Target-specific randomized discontinuation trial design: a novel approach in molecular therapeutics.
OBJECTIVE
To describe a phase II study design to evaluate the activity of novel anti-cancer agents that focuses on molecular pathogenesis rather than tumor histology.


METHODS
We propose an enrichment design that enrolls patients across histologies expressing target X and incorporates randomized discontinuation of drug Y after an initial treatment period to evaluate for potential cystostatic activity.


RESULTS
We are currently evaluating the activity of lapatinib in patients with HER-2 amplified solid tumors using the target-specific, histology-independent, randomized discontinuation design. Patients receive treatment with lapatinib for an initial 12-week period. After restaging, patients with disease progression are removed from study, patients achieving an objective response continue treatment, and patients with stable disease are randomized to continue lapatinib versus initiate treatment with placebo. The primary endpoints are to evaluate the objective response rate during the initial treatment period and to evaluate the proportion of patients progression-free 12 weeks post-randomization.


CONCLUSIONS
The target-specific, histology-independent, randomized discontinuation design is an attractive alternative to the traditional phase II design for the development of "targeted" therapeutics.
Galsky
Matthew D
MD
Translational Oncology Program, US Oncology Research, Dallas, TX, USA. Matthew.galsky@usoncology.com
Zaks
Tal
T
Hassani
Habib
H
Vocila
Linda
L
Sonpavde
Guru
G
Hutson
Thomas E
TE
Von Hoff
Daniel D
DD
D000970:Antineoplastic Agents / Q000494:pharmacology; D006801:Humans; D000077341:Lapatinib; D016013:Likelihood Functions; D011799:Quinazolines / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design
D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib