Abstract
The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 μg/m2 dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 μg/m2 of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 909-912 |
| Number of pages | 4 |
| Journal | Journal of the National Cancer Institute |
| Volume | 102 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Pediatric phase i trial design using maximum target inhibition as the primary endpoint. / Meany, Holly; Balis, Frank M.; Aikin, Alberta; Whitcomb, Patricia; Murphy, Robert F.; Steinberg, Seth M.; Widemann, Brigitte C.; Fox, Elizabeth.
In: Journal of the National Cancer Institute, Vol. 102, No. 12, 06.2010, p. 909-912.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pediatric phase i trial design using maximum target inhibition as the primary endpoint
AU - Meany, Holly
AU - Balis, Frank M.
AU - Aikin, Alberta
AU - Whitcomb, Patricia
AU - Murphy, Robert F.
AU - Steinberg, Seth M.
AU - Widemann, Brigitte C.
AU - Fox, Elizabeth
PY - 2010/6
Y1 - 2010/6
N2 - The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 μg/m2 dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 μg/m2 of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.
AB - The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 μg/m2 dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 μg/m2 of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.
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U2 - 10.1093/jnci/djq174
DO - 10.1093/jnci/djq174
M3 - Article
C2 - 20460632
AN - SCOPUS:77953699935
VL - 102
SP - 909
EP - 912
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 12
ER -