Interim Results of a Phase I/II Clinical Trial of Belinostat in Combination with Idarubicin in Patients with AML Not Suitable for Standard Intensive Therapy.

Patients either with refractory/relapsed AML or with newly diagnosed AML not suitable for intensive induction therapy have a dismal prognosis. Belinostat belongs to a new class of hydroxymate-type histone deacetylase (HDAC) inhibitors. Belinostat has demonstrated effective cell killing in leukemic and lymphoma cells as a single agent and synergy in combination with other therapeutic regimens such as anthracyclines. Preliminary results are presented of the still ongoing open-label non-randomized, multi-centre, phase I/II trial to assess the efficacy and safety of 2 schedules of belinostat in combination with idarubicin in patients with AML not suitable for standard intensive therapy. Belinostat was administered either as a daily 30 min infusion for 5 days q 3 weeks plus iv idarubicin on days 4+5 (regimen A) or as a continuous iv administration over 48 hours q 2 weeks with addition of iv idarubicin at h 24 and 48 (regimen B). Both schedules used a dose escalation design; regimen A, the 3+3 dose escalation design; regimen B, the accelerated titration design.

Currently, 22 patients have been treated (regimen A, n=11; regimen B, n=11). Patient characteristics at inclusion were as follows: median age 72 years (range 37–84); 12 had de novo AML, all were in relapse from previous treatment, 4 had secondary AML, two had received prior treatment, 7 had MDS/AML, 3 received prior treatment. In total, 49 cycles of trial treatment were administered in 22 patients (median = 2, range 1 – 8).

The safety database as of 11.07. 2008 with information available for 19 patients (n=10 in regimen A. n=9 in regimen B) only contained two SAE’s defined by the investigators as related to treatment, they occurred in the same patient and were of the same type neutropenia and thrombocytopenia, conditions known as associated with idarubicin and also fundamentally a part of the progressive leukemic process and therefore in part exempted from the DLT definition in this as in other AML treatment protocols. So far no dose limiting toxicity was defined. Most frequent related adverse events, occurring in less than one third of the patients, were nausea, vomiting, diarrhea.

Antileukemic efficacy was seen both following belinostat single agent (CRi after 2 cycles in one 62 yr old MDS/AML patient receiving 48h CIV at a dose of 800 mg/m²/d, regimen B) and following belinostat in combination with idarubicin (CRi after one cycle in one 84 yr old MDS/AML patient receiving 48h CIV at a dose of 1000 mg/m²/d plus idarubicin 5 mg/m² x1, regimen B; CR after one cycle in one 74 yr old AML patient receiving the 5-d regimen of belinostat 1000 mg/m²/d + idarubicin 10 mg/m² x 1 and extramedullary cutaneous relapse after the 8th cycle, regimen A; CRi after 3 cycles in one 78 yr old MDS/AML patient receiving the 5-d regimen of belinostat 1000 mg/m²/d + idarubicin 7.5 mg/m² x 2, regimen A).

Updated results and pharmacokinetic analysis will be presented.

Conclusion: In the ongoing PXD101-CLN-15 study no dose limiting toxicity was determined so far. Clinical efficacy in the form of complete remissions has been demonstrated both of the belinostat monotherapy and of the combination with idarubicin in the 5-d regimen as well as in the CIV regimen. Dose escalation continues as preparation for a phase 2 expansion.