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 LC50 (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.
Background: Background:Overexpression of CD123 occurs in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute lymphoblastic leukemia (ALL) and others. With limited expression on normal hematopoietic progenitor cells, the CD123 antigen is an attractive target for new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating cytotoxic payload of the IGN (indolinobenzodiazepine pseudodimer) class. In preclinical models of AML, IMGN632 exhibited potent anti-leukemia activity, with a wide therapeutic index. Confirming preclinical expectations, encouraging single-agent activity has emerged for IMGN632 in the ongoing Phase I trial in patients with CD123-positive BPDCN and AML (Daver. Blood ( 2019) 134 (Supplement_1):734.).Preclinical data have demonstrated increased activity with the addition of IMGN632 to AZA alone and to AZA+VEN in multiple AML xenograft and PDX models, leading to improved survival in these models (Kuruvilla. Blood (2019) 134 (Supplement_1):1375.). We have reported compelling activity (ORR 59% and CCR rate 38%) of the IMGN632 triplet in relapsed or refractory AML patients (Daver.
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