Protocol for an Open-Label, Signal-Seeking Trial of Targeted Therapies for Vascular Malformations Using a Novel Individual Outcome Measure
Tara Lane, Natasha Brown, Michelle G. de Silva, Michael S. Hildebrand, Stephen Luen, Anneke C Grobler, Jayesh Desai, Mark Rosenthal, Lisa Orme, Michelle Tew, Roderic Phillips, Lydia Pathmanathan, Kaitlyn Taylor, Jason Qin, Jodie Simpson, Anthony PeningtonObjectives:
To describe a protocol for a novel trial design to evaluate the clinical efficacy of 2 targeted therapy drugs, alpelisib and mirdametinib, in vascular malformations.
Design:
A modular open-label, signal-seeking, phase II trial with separate modules for fast-flow and slow-flow vascular malformations, using individualized outcome measures.
Setting:
A pediatric quaternary care hospital with an active vascular anomalies multidisciplinary team and a nearby adult cancer hospital.
Participants:
It is proposed to recruit 30 patients with slow-flow malformations and 20 with fast-flow malformations from the Vascular Malformations Clinic at the trial study sites, as well as from the practices of team members and others in the same city treating vascular malformations.
Intervention:
In the slow-flow module, the intervention will be 48 weeks of oral alpelisib. Participants in the fast-flow module will receive 12 cycles of oral mirdametinib in a 3-week on, 1-week off cycle. In both modules, a 24-week off-treatment period will follow.
Outcome measures:
This study will pilot a novel strategy of outcome measurement in which each participant will have an individual outcome defined along with a method of measurement of that outcome and a threshold of “clinically significant improvement.” The primary outcome in each module will be the proportion of participants who achieve or exceed clinically significant improvement. A number of secondary outcomes will also be reported.
Discussion:
This study proposes a novel solution to the significant problem in clinical trials of the diversity of symptoms experienced by participants with apparently similar vascular malformations.