PHA-739358, an Aurora Kinase Inhibitor, Induces Clinical Responses in Chronic Myeloid Leukemia Harboring T315I Mutations of BCR-ABL.

Abstract

Background. The T315I BCR-ABL mutation confers high level resistance to clinically available ABL kinase inhibitors (i.e., imatinib, nilotinib, dasatinib, bosutinib, INNO-406). PHA-739358 is an aurora kinase inhibitor that selectively inhibits the ATP site of Aurora-A, Aurora-B and Aurora-C kinases, and binds with high affinity to both wild type Abl and Abl/T315I in vitro. A multicenter phase II study of PHA-739358 is being conducted in patients with chronic myeloid leukemia (CML) relapsing on imatinib or other c-ABL therapy. Methods. Seven consenting CML patients (1 in chronic phase, 1 in accelerated phase, 5 in blast phase) were initially entered in this trial and received PHA-739358 dosed at 250 or 330 mg/m2/day administered by a once-weekly 6-hour infusion for 3 consecutive weeks, every 4 weeks. Six out of seven patients had the BCR-ABL T315I mutation. Pharmacokinetic and pharmacodynamic (PD) samples were collected and analyzed during cycle 1. The PD analyses evaluated BCR-ABL inhibition (phospho-CRKL) and Aurora kinase inhibition (phospho-histone H3). Results. Two patients with T315I mutated BCR-ABL achieved a complete hematologic response (CHR) to PHA-739358. One of these patients treated in accelerated phase achieved a complete cytogenetic response (CCyR) and a complete molecular response after 3 months on the 330 mg/m2 dose level. The CCyR is ongoing after 6 months of treatment. The second patient who achieved a CHR initiated therapy in chronic phase. A minor cytogenetic response was achieved after 3 cycles of therapy at the 330 mg/m2, and a minimal cytogenetic response persists after nine months of treatment. Uncomplicated grade 4 neutropenia and an infusion-related reaction requiring acetaminophen, benadryl and hydrocortisone premedication was observed in one patient. No other grade 3/4 non-hematologic toxicity was observed. Patients with blast crisis did not have CHRs at the dose and schedule employed, although suppression of peripheral blood blasts was evident. PHA-739358 pharmacokinetics were in good agreement with those observed in other phase I - II studies. Average exposure, AUC0-t(168h), observed at 330 mg/m2/day was about 45 uM/h with Cmax values around 4 – 6 uM/h. Pharmacodynamic analyses demonstrated treatment-associated decreases of CRKL phosphorylation in 6 out of 7 patients, including both responders. Modulation of histone H3 phosphorylation was observed in 3 of 5 evaluable patients. Conclusions. Objective clinical responses to PHA-739358 have been observed in two CML patients with T315I mutations of BCR-ABL, with an acceptable tolerability and safety profile. Additional doses and schedules of PHA-739358 are being investigated in patients with advanced phase CML.

Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance

“…The CP-CML patient also had a minor cytogenetic response, and the AP-CML patient had a CCyR and a CMR. 95 Additional studies are reportedly ongoing to explore alternative dosing schedules.…”

Targeted therapy in haematological malignancies

“…PHA‐739 358 is a novel small molecule inhibitor which selectively targets BCR–ABL and Aurora kinases A, B and C. PHA‐739 358 demonstrated anti‐proliferative and pro‐apoptotic activity against CML cell lines, wild‐type or IM‐resistant BCR–ABL mutants and primary CD34 + cells derived from CML patients in CP or blast crisis, including those harbouring the T315I mutation 27. A phase II trial with CML patients who have failed IM and/or nilotinib or dasatinib therapy is currently ongoing 28.…”

New Agents in the Treatment of Chronic Myelogenous Leukemia

“…PHA-739358: PHA-739358, a pan-Aurora kinase inhibitor, is currently being evaluated in a multicenter phase II trial. 67 In vitro experiments in cellular assays have shown that the antiproliferative activity of PHA-739358 is partially independent of BCR-ABL1 kinase, because the sensitivity to PHA-739358 is not dependent on BCR-ABL1 mutational status given that similar inhibitory activities were elicited in all imatinib-resistant mutants, including T315I. Preliminary results, reported on 7 patients, showed that 2 of 6 with the T315I mutation experienced response to therapy at a dosage of 330 mg/m 2 .…”