Phase I study of TP300 in patients (pts) with advanced solid tumors

Abstract

2563 Background: TP300 (CH4556300) is a synthetic camptothecin analogue and potent topoisomerase I inhibitor designed to have superior efficacy, tolerability and pharmacokinetic (PK) characteristics compared to current inhibitors. Intravenous (i/v) TP300 undergoes rapid chemical conversion to the active compound CH0793076, then enzymatic conversion to an active metabolite, CH0793011. The objectives of this study were to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and PK profiles of TP300; antitumor activity and pharmacodynamics (PD) were also evaluated. Methods: Eligible pts with refractory, advanced solid tumors who had adequate PS, hematologic, renal, and hepatic function were recruited into this open-label, modified- Fibonacci dose escalation (“3 + 3” pts/dose level, with expansion at the MTD) study. TP300 was given as a 1-hour i/v infusion 3-weekly; the starting dose was 1 mg/m2. The MTD was defined as the dose level below that where > 2 of 3–6 pts experienced DLT. PK profiles of TP300, CH0793076 and CH0793011 were analysed; DNA strand breaks in peripheral blood mononuclear cells (PBMCs) were measured with the comet assay as a PD marker. Results: 32 pts (m=20; f=12), median age 58 (range 31–72), received TP300 at doses of 1, 2, 4, 8, 12, then 10mg/m2. The MTD was 10mg/m2; DLTs seen at 12mg/m2 (2/4 pts) and 10mg/m2 (3/12 pts) included anaemia, thrombocytopenia and febrile neutropenia. Other grade 3/4 toxicities included lethargy, chills and lower back pain. Diarrhoea was uncommon. Seven pts, all previously treated with irinotecan, had disease stabilisation for 1.5–5 months. CH0793076 PK (AUC and Cmax) were linear from 1 to 10mg/m2. There was a strong PD relationship between CH0793076 AUC and fall in neutrophils, the threshold AUC for DLT neutropenia being 5 hr.umol/L. DNA strand breaks were detected consistently in PBMCs on completion of TP300 infusion . Conclusions: The Phase II starting dose will be 8mg/m2 because hematologic toxicity was seen in cycle 1 at the MTD. As the AUC of CH0793076 at MTD is substantially greater than that of SN38 in pts treated with irinotecan, and CH0793076 is almost equipotent to SN38 pre-clinically, a PK advantage for TP300 is confirmed. Further investigation is warranted. [Table: see text]