Activity of the Histone Deacetylase (HDAC) Inhibitor PXD101 in Preclinical Studies and in a Phase I Study in Patients with Advanced Haematological Tumors.

Previous investigations have shown that the novel hydroxamate PXD101 potently inhibits the enzymatic activity of histone deacetylase (HDAC) at nanomolar concentration, and the growth of cancer cell lines derived from solid malignancies at low micromolar potency. We have now examined and present results showing the activity of PXD101 on > 20 cell lines corresponding to a variety of haematological cancer types including acute T-cell leukaemia, cutaneous T-cell lymphoma, anaplastic large T-cell lymphoma, mantle cell lymphoma, Burkitt’s lymphoma, diffuse large-cell lymphoma, plasma cell leukaemia and multiple myeloma (MM). Our data show that PXD101 strongly inhibits the growth of these cancer types at submicromolar potency. In addition, we will present in vitro data demonstrating that PXD101 efficiently inhibits the growth of doxorubicin-resistant leukemic cells, thereby supporting the possibility that this compound may be effective on drug-resistant haematological cancers. Finally, we will present results demonstrating that PXD101 used in combination with Velcade mediates greater growth-inhibition than does either drug used as monotherapy on a multiple myeloma cell line. These promising preclinical findings, taken together with previous results demonstrating the activity of PXD101 in a murine leukaemia animal model, support the evaluation of PXD101 for the treatment of haematological malignancies in a clinical setting. To this end, a Phase I trial using PXD101 in patients with advanced hematological tumors refractory to standard therapy was initiated. PXD101 is administered as a 30 minute i.v. infusion on days 1 to 5 of a 21 day cycle. Dose levels 600 mg/m²/d and 900 mg/m²/d have been examined (3 patients each) and recruitment to the dose level 1000 mg/m²/d is ongoing (5 patients to date). Patient characteristics are 8 males and 3 females with median age of 67 (range 58 – 73). Median number of prior therapies is 5 (range 4 – 7). Of the 11 patients enrolled to date, diagnoses were: MM (2), Non-Hodgkin’s lymphoma (5), CLL (4). Eleven patients have been treated with 1–8 cycles of therapy. Adverse events related to PXD101 treatment have mainly been grade 1–2. The most frequent adverse events were nausea (12/23 cycles), fatigue (9/23 treatment cycles), vomiting (8/23 cycles) and diarrhoea (7/23 cycles). Potential antineoplastic activity has been observed. One patient with MM had a possible tumor lysis syndrome with decrease in M-component, increasing urate and serum creatinine requiring dialysis. In addition, one patient with Richter transformation of CLL refractory to other treatments has now been in stable disease for > 6 months. We continue to accrue patients in this study, and updated data will be presented.