A Phase II Study of AT9283, an Aurora Kinase Inhibitor, in Patients with Relapased or Refractory Multiple Myloma; NCIC Clinical Trials Group IND.191

Background:Although outcomes for patients with multiple myeloma (MM) have improved, it remains an incurable malignancy for which new therapies are needed. Aurora kinases are overexpressed in MM. Inhibition of Aurora A kinase, a key component of the centrosome, in MM cell lines induces apoptotic cell death. Inhibition of Aurora B, a chromosome passenger protein, has therapeutic effects against myeloma lines, primary bone marrow plasma cells and murine xenografts. Histone H3 is a direct downstream substrate of Aurora B. The Aurora A and B kinase inhibitor AT9283 has shown anti-myeloma activity in pre-clinical studies. Based on an NCIC CTG phase I trial in patients with advanced malignancy the recommended phase 2 dose (RP2D) was 40 mg/m² on days 1 and 8 of a 21 day cycle. This single arm phase II trial was designed to explore the efficacy of AT9283 in patients with relapsed and refractory multiple myeloma.

Methods: Eligibility criteria included age ≥ 18, neutrophils ≥ 1 and platelets ≥ 70 x10⁹/L. There was no upper limit on the number of prior regimens. The primary endpoint was response rate; secondary endpoints included toxicity and evaluation of potential biomarkers. According to the 2-stage design at least 1 response was required in the first 15 patients to proceed to a full sample size of 30, assuming an H_A of ≥ 0.20. Initially AT9283 was administered by 24 hour continuous infusion at the RP2D. Hematological toxicity in the first 2 patients met protocol specified criteria for reduction of the starting dose to 30 mg/m² for subsequent patients. Adverse events were graded according to CTCAE V4.0. Phosphorylated Histone H3 (Ser10), a marker of Aurora B activity, and total Histone H3 protein expression was measured by western blot analysis in baseline and day 21 bone marrow samples.

Results:Over 18 months, eight eligible patients (3 male, 5 female) with MM (4 IgG, 2 IgA, 2 light chain) were accrued. All were evaluable for toxicity and 7 evaluable for response. Median age was 60 (range 48 – 75). The median number of prior regimens was 3 (range 1 - 5). Patients received between 1 – 4 cycles of AT9283 (median 1) with 25% of patients receiving ≥ 90% of the planned dose intensity. No responses were observed. The trial was closed due to slow accrual and toxicity, in particular myelosuppression. Transient neutropenia occurred in all patients (63% grade 3, 37% grade 4). Recovery from nadir to normal range was rapid in the majority (range 1 – 8 days, median 5) but prolonged in 2 patients who were neutropenic at baseline (11 and 13 weeks). Grade 3/4 thrombocytopenia occurred in 50% of patients. There were 3 infections ≥ grade 3 including 1 death. Grade 3 skin ulceration thought possibly related to AT9283 by the investigator occurred in 1 patient. The most common non-hematologic adverse events reported as possibly, probably or definitely related to AT9283 were grade 1-3 nausea (50%), grade 1 and 3 vomiting (38%), grade 4 febrile neutropenia (25%), grade 1/2 anorexia (25%), grade 1/2 diarrhea (25%) and grade 1/2 fatigue (25%).

Paired baseline and day 21 bone marrow samples were provided from 4 patients; sufficient protein was extracted from both samples for western blot analysis from 3 patients. Of these, 2 showed a reduction in Histone 3 phosphorylation (H3-P) after the first cycle of treatment consistent with inhibition of Aurora B. Both of these patients had a best response of stable disease (SD).

Conclusions: This study failed to reach full accrual. No objective responses were observed. Administration of AT9283 to patients with previously treated myeloma at this dose and schedule is associated with toxicity, particularly myelosuppression.