Abstracts Health Sciences

Analysis of initial efficacy results of a new cytotoxic prodrug, CAP7.1, in adults with therapy refractory solid tumours in a phase I clinical trial

by Laura Rohde

This work analyzes the preliminary anti-tumour activity of the new cytotoxic compound CAP7.1 in a first in human phase I trial in adults. Cancer is one of the leading diseases and causes of death worldwide, but therapeutic options are often unsatisfactory. Etoposide is a widely prescribed and highly effective cytotoxic drug, but its therapeutic use is limited by systemic toxicity and induction of drug resistance mechanisms. CAP7.1 is a newly developed prodrug of etoposide and is enzymatically activated by carboxylesterase (CES). Preclinical data showed an improved safety profile and better efficacy (compared to etoposide) in animals and different cell lines, including etoposide resistant cell lines. Eligible for this open-label, non-randomized, dose escalating trial were adult patients with refractory malignancies, adequate bone marrow and organ function and good performance status. CAP7.1 was administered on 5 consecutive days as a 60-minute intravenous infusion every 21 days for up to 6 cycles. Tumour assessment was scheduled every second cycle and analyzed according to RECIST 1.0 criteria. 19 patients with a wide range of tumours were included; their median age was 63 years. Patients were treated in four different escalating dose cohorts (dosage: 45, 90, 150 mg/m²/day up to the maximum tolerated dose (MTD) of 200 mg/m²/day). In total, 62 cycles of CAP7.1 were administered (range 1-6 cycles). Four patients, all in the last cohort, completed all six cycles. 17 patients were assessable for tumour response. One partial response was observed in a heavily pre-treated patient who suffered from Merkel cell carcinoma. 11 patients achieved stable diseases (SD), with a wide range of tumour entities. Six patients had an SD duration of over 3 months. 10 patients survived over six months. The longest overall survival (25 months) was seen in a patient who suffered from gallbladder carcinoma, the second longest survival (20 months) was assessed in a patient diagnosed with cancer of unknown primary (CUP). Overall efficacy showed promising initial results in various tumour entities. Due to the small number of patients, only limited comparison of efficacy of this trial with other studies is possible, being a conceivable issue in phase I testing. A preliminary anti-tumour efficacy was demonstrated and CAP7.1 compares favourably with most of the other compounds analysed. Therefore, further investigation in clinical trials with various tumour entities is warranted. Ziel dieser Arbeit ist die Analyse und Bewertung der initialen Wirksamkeit von CAP7.1, einer neuen zytotoxischen Substanz, welche kürzlich in einer Phase-I-Studie an Patienten mit therapierefraktären Krebserkrankungen getestet wurde. Maligne Erkrankungen sind eine der führenden Todesursachen weltweit, therapeutische Optionen sind jedoch nach wie vor unzureichend. Ein weit verbreitetes, hoch effektives zytotoxisches Medikament ist Etoposid, welches jedoch aufgrund von systemischer Toxizität und enzymatisch aktivierten Resistenzmechanismen nur begrenzt einsatzfähig ist.…