse LD 10 achievable in humans (6,19). On the basis of the delayed toxicity profile and the potential for a low achievable dose in humans, we decided not to advance ADCs of the cross-linking IGN subclass.…”

“…ADCs of pyrrolobenzodiazepine (PBD) dimers, potent DNA cross-linkers, have recently been advanced into clinical evaluation (16)(17)(18). These ADCs incorporate derivatives of the PBD dimer SJG-136, a highly toxic small molecule with a maximally tolerated dose (MTD) of $1.2 mg/kg in humans (19).…”

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

“…It is now increasingly used to monitor ICL formation and unhooking in clinical samples (30,40) as a pharmacodynamic end point in clinical trials (41,42), and following ex vivo treatment (39,43).…”

From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

“…Based on the outcomes from one of the previous clinical trials,18b this study evaluated two different dose schedules. In Schedule A, patients were given doses of 6, 12, 24, or 48 μg m −2 per day for 5 consecutive days of a 21 day cycle with the aim of studying DLTs and PK after multiple dosing.…”