Study design
neurotoxicity, toxicity, tumour
CYTOKINE RELEASE SYNDROME, TUMOUR
The study used an open-label, dose-escalating design, with the starting dose selected based on the minimum anticipated biological effect level determined from in vitro data and PK models as no relevant in vivo data were available. AFM11 was planned to be escalated at the predefined doses of: 0.0003, 0.001, 0.003, 0.01, 0.03, 0.09, 0.20, 0.40, 0.80, 1.5 and 2.5 μg/kg. AFM11 was given as an intravenous infusion over 4, 24, or 48 h in a stepwise manner with a separate dose escalation scheme for each infusion time until an MTD had been reached (Supplementary Fig. Escalation to the next dose cohort only occurred when patients receiving the prior dose level had completed cycle 1 (4 weeks). Patients received the prior cohort dose in cycle 1 week 1 and escalated to their cohort dose in cycle 1 weeks 2–4. Intrapatient dose reduction was only permitted if a patient experienced cytokine release syndrome or neurotoxicity; intrapatient dose escalation only occurred between cycle 1 week 1 and cycle 1 week 2, and dose escalation beyond the assigned cohort dose was not permitted. Dosing could be delayed by up to 21 days in each cycle to allow toxicity to return to grade 1 or baseline. If a dose could not be given within 21 days of the scheduled date, the patient was withdrawn from the study.Initially, a dosing frequency of 5 times/week in week 1 and 3 times/week in weeks 2–4 was selected based on animal models that demonstrated more intensive dosing produced the most effective inhibition of tumour growth. After the first five patients were treated, dosing frequency was reduced to once weekly as this was expected to result in a more favourable safety profile.Patients were hospitalised for at least 24 h or the duration of the infusion. At PK sampling visits, patients were hospitalised for 24, 48, or 72 h for the 4-, 24- and 48-h infusions, respectively. Patients who were clinically stable or showed either B-cell depletion or T-cell expansion after cycle 1 and who had no unacceptable toxicity could receive a second cycle of therapy at the investigator’s discretion. Based on either the investigator’s decision or the patient’s request, patients could be withdrawn from the study at any time.