An Open-label Randomized Controlled Phase II Study of AS1411 Combined With Cytarabine in the Treatment of Patients With Primary Refractory or Relapsed Acute Myeloid Leukemia

This is an open label randomized controlled phase II study of AS1411 combined with Cytarabine in the treatment of patients with primary refractory or relapsed acute myeloid leukemia.

Start Date01 Jan 2010

Sponsor / Collaborator

Antisoma Research Ltd.

NCT01066494 / Unknown statusPhase 2

A Phase IIa Pharmacokinetic and Efficacy Study of Amonafide L-malate (AS1413) in Combination With Cytarabine in Adult Patients With Acute Myeloid Leukemia (AML)

A phase IIa study to evaluate the pharmacokinetic and efficacy of amonafide L-malate (AS1413) in combination with cytarabine in treating patients with acute myeloid leukemia (AML)

Start Date01 Jan 2010

Sponsor / Collaborator

Antisoma Research Ltd.

EUCTR2007-004427-38-GB / Not yet recruitingNot Applicable

Phase 3 Open-Label Randomized Study of Amonafide L-Malate in Combination withCytarabine Compared to Daunorubicin in Combination with Cytarabine in Patients with Secondary Acute Myeloid Leukemia (AML) - ACCEDE

Start Date17 Jul 2009

Sponsor / Collaborator

Antisoma Research Ltd.

100 Clinical Results associated with Antisoma Research Ltd.

0 Patents (Medical) associated with Antisoma Research Ltd.

Literatures (Medical) associated with Antisoma Research Ltd.

15 Apr 2011·Cancer Research

Abstract 5384: Amonafide demonstrates a clearly differentiated chemoresistance and chemosensitivity profile when compared to classical TopoII inhibitors

Author: Chau, MyDoanh ; Christensen, Jennifer ; Green, Colin F. ; Ajami, Alfred

AbstractBackground: Amonafide is a novel DNA intercalator that induces apoptosis by mechanisms involving Topo II. Previous pharmacogenomic studies have shown differences between amonafide and classical TopoII inhibitors. Here data from publicly available gene expression studies have been analyzed to determine the chemoresistance and chemosensitivity profiles of amonafide compared to other agents.Methods: Data were mined from the Stanford, MIT-Broad and NCI databases. A subset of genes associated with drug efflux, chemo-sensitivity & -resistance was selected from the array data. Effects on gene expression were assessed by determining Pearson correlation coefficients (PCC) for gene-drug pairs.Results: For drug efflux genes & 15 genes associated with cell regulation, amonafide, and 5-azacytidine (azaC) had a positive correlation between expression & cytotoxicity; doxorubicin (Dox), and daunorubicin (Dnr) showed a negative correlation; cytarabine (araC) was unaffected. The chemo-sensitivity and -resistance profiles were determined by identifying the 15 genes with the highest correlation for each of the 5 drugs vs the other 4. Amonafide & aza-C differed clearly from araC, Dnr & Dox. Genes conferring chemosensitivity to amonafide had a negative correlation for araC, Dnr, and Dox. Genes with a positive correlation for araC, Dnr, and Dox, had a negative correlation with amonafide & azaC. A similar pattern of differences was seen for chemoresistance.Conclusions: Amonafide is a unique chemical entity whose cytotoxicity is not affected by multi-drug resistance expression. Amonafide may evade many of the pharmacogenomic drivers confering resistance to ara-C and anthracyclines. It should therefore retain greater efficacy in combination with araC and as an alternative to anthracyclines, especially in the treatment of myeloid leukemias.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5384. doi:10.1158/1538-7445.AM2011-5384

15 Apr 2010·Cancer Research

Abstract 3665: The novel DNA intercalator amonafide (AS1413), disrupts the cell cycle by mechanisms distinct from those of Topo II inhibitors daunorubicin and etoposide

Author: Senderovich, Shai ; Ajami, Alfred ; Jones, David ; McLaughlin, Fiona

AbstractAmonafide-L-malate (amonafide, AS1413) is a novel DNA intercalator that induces apoptosis through mechanisms involving Topoisomerase II. Previous studies have indicated that amonafide has a number of important properties that differ from those of classical TopoII poisons: 1. Amonafide is not a substrate for Pgp, MRP-1 or BCRP, resistance mechanisms that may contribute to treatment failure with classical TopoII inhibitors. 2. Amonafide is a non-quinodal napthylamide derivative, which is structurally unrelated to anthracycline or anthracenedione classes of antileukemic agents. It therefore lacks the redox and free radical reactive pharmacophores associated with the cardiotoxicity of the anthracyclines. 3. While amonafide exerts cell killing by acting on the Topoisomerase II cycle, it does not form cleavable complexes. Further work on elucidating the action of amonafide on the Topoisomerase II cell cycle is outlined here.Cell cycle analysis was performed on the AML cell lines Thp1 and KG1. Cells were exposed to AS1413, etoposide or daunorubicin at IC50 doses for 24 hours (etoposide and daunorubicin) or 48 hours (amonafide). Amonafide exposure resulted in a G2/M cell cycle arrest. Further analysis of the G2/M checkpoint by microscopic analysis of metaphase spreads from cells exposed to IC50 levels of amonafide showed that approximately 10% of the cells were arrested in metaphase (with chromosomes clearly visible), a higher proportion than seen in untreated cells. Furthermore, there was evidence for DNA bridge formation between cells which were not fully divided, indicating inhibition in metaphase. In contrast, etoposide treatment resulted in a G2/M arrest, with no cells visible in metaphase. Daunorubicin exhibited a G1/S arrest; while this was unexpected, the mechanism of action of daunorubicin has been shown to be less cell cycle specific, so this effect may be specific for the cell lines tested here. Again, no cells were arrested in metaphase. Cell cycle regulators such as p21 were up-regulated to a greater extent after exposure to amonafide than after etoposide or daunorubicin treatment. Further investigation of pharmacodynamic markers indicative of AS1413 clinical activity will be carried out.Amonafide has shown activity in AML, a setting where anthracyclines are currently used. The findings outlined here and the other distinctive properties of amonafide, notably evasion of multi-drug resistance mechanisms, suggest that amonafide could offer a clinical profile distinct from that of classical TopoII poisons. The value of replacing an anthracycline with amonafide is currently being tested in a large randomised phase III trial comparing amonafide plus cytarabine with daunorubicin plus cytarabine in patients with secondary AML.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3665.

15 Apr 2010·Cancer Research

Abstract 2614: Anti-tumor efficacy and pharmacokinetics of the novel aptamer AS1411 in a continuous infusion nude rat xenograft model

Author: Dobinson, Donna ; McLaughlin, Fiona ; Green, Colin ; Bestwick, Michael ; Djeha, Hakim

AbstractAS1411 is a novel DNA aptamer that binds to the multi-functional protein nucleolin and induces cell death. AS1411 has shown activity at two different doses in combination with cytarabine in a phase II study of patients with AML.We have previously shown that AS1411 has activity against a range of solid and hematological cancer cell lines, with IC50 values between 1 and 10 μM, when cells are exposed to AS1411 continuously for more than 3 days. We have also demonstrated efficacy in vivo in both lung (A549) and renal (A498) mouse xenografts. However, it has been challenging to provide optimal continuous dosing of AS1411 in mice; use of osmotic pumps or intraperitoneal bolus injection have been associated with low drug exposure. In the current study, we optimized the continuous infusion model by using nude, athymic rats with a surgically implanted catheter in a two-cycle xenograft study. Plasma and tumor samples were collected for PK determination, allowing a correlation of PK with efficacy.The colorectal cell line HT29, which is sensitive to AS1411 in vitro, was used in this study. Cells (5×106) were implanted subcutaneously in the flank of female nude rats and tumors were allowed to grow to approximately 200 − 300 mm3 before surgical cannulation of the femoral vein. Following recovery, animals received AS1411 at 40, 80 or 180 mg/kg/day for two 7 day cycles of continuous infusion, 7 days apart. A vehicle control group received saline.Animals in the 80 and 180 mg/kg/day groups exhibited a significant (p<0.01) reduction in tumor volume compared to control animals at day 33 and at day 22 (interim analysis); this was not observed for animals in the 40mg/kg/day group (40mg kg/day in this model does not directly correlate to the clinical dose of the same name). AS1411 was well-tolerated by all animals in all dose groups.Plasma levels of AS1411 were measured at the three dose levels after one cycle of treatment. Mean AS1411 plasma concentrations were 0.7, 2.5 and 5.0 μM, for rats treated at 40, 80 and 180 mg/kg/day, respectively. The plasma concentrations in the two higher dose groups are within the range of the in vitro IC50 concentrations of a panel of cell lines.We conclude that AS1411 shows activity in vivo in the HT29 nude rat xenograft model. Doses associated with significant reductions in tumor volume were those that produced plasma concentrations close to the IC50 level for AS1411. This correlation has been used in planning further clinical development of AS1411, including a phase IIb study of patients with AML.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2614.

News (Medical) associated with Antisoma Research Ltd.

21 May 2010

·www.biospace.com

Antisoma PLC to Present at the Citi Investment Research Global Health Care Conference

LONDON--(Marketwire - May 21, 2010) - 21 May 2010, London, UK, and Cambridge, MA: Antisoma plc (LSE: ASM; USOTC:ATSMY) announces that its CEO, Glyn Edwards, will present at the 2010 Citi Investment Research Global Health Care Conference in New York at 10.30 am local time (3.30 pm BST) on Thursday 27 May. A webcast of the presentation will be available on Antisoma's website at For live viewing of the webcast, it is recommended that viewers log on 15 minutes early in order to register and download any necessary software. Enquiries: Alison Saville Senior Marketing and Communications Executive Antisoma plc +44 (0)20 3249 2144 Background on Antisoma Antisoma is a London Stock Exchange-listed biopharmaceutical company that develops novel products for the treatment of cancer. The Company has operations in the UK and the US. Please visit for further information about Antisoma. [HUG#1417932] Enquiries: Alison Saville Senior Marketing and Communications Executive Antisoma plc +44 (0)20 3249 2144

16 Feb 2007

·www.pharmatimes.com

Antisoma losses narrow, partnership deal soon for AS1404

The UK’s Antisoma says that its half-year operating losses have narrowed 18.8% and is predicting a strong 2007 on the back of progress through the pipeline of a number of drugs. The loss was £7.8 million while revenues for the six months ended December 31 were £300,000, down from £1.3 million in the like, year-earlier period. The company ended the year with cash and equivalents of £33.6 million. Antisoma’s chairman Barry Price said the company had ended the year on a high, most notably after having announced positive data from three Phase II trials of AS1404 in lung, prostate and ovarian cancer. Preparations are being made for a Phase III trial in lung cancer progressing through talks with potential marketing partners for the drug. Dr Price noted that “interest in licensing AS1404 has been considerable and we are confident that we will reach an agreement with a strong partner during the first half of 2007.” Roche, which had first refusal on AS1404 through another licensing deal with Antisoma, chose not to exercise its option to take the drug into Phase III in June, leading to a dramatic fall in the UK firm’s share price. Sanofi-Aventis, AstraZeneca and Pfizer have been rumoured to be interested in a partnership. Regarding the rest of the pipeline, AS1411 is progressing to Phase II trials in renal cancer and acute myeloid leukaemia and a Phase I study shows promising activity in renal cancer. Plans are being made to begin a Phase II trial of the anti-MUC1 antibody drug AS1402 during this year and first trials of the antibody-cytokine drug, AS1409, in melanoma and renal cell carcinoma, should start in 2007. In December, Antisoma raised £26.3 million, before expenses, through an oversubscribed placing of almost 74 million new shares and “the proceeds will enable us to press ahead with the development of our promising pipeline,” Dr Price concluded.

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Drug(Targets)	Indications	Global Highest Phase

Monoclonal antibody HMFG1(Cancer Research UK) ( MUC1 )	Locally advanced breast cancer More	Discontinued
AS-1411 ( NCL )	Relapsing acute myeloid leukemia More	Discontinued
Amonafide Maleate ( DNA x Top II )	Acute Myeloid Leukemia More	Pending
AS-1409 ( EDB-FN x IL-12R )	Metastatic Renal Cell Carcinoma More	Pending
Vadimezan ( STING )	Metastatic castration-resistant prostate cancer More	Pending

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