Adam Craig

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

BACKGROUND Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). INTERPRETATION Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. FUNDING Sunesis Pharmaceuticals.

Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors

Omacetaxine mepesuccinate (omacetaxine) is a first‐in‐class cephalotaxine with a unique mode of action, independent of BCR‐ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open‐label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1–14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1–7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty‐six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1–36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression‐free survival was 7.0 months [95% confidence interval (CI), 5.9–8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months—not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic‐phase CML with resistance or intolerance to multiple TKI therapies. Am. J. Hematol. 88:350–354, 2013.

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10–90 mg/m2; days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m2/day, days 1–5) or schedule B (2-hour intravenous infusion, 1 g/m2/day, days 1–5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m2 for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m2). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80–90 mg/m2; n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80–90 mg/m2. Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia.

Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors

Abstract Omacetaxine mepesuccinate promotes apoptosis by inhibiting the production of short-lived oncoproteins. The efficacy and safety of omacetaxine in patients with advanced chronic myeloid leukemia (CML) previously treated with tyrosine kinase inhibitors were assessed in two phase II trials (CML-202 and CML-203). Fifty-one patients in accelerated phase (AP-CML) and 44 in myeloid blast phase (BP-CML) received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1–14 every 28 days until hematologic response/improvement or any cytogenetic response, then days 1–7 every 28 days until disease progression. The primary endpoint was maintenance or attainment of a major hematologic response (MHR). Cytogenetic responses were also evaluated. MHR was 37% in patients with AP-CML and 9% with BP-CML (22% and 5% in those with a history of T315I). Most grade 3/4 adverse events were related to myelosuppression, and were generally manageable. Omacetaxine demonstrates activity and an acceptable safety profile in pretreated patients with advanced CML, irrespective of mutational status.

Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors.

Accelerated phase chronic myeloid leukemia (AP-CML) is characterized by tyrosine kinase inhibitor (TKI) resistance, additional cytogenetic abnormalities, and tyrosine kinase mutations.[1][1],[2][2] Although the recently approved TKI ponatinib may be effective in some patients with TKI-resistant AP-

Abstract C186: SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation

Background and purpose: BTK mediates B-cell receptor signaling and was validated as a target by the BTK inhibitor ibrutinib in several B-cell malignancies, including mantle cell lymphoma and chronic lymphocytic leukemia (CLL). However, patients may have or acquire resistance. Resistance mechanisms include mutation of the cysteine in the BTK active site that ibrutinib requires for covalent binding (C481). We identified and characterized SNS-062, a potent, noncovalent BTK inhibitor with activity towards BTK harboring resistance mutations that also inhibits ITK and may provide enhanced anti-tumor immune responses. SNS-062 shows restricted kinase selectivity and nonclinical pharmacology, pharmacokinetics (PK) and toxicology profiles distinct from ibrutinib and merits clinical investigation. Methods and Results: In in vitro kinase binding assays, SNS-062 bound to 9 kinases with Kd Citation Format: Minke E. Binnerts, Kevin L. Otipoby, Brian T. Hopkins, Tonika Bohnert, Stig Hansen, Gene Jamieson, Pamela A. Howland, Eric H. Bjerkholt, Deborah A. Thomas, Judith A. Fox, Adam R. Craig. SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C186.

Abstract C198: PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors

Background and purpose: Phosphatidyl-inositol (PI) dependent kinase 1, PDK1, is a master kinase that activates kinases important in cell growth and survival including members of the AKT, PKC, RSK and SGK families. PDK1 can interact with its substrates through PI-dependent (PH-mediated) or PI-independent (PIF-mediated) mechanisms. Here we report characterization of two potent PDK1 kinase inhibitors, SNS-229 and SNS-510, that block both PI-dependent and PI-independent substrate phosphorylation and have broad anti-tumor activity in hematologic cancers. Methods and results: SNS-229 and SNS-510 belong to a series of novel PDK1 inhibitors that bind the inactive conformation of PDK1 as determined by X-ray crystallography. The compounds bind deep in the adaptive pocket, distorting the N-terminal domain and perturbing the PIF-pocket, thereby affecting PI-independent substrate binding. SNS-510 was evaluated in more than 20 cell lines derived from hematologic cancers including AML, MM, DLBCL, and MCL and showed strong anti-proliferative activity with EC50s ranging from 3 nM to 900 nM, with particularly strong activity observed in the AML cell lines Molm-13 and MV4-11 (EC50 3 and 7 nM), the DLBCL cell line U-2932 (EC50 56 nM) and the MM cell lines U-266 and RPMI-8226 (EC50 130 and 163 nM). Anti-proliferative activity correlated with pathway modulation as assessed by inhibition of phosphorylation of PDK1, RSK, and AKT. Interestingly, inhibition of PDK1 phosphorylation was time-dependent showing 2 to 5-fold more inhibition after 24 hours than at 4 hours. In addition, SNS-510 produced substantial apoptosis after 24 hours. SNS-510 was compared to the PDK1 inhibitor GSK2334470, showing comparable biochemical potency. However, SNS-510 was 10 to 30 fold more potent at inhibiting PDK1 and RSK phosphorylation in all cell lines tested. SNS-510 was at least 10-fold more potent than GSK2334470 in 72 hour viability assays. In mice, SNS-229 and SNS-510 showed good oral bioavailability (%F>40%) with a Tmax of 4 to 8 hours and prolonged exposure. Pathway modulation was evaluated in vivo in a MV4-11 xenograft mouse model. Potent, dose-dependent pathway modulation was observed at 4 and 24 hours after a single oral dose of SNS-229 and SNS-510 (1 to 25 mg/kg). After 21- day dosing in MV4-11 xenografts, both SNS-229 and SNS-510 showed dose-related efficacy with > 95% tumor growth inhibition and partial regression (>50% tumor shrinkage) in 70% and 100% of animals at the highest dose. Conclusion: With this class of PDK1 inhibitors, we have previously reported strong tumor growth inhibition (66%-95%) in gastric, lung, pancreatic and colorectal cancer xenograft models. Here we report a PK/PD (pathway modulation) relationship that correlates with profound tumor growth inhibition in hematologic cancers. Thus, targeting the inactive conformation of PDK1 and inhibiting PI-independent substrate binding has broad potential for the treatment of solid and hematologic cancers. Citation Format: Stig Hansen, Johan Enquist, Jeff Iwig, Minke E. Binnerts, Gene Jamieson, Judith A. Fox, Adam R. Craig. PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C198.

Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome

Vosaroxin is an anti-cancer quinolone-derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥60 years of age with newly diagnosed acute myeloid leukemia (n=58) or myelodysplastic syndrome (≥10% blasts) (n=7) in a phase II non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on days 1 and 4 with decitabine 20 mg/m2 on days 1–5 every 4–6 weeks for up to seven cycles. Due to a high incidence of mucositis the subsequent 43 patients were given vosaroxin 70 mg/m2 on days 1 and 4. These 65 patients, with a median age of 69 years (range, 60–78), some of whom with secondary leukemia (22%), adverse karyotype (35%), or TP53 mutation (20%), are evaluable. The overall response rate was 74% including complete remission in 31 (48%), complete remission with incomplete platelet recovery in 11 (17%), and complete remission with incomplete count recovery in six (9%). The median number of cycles to response was one (range, 1–4). Grade 3/4 mucositis was noted in 17% of all patients. The 70 mg/m2 induction dose of vosaroxin was associated with similar rates of overall response (74% versus 73%) and complete remission (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (14.6 months versus 5.5 months, P=0.007). Minimal residual disease-negative status by multiparametric flow-cytometry at response (± 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with better median overall survival (34.0 months versus 8.3 months, P=0.023). In conclusion, the combination of vosaroxin with decitabine is effective and well tolerated at a dose of 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320

Phase 3 results for vosaroxin/cytarabine in the subset of patients ≥60 years old with refractory/early relapsed acute myeloid leukemia

Refractory/early relapsed (Ref/eRel) acute myeloid leukemia (AML) in patients ≥60 years old is the most important unmet medical need in the salvage setting, where outcomes are exceptionally poor and no standard of care exists.[1][1] Vosaroxin is a first-in-class anticancer quinolone derivative

Clofarabine plus cytarabine (ara-C) is an active induction regimen for newly diagnosed patients (pts) ≥ age 50 with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

6609 Background: Clofarabine is a new-generation nucleoside analog with activity in acute leukemias. As a potent inhibitor of ribonucleotide reductase, it is also suited for biochemical modulation strategies with other nucleoside analogs. In a phase I/II study of clofarabine + ara-C in pts with relapsed/refractory AML/MDS, we reported a response rate of 41% (24% CR, 17% CRp) (Blood 102:615a, 2003). Cellular pharmacology studies suggested that accumulation of intracellular clofarabine triphosphate resulted in higher ara-CTP accumulation of the leukemia blasts. METHODS We are conducting a phase II study of clofarabine + ara-C to evaluate efficacy and safety of this combination in pts ≥ 50 years (yrs) with newly diagnosed AML and high-risk MDS (≥ 10% marrow blasts). Pts with good prognosis karyotypes [t(8;21), inv(16), t(15;17)], ECOG PS > 2, and age ≥ 75 are excluded. Clofarabine is given at 40mg/m2/d as a 1-hour (hr) i.v. infusion for 5 days (d2-6) followed 4 hrs later by ara-C at 1g/m2/d as a 2-hr i.v. infusion for 5 days (d1-5). RESULTS 31 (28 AML, 3 MDS) of 37 pts are evaluable. Median age 61 yrs (range 50-72). Cytogenetics: diploid in 16 and abnormal in 15 pts. Median WBC 9.1 x 109/L (1-135.8). Median platelet count 44 x 109/L (8-871). 16 pts (52%) achieved CR after one induction course; another 4 pts (13%) achieved CRp. Of 6 pts who received a second induction course, one pt (CRp) responded. The CR rate was 63% (10/16 pts) in the diploid and 40% (6/15) in the abnormal group. Median time to CR: 28 days (23-56). 4 pts (13%) died on study: 1 pt died on d35 of complications due to sepsis; the remaining 3 pts died following a second induction course (d 47, 52, 78) due to prolonged cytopenias and sepsis. Clofarabine infusion related adverse events included facial flushing and headaches (< gr. 3) and were transient. Other toxicities included hyperbilirubinemia (gr. 3 in 3 pts) and pancreatitis (1 pt). CONCLUSIONS The combination of clofarabine + ara-C is active in older pts with newly diagnosed AML/high-risk MDS. The toxicity profile is acceptable. An update of response and toxicity data will be presented. [Table: see text].