Danusertib Hydrochloride (PHA-739358), a Multi-Kinase Aurora Inhibitor, Elicits Clinical Benefit in Advanced Chronic Myeloid Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia .

Despite the availability of novel ABL tyrosine kinase inhibitors ( TKI ) in addition to imatinib mesylate, the acquisition of the T315I BCR-Abl mutation remains a major cause of resistance to registered therapeutic compounds. Some patients (Pts) may also fail therapy with ≥ 2 TKI and need additional treatment. PHA-739358 is a small ATP competitive molecule that specifically inhibits Aurora A, B and C kinases. PHA-739358 possesses high affinity binding capacity to both wild-type Abl and Abl/T315I in in vitro assays.

An international, multicenter, open-label, single agent, non-comparative, phase I study is being conducted in adult Pts with advanced Chronic Myeloid Leukemia (Accelerated AP-CML/Blastic phase BP-CML) and Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) resistant or intolerant to imatinib and/or 2^nd generation c-Abl therapy. Primary objective of the study is to determine the Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicity (DLTs) during the first cycle. Two schedules were planned. Schedule A (PHA-739358 given as daily 3-hrs iv infusion for 7 consecutive days, every 2 wks) is open. Schedule B, not yet started, foresees a more aggressive approach and is currently being amended.

Twenty-three Pts with CML and Ph+ ALL have been treated so far (4 with AP-CML; 8 with BP-CML and 11 with Ph+ALL). Five dose levels have been tested: 90 (N=7); 120 (N=4); 150 (N=6); 180 (N=3) and 200 (N=3) mg/m². Only one DLT occurred at 90 mg/m² (NCI-CTC AE Gr3 fainting). Presently the MTD has not been defined. Fifteen out of 23 Pts have confirmation of BCR-Abl T315I mutation. A response occurred in 6/14 Pts, including 3 cytogenetic (1 complete, 1 partial, 1 minimal), 5 hematologic, and 1 clinical improvement (reduction in extramedullary disease mass). One severely pretreated (chemotherapy+Imatinib, SCT, Dasatinib and Donor Lymphocyte Infusion) pt with T315I mutated Ph+ALL reached Complete Hematological Response since Cycle (Cy) 4, Complete Cytogenetic Response since Cy 8 and Molecular Response (BCR/ABL undetectable transcripts) since Cy 9. Treatment continues after 10+ months. Last cycles were given every 4 wks due to mild/moderate transaminitis. This Pt at baseline showed: Peripheral Blood Blasts=0%; Bone Marrow (BM) blasts= 33%; % of Ph+ Metaphases = 80%. Two additional Pts (AP-CML and Ph+ ALL) achieved cytogenetic responses, one minimal and one partial reached at Cy2 and Cys 1-6, respectively. Another Pt (BP-CML) who received multiple transplants (3 times) and progressed after Imatinib, Dasatinib, Bosutinib, Nilotinib and Homoharringtonine, with 4 cycles of PHA-739358 had significant improvement of a large extramedullary lesion in the left neck impeding breathing and swallowing. Significant but transient reduction in the White Blood Cells (8/13 pts) and peripheral blood blast counts (3/13 Pts) were obtained with PHA-739358. An acceptable tolerability and safety profile characterized the study therapy: max non-hematological tox (regardless of causality) was as follows (most frequent Adverse events ≥ 30 %): diarrhoea 57% (CTC Gr 3 one Pt), pyrexia 50%; headache 43% (CTC Gr 3 one Pt); dyspnoea 36% (CTC Gr 3 one Pt ) and nausea 36%. Data analysis ongoing.

The preliminary results obtained with our study show that PHA-739358 can elicit significant response with clinical benefit in severely pretreated populations of Pts affected with advanced leukemias resistant/intolerant to Imatinib and other 2^nd generation TKI.

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