C120
A Cancer Research UK phase I trial combining the dinitrobenzamide prodrug CB1954 (tretazicar) and the NQO2 substrate EP-0152R (caricotamide) intravenously (IV) every 3 weeks
Emma Cattell1, Debashis Sarker3, Diana Anderson3, Victoria Spanswick4, Scott Davies2, R Agarwal3, Nicki Heywood1, David Kerr2, Ian Judson3, John Hartley4, Mark Middleton1
1Churchill Hospital, Oxford, UK, 2University of Oxford, UK,3Royal Marsden Hospital, Sutton, UK, 4University College London, UK
Background
CB1954 (CB) is a dinitrobenzamide prodrug that is converted in the presence of the enzyme NQO2 and co-substrate EP-0152R (EP) into a potent cytotoxic bifunctional alkylating agent.
Method
Patients (pts) with histologically confirmed advanced solid tumours and WHO Performance Status 0 - 2 were treated with CB and EP. CB was administered IV over 15 minutes midway through a 4 hour IV infusion of EP every 3 weeks. Objectives were to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the combination, evaluate pharmacokinetics (PK) and pharmacodynamic (PD) effects and describe antitumour activity. PD effects were assessed in lymphocytes and tumour biopsies by the Single Cell Gel Electrophoresis (Comet) assay. Early PK data indicated that 200 mg/m2 EP maximally activated NQO2. Subsequent patients were treated at this dose whilst dose escalating CB in cohorts of 3-6 patients.
Results
32 pts (median age 57.5 yrs; 17 Male/15 Female) were treated in 5 cohorts (escalating doses of CB: 12, 16, 20, 26.6, 35 mg/m2). DLTs were seen at 35 mg/m2 (1 pt grade 3 transaminitis and 1 pt grade 3 diarrhoea). 15 pts were treated with 26.6mg/m2 CB: 3 patients experienced DLT (1 pt, grade 3 transaminitis, 1 pt, grade 4 vomiting, 1 pt, grade 3 fatigue). Other drug-related toxicities at these dose levels included grade 1 - 3 nausea and vomiting, and grade 2 anorexia, dehydration and abdominal pain. There was a 20-fold reduction in the half-life of CB when co-administered with EP, from 0.85 hrs to 0.04 hrs. There was also a transient reduction in EP concentration, coinciding with the introduction of CB. The Comet assay showed evidence of DNA interstrand cross-linking in lymphocytes and tumour tissue (paired samples from 4 pts) when CB and EP were co-administered, but not with CB alone, consistent with activation of CB by NQO2 in the presence of EP. Of 23 patients evaluable for response, 1 pt with ocular melanoma had evidence of stable disease for over 6 months.
Conclusion
The MTD was CB 26.6 mg/m2 and EP 200 mg/m2.
