ALBERT

Description: Abstract 411 Background: LDAC is an established treatment option for patients (pts) with AML considered ineligible for intensive remission induction treatment. However, the outlook for pts who receive LDAC remains unsatisfactory, and novel therapeutic strategies are needed to improve clinical outcome in these pts. Plk1 plays a key role in mitosis and cell cycle progression and is an attractive target for novel therapeutic approaches in cancer. Volasertib (V) is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plks. The phase I part of this trial determined the maximum tolerated dose of V in combination with LDAC (V + LDAC) to be 350 mg and demonstrated antileukemic activity of V and V + LDAC in pts with relapsed/refractory AML ineligible for intensive therapy (Bug et al, ASH 2010 and 2011). Here we present preliminary phase II data for the randomized comparison of V + LDAC vs LDAC in pts with newly diagnosed AML ineligible for intensive treatment. Methods: In the phase II part of this open-label study, eligible pts were randomized to receive V (350 mg 1-hr intravenously, days 1, 15 Q4W) + LDAC (20 mg bid subcutaneously, days 1–10 Q4W), or LDAC alone until progression/relapse or intolerance. The primary endpoint was objective response (complete remission [CR] or CR with incomplete blood count recovery [CRi]); secondary endpoints included event-free survival (EFS), overall survival (OS), safety and pharmacokinetics (PK). Results: 87 pts were treated with V + LDAC (n=42) or LDAC (n=45). Pt characteristics (V + LDAC/LDAC) were largely balanced: median age, 75/76 yrs; secondary AML, 40.5%/64.4%; adverse cytogenetic group, 35.7%/33.3%. At time of analysis (February 22 2012) 15 pts were still on treatment (12 with V + LDAC). Pts received a median (range) of 2 (1–12) cycles of V + LDAC and 2 (1–11) cycles with LDAC. A significantly greater proportion of pts who received V + LDAC achieved a CR or CRi compared with pts who received LDAC (31.0% vs 11.1%; odds ratio 3.59 [95% CI: 1.15, 11.18]; P = 0.0277), with a median (range) time to remission of 71 (29–158) days and 69 (34–125) days, respectively. Remissions with V + LDAC were observed across genetic groups, including pts with adverse cytogenetics. A trend for longer median EFS was observed for pts who received V + LDAC compared with those who received LDAC (HR 0.61 [95% CI: 0.35, 1.05]; P = 0.0725; Figure). Follow-up for OS was ongoing at the time of this analysis. Among pts achieving CR/CRi, only 2 had experienced recurrence or death at the time of analysis (1 in each arm after a remission duration of 57 [V + LDAC] or 67 [LDAC] days). For all other pts ongoing in remission, the remission duration was censored after 53–407 days (LDAC + V) or 32–282 days (LDAC), consistent with prolonged duration of remission in some pts. The most frequent all grade adverse events (AEs) in the V + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%) and anemia (40.5%). In the LDAC arm, the most common all grade AEs were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), and constipation, asthenia and diarrhea (26.7% each). More pts who received V + LDAC experienced ≥ grade 3 AEs than those who received LDAC (95.2% vs 68.9%), particularly for blood and lymphatic system disorders (81.0% vs 44.4%), gastrointestinal disorders (21.4% vs 6.7%), and infections and infestations (45.2% vs 22.2%). The early death rates (V + LDAC/LDAC) at 30, 60 and 90 days were comparable between the two treatment arms: 30 days, 9.5%/8.9%; 60 days, 21.5%/17.8%; 90 days, 28.9%/33.4% (rates calculated using Kaplan-Meier method). PK analyses demonstrated that V is a moderate clearance drug with multi-compartmental PK behavior, a large volume of distribution and a long terminal half-life. Preliminary data suggest no drug-drug interactions following combination of V with LDAC. Conclusions: These preliminary phase II data demonstrate a significantly improved CR/CRi rate and a trend for EFS benefit with V + LDAC compared with LDAC alone in pts with newly diagnosed AML ineligible for intensive treatment. An increased frequency of AEs was observed with the addition of V, which was expected given its myelosuppressive mechanism of action; available data do not suggest increased early mortality for V + LDAC vs LDAC. A confirmatory phase III trial is needed to determine the clinical benefit of V + LDAC in pts with AML ineligible for intensive treatment. Disclosures: Off Label Use: Volasertib is an investigational agent. Fiedler:Pfizer, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Tidow:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer-Ingelheim: Employment. Döhner:Celgene, Amgen, Ambit, Astellas, Lilly: Consultancy.

Description: Key Points Volasertib plus low-dose cytarabine increased the response rate and improved survival in AML patients ineligible for intensive treatment. Volasertib plus low-dose cytarabine resulted in responses across all AML genetic subgroups and had a clinically manageable safety profile.

Description: Abstract 1549 Background: The prognosis of patients (pts) with relapsed or refractory (rel/ref) AML who are considered unlikely to benefit from or tolerate intensive salvage treatment is unfavorable and novel treatment strategies are needed. Repeated cycles of LD-Ara-C are a therapeutic option for palliative treatment; however, the outlook for these pts remains unsatisfactory. Plks are critical in cellular division and mitotic progression and Plk1 is overexpressed in many cancers including AML. Volasertib is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. In phase I/II trials in pts with solid tumors, volasertib demonstrated a favorable safety profile and encouraging antitumor activity. Here, we present updated results from the phase I part of an ongoing phase I/II study of volasertib in combination with LD-Ara-C or as monotherapy in AML pts considered ineligible for intensive salvage treatment. Material and Methods: This study follows a two-stage design. The phase I part, reported here, investigates the maximum tolerated dose (MTD) of volasertib as a 1-hr intravenous infusion on days 1 and 15 Q4W as monotherapy or in combination with fixed dose LD-Ara-C 20 mg bid subcutaneously on days 1–10 Q4W in pts with rel/ref AML. Dose escalation follows a 3+3 design with de-escalation. Blood samples for pharmacokinetic (PK) analyses were taken in cycles 1 and 2 and concentrations of volasertib and LD-Ara-C were determined. Results: In the monotherapy arm, increasing volasertib doses (150, 200, 350, 400, 450 mg) were evaluated in 29 pts (median age: 71 yrs [range 26–84]). Drug-related adverse events (AEs) were reported in 8 pts (27.6 %). Most frequent drug-related AEs (〉5%) were anemia in 3 pts (10.3%), and thrombocytopenia, epistaxis, and nausea in 2 pts each (6.9%). Grade 3/4 drug-related AEs included thrombocytopenia (2 cases), anemia, diarrhea, mucositis, neutropenia, and pneumonia (1 case each); there was 1 fatal (grade 5) drug-related AE (fungal pneumonia). Of the drug-related AEs, the following were dose-limiting toxicities (DLTs) per protocol: grade 4 pneumonia and fatal fungal pneumonia (n=1, at 150 mg), and grade 3 mucositis (n=1, at 400 mg). Monotherapy dose escalation is ongoing; pts have received volasertib doses of 500 mg without having reached the MTD. Preliminary best response data indicated minor antileukemic activity at low doses (150 and 200 mg); with 4/13 pts achieving no change as best response, mostly of short duration (median number of cycles initiated: 1 [range 1–5]). At higher monotherapy doses (≥350 mg), antileukemic activity was observed with 4/16 pts achieving a complete remission with incomplete blood count recovery (CRi) and 5/16 having temporarily stable blood values as best response. In the combination arm, volasertib doses of 150–400 mg were investigated. The MTD for volasertib in combination with LD-Ara-C was 350 mg (Bug et al ASH 2010). Seven out of 32 pts treated with volasertib + LD-Ara-C achieved a complete remission (CR or CRi). In responding patients, a median number of 6 treatment cycles was initiated (range 3–13) and a preliminary analysis revealed a median overall survival of 551 days (range 165–595). PK analysis showed that volasertib is a moderate clearance drug with multi-compartmental PK behavior with a large volume of distribution (〉4000 L) and a long terminal half-life (∼111 hrs). No drug interaction after co-administration of LD-Ara-C was observed. Conclusions: The phase I part of the study determined the MTD of volasertib in combination with LD-Ara-C to be 350 mg; the MTD of volasertib monotherapy has not yet been determined. Volasertib was well tolerated in this heavily pretreated AML pt population at doses above the recommended phase II volasertib dose used in pts with solid tumors. Most of the reported higher grade drug-related AEs were due to the myelosuppressive effect of volasertib. Preliminary results from the phase I trial show antileukemic activity of volasertib as monotherapy and in combination with LD-Ara-C. These results indicate Plk to be a potential new target for AML treatment and warrant proceeding with further clinical investigation of volasertib in AML pts. Disclosures: Bug: Novartis Pharma GmbH: Consultancy, Honoraria; Celgene GmbH: Consultancy, Honoraria. Off Label Use: Volasertib is an investigational agent. Müller-Tidow:Boehringer Ingelheim: Research Funding. Krug:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer Ingelheim: Employment. Garin-Chesa:Boehringer Ingelheim: Employment. Ottmann:Boehringer Ingelheim: Consultancy. Döhner:Celgene, Clavis: Membership on an entity's Board of Directors or advisory committees.