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Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia
Author(s) -
Blum Kristie A.,
Advani Anjani,
Fernandez Louis,
Van Der Jagt Richard,
Brandwein Joseph,
Kambhampati Suman,
Kassis Jeannine,
Davis Melanie,
Bonfils Claire,
Dubay Marja,
Dumouchel Julie,
Drouin Michel,
Lucas David M.,
Martell Robert E.,
Byrd John C.
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07881.x
Subject(s) - fludarabine , medicine , chronic lymphocytic leukemia , rituximab , concomitant , histone deacetylase inhibitor , histone deacetylase , tolerability , gastroenterology , pharmacokinetics , toxicity , refractory (planetary science) , oncology , pharmacology , lymphoma , leukemia , chemotherapy , adverse effect , histone , biology , cyclophosphamide , biochemistry , gene , astrobiology
Summary 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 μmol/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.