Acute Myelogenous Leukemia (AML)

August 10, 2015

Sunesis Pharmaceuticals issued results of a phase III trial of vosaroxin and cytarabine in 711 patients with relapsed or refractory acute myeloid leukemia (AML). VALOR is a randomized, double-blind, placebo-controlled trial conducted at 124 sites in 15 countries. Patients were stratified for age, geographic region and disease status and randomized one-to-one to receive either vosaroxin and cytarabine or placebo and cytarabine. Although no significant difference was observed in the primary endpoint of overall survival (OS) between groups (unstratified analysis, median 7.5 months for vosaroxin and cytarabine [vos/cyt] v. 6.1 months for placebo and cytarabine [pla/cyt], HR=0.87, p=0.061), OS was significantly prolonged in a predefined analysis that stratified by factors used in randomization (stratified log-rank p=0.024). This was supported by a sensitivity analysis of OS censoring for subsequent transplant (median 6.7 months [vos/cyt] v. 5.3 months [pla/cyt], HR=0.81, p=0.024). Prespecified subgroup analyses according to randomization strata demonstrated that OS benefit with vosaroxin was greatest in patients age =60 years (7.1 months [vos/cyt] v. 5 months [pla/cyt], HR=0.75; p=0.0030). Median OS was not significantly different between treatment arms in patients age <60 years (HR=1.08; p=0.60). The complete remission (CR) rate, the sole secondary efficacy endpoint in the VALOR trial, was significantly greater with vosaroxin (30.1% v. 16.3% with pla/ cyt, p<0.0001). Combined complete remission rate was 37.1% and 18.6% for the vos/cyt and pla/cyt treatment arms, respectively (p<0.0001). Prespecified subgroup analyses demonstrated significantly higher response rates for vos/cyt-treated patients across all randomization strata except for those less than 60 years of age, with the most pronounced improvement in patients aged =60 years (CR: 31.9% for vos/cyt vs 13.8% for pla/cyt; p<0.0001). A higher proportion of patients in the vos/cyt arm achieved CR with study drug prior to transplant (48% vos/ cyt; 32% pla/cyt). In patients with CR, median leukemia-free survival (LFS) was 11 months with vos/cyt v. 8.7 months with pla/cyt (HR=0.89; p=0.63). Event-free survival (EFS) was significantly prolonged in vos/cyt-treated patients (HR=0.67; p<0.0001). Thirty-day and 60-day all-cause mortality was similar in the two treatment arms (30-day: 7.9% v. 6.6%; 60-day: 19.7% v. 19.4% for vos/cyt vs pla/cyt, respectively). The company is proceeding with registration in Europe and the U.S.

January 19, 2015

Celator Pharmaceuticals issued results of a phase II study of CPX-351 in adult patients with first-relapse acute myeloid leukemia (AML). The randomized, controlled phase II study enrolled 125 patients, ages 18 to 65, from 35 centers in the U.S., Canada and Europe diagnosed with AML in first relapse after an initial complete remission lasting for one month or longer. Patients were randomized 2:1 to receive CPX-351 (100 u/m(2) days one, three and five by 90-minute infusion) or investigators’ choice of first salvage chemotherapy. Control salvage treatment was usually based on cytarabine and an anthracycline, often with one or more additional agents. The primary endpoint for the study was survival at one year post treatment. Patients were stratified per the European Prognostic Index (EPI) into favorable, intermediate and poor-risk groups based on duration of first complete remission, cytogenetics, age and transplant history, and were well-balanced between the control and the treatment arms. Results showed improved efficacy following CPX- 351 and the protocol-defined EPI-poor-risk subset demonstrated statistically significant improvement in overall survival (HR, 0.55; P=0.02), improvement in event-free survival (HR, 0.63; P=0.08) and higher response rate (39.3% v. 27.6%). Additionally, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% v. 24.1%). CPX-351 currently is in phase III trials.

July 21, 2014

Boehringer Ingelheim released results of a phase II trial of volasertib for older patients with acute myeloid leukemia (AML). The open- label study enrolled 87 adult patients (median age 75) with AML not considered suitable for intensive induction therapy. Patients were randomly assigned to receive either volasertib in combination with LDAC (n=42) or LDAC (n=45). Patients were randomized in a 1:1 ratio to receive the combination of LDAC plus volasertib 350mg intravenously over one hour on days one and 15 versus LDAC 20mg twice daily subcutaneously on days one to 10 alone. Cycles were scheduled every four weeks until progression, relapse, intolerance or patient/ investigator requested discontinuation. The study’s primary endpoint showed the objective response rate (complete remission or complete remission with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC versus LDAC alone (31% v. 13.3%, p=0.052). The trial showed patients treated with volasertib combined with LDAC had a median overall survival of eight months versus 5.2 months in patients treated with LDAC (p=0.047). Median event-free survival was prolonged in patients receiving volasertib and LDAC versus LDAC (5.6 months v. 2.3 months; p=0.021). Relapse- free survival for volasertib and LDAC versus LDAC was 18.5 months versus 10 months. There is an ongoing phase III study initiated for volasertib.

June 23, 2014

Ambit Biosciences released results of a phase II study of quizartinib (AC220) for FLT3-ITD (+) relapsed or refractory acute myeloid leukemia. A total of 76 subjects were enrolled. Dosing was 30mg/day and 60mg/day. The CRc rate remained at 47% (5% CR+CRp, 42% CRi). The rate of hematopoietic stem cell transplantation (HSCT) after quizartinib use remained at 34%. The median overall survival was 20.9 weeks for patients initially treated at 30mg/day and 25.4 weeks for patients at 60mg/day, with 24/38 patients censored as they remained alive in follow-up at the time of the analysis. In addition, the further follow-up now shows 24 subjects were alive at >24 weeks with four subjects alive >12 months. Overall, the additional follow up continued to show that both the 30mg and the 60mg doses of quizartinib showed substantial activity in terms of overall CRc rate and bridge to HSCT with impact on improved median OS. The safety profile is similar at both doses and QTcF prolongation did not worsen with additional duration of treatment and/or follow up. There is a currently ongoing phase III study of quizartinib (AC220).

December 13, 2010

Celator issued positive results from a phase II trial of CPX-351 for the treatment of acute myeloid leukemia (AML).This North-America-based, randomized, open-label enrolled 126 subjects with newly diagnosed AML. The subjects received CPX- 351 or the conventional cytarabine and daunorubicin regimen. At 12 months, CPX-351 resulted in the following improvements over the conventional regimen: a higher aplasia rate (87.7% vs. 71.1%), a higher remission rate (complete remissions and complete remissions with incomplete neutrophil/platelet recovery; 66.7% vs. 51.2%), lower induction mortality (4.7% vs. 14.6%), improved median event-free survival (5.4 vs. 2 months) and improved median overall survival (14.7 vs. 12.9 months). Greater improvements over the conventional regimen were also observed in a subset of high-risk subjects and those with secondary AML. Adverse events were comparable between the treatment arms.

March 29, 2010

BioSante issued positive results from a phase II trial of GVAX, a potential vaccine for the treatment of acute myelogenous leukemia (AML). This open-label trial enrolled 54 subjects who received either immunotherapy-primed lymphocytes following autologous stem cell transplantation, with or without GVAX. Of the 54 subjects enrolled, 28 (52%) received a pre-transplantation GVAX AML dose. A total of 46 (85%) subjects achieved complete remission during the treatment period. For all subjects who achieved complete remission, the 3-year relapse-free survival rate was 47.4% compared to 61.8% in the GVAX-treated group. While the overall survival rate in all subjects was 57.4%, it was 73.4% in the GVAX-treated group.

December 14, 2009

Sunesis reported positive results from a phase II trial of voreloxin for the treatment of acute myeloid leukemia. This open label study, dubbed REVEAL-1 (Response Evaluation of Voreloxin in Elderly AML), enrolled l 13 previously untreated, elderly subjects who were unlikely to benefit from standard induction chemotherapy. The trial included three dosing schedules: Schedule A, once weekly for three weeks, Schedule B, once weekly for two weeks and Schedule C, on days one and four at either 72 mg/m2 or 90 mg/m2. Median survival was 8.7 months in Schedule A; 5.8 months in Schedule B; and 7.3 months in Schedule C (72 mg/m2 on days one and four). Median duration of remission was 10.7 months and one year survival was 38% for Schedule A. For the other schedules, median duration of remission has not been reached and one year survival is too early to evaluate. Subjects aged 75 or older (n≡49) with at least 1 additional risk factor at diagnosis experienced a CR rate of 30% and a 30-day all-cause mortality of 5%. Survival in these patients was too early to evaluate. For Schedule C, response rates were 38% and 30- and 60-day all-cause mortality were 7% and 17%, with improved tolerability over Schedule A. Based on trial results, Schedule C was determined to be the optimal regimen for future studies.

February 4, 2008

Bayer and Onyx released positive results from an ongoing phase I/II trial of sorafenib for the treatment of acute myeloid leukemia (AML). This trial enrolled newly relapsed subjects and those newly diagnosed with high-risk disease. The subjects received sorafenib in combination with the standard of care chemotherapy combination for AML, idarubicin and cytosine arabinoside. Results showed that sorafenib targeted the FLT3-ITD mutation, a genetic mutation active in about one third of the subjects with AML. In sixteen evaluable subjects with this mutation, sorafenib reduced the median percentage of leukemia cells circulating in the blood from 81% to 7.5% and in the bone marrow from 75.5% to 34%. In addition, two subjects had circulating leukemia cells, or blasts, drop to zero. Treatment was well tolerated to date and the maximum tolerated dose has not been reached. Based on the results the trial will continue as planned.

Wilex released positive results from a phase I trial of WX-UK1 for the treatment of solid tumors. This dose escalation study enrolled twenty five subjects who received once weekly infusions of WX-UK1 for three weeks at various fixed doses and daily capecitabine (Xeloda) concomitantly for two weeks. This three-week cycle was repeated until disease progression or toxicity, or for a maximum of fifteen treatment cycles. Treatment was safe and well tolerated, with no increase in adverse events and no reported serious adverse events. Pharmacokinetic analysis showed no significant reciprocal drug-drug interactions. WX-UK1 showed dose-linear pharmacokinetic profile over the dose range tested. Preliminary efficacy data revealed prolonged stable disease and partial response in several of the subjects. Based on the results, Wilex plans to continue the development of WX-UK1.

June 3, 2002

Further analysis of phase III trial results indicate that Zamyl was well tolerated but did not achieve a statistically significant overall response in subjects with relapsed or refractory acute myeloid leukemia. With all evaluable subjects analyzed on an intent-to-treat basis, the overall response rate from Zamyl in combination with chemotherapy was 36%, compared to 28% for subjects who received chemotherapy alone. Twenty-nine percent of subjects receiving Zamyl plus chemotherapy achieved a complete response, compared to 23% treated with only chemotherapy. Based on these results, Protein Design Labs does not plan to file a Biologic License Application (BLA) for Zamyl at this time.

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