Danaee, Hadi

Abstract Abstract 2477 Background: Aurora A kinase (AAK) is a key mitotic regulator, inhibition of which results in mitotic spindle defects, mitotic delay, and apoptosis. AAK is amplified or overexpressed in a number of heme-lymphatic malignancies. This phase 1, multicenter study (NCT00697346) is the first to assess safety, tolerability, and pharmacokinetics (PK) of the investigational AAK inhibitor alisertib (MLN8237) in patients with advanced hematologic malignancies. Methods: Patients aged ≥18 years with relapsed/refractory hematologic malignancy, confirmed radiographically or clinically evaluable disease, and ECOG performance status 0–2, were eligible for inclusion. Patients with prior allogeneic transplant were excluded; there was no restriction on the number of prior therapies. Patients received escalating doses (standard 3+3 design) of alisertib as either a powder-in-capsule (PIC) or enteric coated tablet (ECT) formulation. Alisertib PIC was administered as a twice-daily (BID) loading dose on Day 1, then once daily (QD) on Days 2–14 or 2–21, followed by 14 or 7 days' rest, respectively, in 28-day cycles. Alisertib ECT administration followed the same scheme in the first dose group, and subsequent groups received divided (BID) doses for 7 days plus 14 days' rest in 21-day cycles. Endpoints included maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, PK, and response. Results: 55 patients were included (PIC n=28, ECT n=27); median age was 61 years (range 27–82), 42% had prior ASCT, and 78% had received ≥3 prior therapies. 60% of patients had non-Hodgkin's lymphoma, 35% multiple myeloma, and 5% chronic lymphocytic leukemia/small lymphocytic lymphoma. Patients received a median of 2 cycles (range 1–14); 8 patients are ongoing. The MTD on the alisertib PIC 14-day + 14 days' rest schedule was 45 mg QD, established following occurrence of DLTs in four patients at higher dose levels: Gr 4 thrombocytopenia, Gr 4 neutropenia (65 mg QD); Gr 3 febrile neutropenia, Gr 4 thrombocytopenia (90 mg QD). In patients receiving alisertib ECT, the MTD was determined as 50 mg BID on a 7-day + 14 days' rest schedule; four DLTs were observed in three patients: at 40 mg QD for 14 days, one patient had Gr 4 febrile neutropenia, and one patient had Gr 4 bullous dermatitis and Gr 4 neutropenia; at 50 mg BID for 7 days, one of nine patients had Gr 4 neutropenia. The most common drug-related adverse events (AEs) were neutropenia (PIC 46%, ECT 63%), thrombocytopenia (39%, 41%), and diarrhea (29%, 41%); most common Gr ≥3 drug-related AEs were neutropenia (PIC 36%, ECT 52%), thrombocytopenia (29%, 26%), and anemia (14%, 26%). 24 patients (PIC n=12, ECT n=12) had serious AEs; the most common was febrile neutropenia (PIC n=1, ECT n=4). Tolerability appeared generally similar between the PIC and ECT formulations. Six patients (PIC n=3, ECT n=3) died during the study (PIC: renal failure, airway obstruction, progressive large cell lymphoma; ECT: progressive myeloma [n=2], hypercalcemia); no deaths were considered to be related to alisertib. Alisertib absorption was rapid with an overall median Tmax of 2 hours. The overall mean terminal half-life following multiple dosing was 19 hours. The mean peak/trough (P/T) ratio was 5 following QD dosing as PIC. The mean accumulation ratio and P/T ratio were 2.5 and 2.1, respectively, following BID dosing as ECT. At data cut-off (29 March, 2011), 42 patients were evaluable for response. Antitumor activity was observed in five patients (PIC n=3, ECT n=2) who had partial responses; 11 patients had a best response of stable disease (PIC n=6, ECT n=5) and 26 had progressive disease (PIC n=14, ECT n=12). Seven patients received ≥5 cycles of therapy, including one patient (PIC group; post-transplant grade 3B follicular lymphoma) with resolution of B symptoms who received alisertib for >1 year. Conclusions: The MTDs of the PIC and ECT formulations of alisertib are 45 mg QD for 14 days (+14 days' rest) and 50 mg BID for 7 days (+ 14 days' rest), respectively, in patients with advanced, non-leukemic hematologic malignancies. AEs were generally manageable and were consistent with inhibition of AAK in highly proliferative tissues (gastrointestinal and hematologic AEs). Current data support further investigation and expansion at the MTDs is ongoing. Data from PK, safety, and tolerability collectively support the progression of ECT formulation at 50 mg BID for 7 days in a 21-day cycle into phase 2 development. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies and solid tumors. Goy:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Reeder:Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding; Celgene: Institutional research funding. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Danaee:Millennium Pharmaceuticals, Inc.: Employment. Xiao:Millennium Pharmaceuticals, Inc.: Employment. Benaim:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Shea:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Abstract Multiple myeloma is a disease of the antibody producing plasma cells in the bone marrow. It has been characterized by frequent genomic alterations including gains and losses of chromosomes. Some of these alterations result in poor clinical prognosis. Bortezomib, a first in class proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma. To better understand how the genome wide changes observed in myeloma relate to prognosis and treatment response, we have used single nucleotide polymorphism (SNP) array technology to assess genotypes and DNA copy number at up to 100,000 genomic loci. DNA from 147 bone marrow tumor biopsies collected in multi-center phase II and III clinical trials of relapsed multiple myeloma patients prior to treatment with Bortezomib were hybridized on SNP arrays to assess genomic aberrations. Commonly seen genomic alterations in myeloma were observed, including deletions of chromosome 13 (37%), 1p (25%), 6q (23%), and amplifications on 1q (35%). We found that 35% of this relapsed myeloma population exhibited a hyperdiploid genome characterized by gains of chromosomes 3, 5, 7, 9, 11, 15, and 19. Other notable genomic deletions included 17p (22%), 8p (27%) and 10p (16%). A correlation of response to bortezomib therapy in patients with differential gains and losses at the chromosomal level is ongoing. Consistent with previous reports, response to bortezomib was observed in patients with poor prognostic chr 13 deletions. A more in-depth analysis of specific loci associated with clinical outcome will be discussed. In summary, this data will help further define genomic aberrations in multiple myeloma and their association with treatment outcome.