Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors.
OBJECTIVE
MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies.


METHODS
A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs.


RESULTS
Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103.


CONCLUSIONS
At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.
Siu
Lillian L
LL
Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Ste 5-718, Toronto, Ontario, M5G 2M9, Canada. lillian.siu@uhn.on.ca
Pili
Roberto
R
Duran
Ignacio
I
Messersmith
Wells A
WA
Chen
Eric X
EX
Sullivan
Rana
R
MacLean
Martha
M
King
Serina
S
Brown
Shirley
S
Reid
Gregory K
GK
Li
Zuomei
Z
Kalita
Ann M
AM
Laille
Eric J
EJ
Besterman
Jeffrey M
JM
Martell
Robert E
RE
Carducci
Michael A
MA
D000107:Acetylation / Q000187:drug effects; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000097:blood; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010349:Patient Compliance; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011743:Pyrimidines; C523184:mocetinostat