Groups were treated according to a standardised dose-escalation scheme, depending on the worst toxicity experienced by patients enrolled at the prior dose level, and the clinical significance of that toxicity.
Subjects remained at each dose level for 2 3 days (minimum 4 consecutive doses) with dose escalation predicated on tolerability of the prior dose.
If DLT was not reached at the seventh dose level of 90 mg m−2, further dose increments would be in steps of 20 25% above the prior dose level.
Vital signs were recorded at screening, prior to dosing and at scheduled intervals during each treatment period.
Serum samples were obtained at baseline, prior to dosing in each treatment cycle, at cycle 1, day 17 and 28 30 days after the last dose of mapatumumab.
In study 2, exercise challenge was performed at baseline prior to dosing and on study days 28, 56, and 150 after dosing [ 26].
Blood samples (500 μL) were directly collected into a clean tube from the tail vein at 0 (prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after oral administration; serum was separated by centrifuging at 5000 rpm for 10 min and kept frozen at −80°C until analysis.
The animals were fasted at least 10 h prior to dose administrations and for 4 h after dosing with free access to water.
Treatment was initiated at 1 of 3 dosing levels that matched prior OXY dose requirement.
