Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia.
MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC(50) (concentration lethal to 50%) of 0.23 micromol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0-12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3-4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.
Blum
Kristie A
KA
Division of Hematology/Oncology, Ohio State University Medical Center, Columbus, OH 43210, USA. kristie.blum@osumc.edu
Advani
Anjani
A
Fernandez
Louis
L
Van Der Jagt
Richard
R
Brandwein
Joseph
J
Kambhampati
Suman
S
Kassis
Jeannine
J
Davis
Melanie
M
Bonfils
Claire
C
Dubay
Marja
M
Dumouchel
Julie
J
Drouin
Michel
M
Lucas
David M
DM
Martell
Robert E
RE
Byrd
John C
JC
D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002869:Chromosome Aberrations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069283:Rituximab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines; D000069283:Rituximab; C523184:mocetinostat; D006655:Histone Deacetylases