Antisoma Research Ltd

Cambridge, MA, United States

Antisoma Research Ltd

Cambridge, MA, United States
SEARCH FILTERS
Time filter
Source Type

Isambert N.,Center Georges Francois Leclerc | Isambert N.,French Institute of Health and Medical Research | Campone M.,Site Hospitalier Nord Bd J Monod | Bourbouloux E.,Site Hospitalier Nord Bd J Monod | And 7 more authors.
European Journal of Cancer | Year: 2010

Purpose: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311. Patients and methods: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3 consecutive weeks followed by 1 week rest (constituting 1 cycle) in subjects with advanced solid tumours. Results: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640 mg/m2. All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1-2, except for the blood and lymphatic system disorders, which were primarily of grades 3-4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3 weeks every 4 weeks is 480 mg/m2, with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7 days. Treatment at this dose offers a predictable safety profile and excellent tolerability. Conclusion: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound. © 2009 Elsevier Ltd. All rights reserved.


Ibrahim N.K.,University of Houston | Yariz K.O.,University of Miami | Bondarenko I.,Dnipropetrovsk State Medical Academy | Manikhas A.,St Petersburg State Medical Institution Municipal Clinical Oncology Center | And 11 more authors.
Clinical Cancer Research | Year: 2011

Purpose: AS1402 is a humanized immunoglobulin G1 antibody that targets the aberrantly glycosylated antigen MUC1, which is overexpressed in 90% of breast tumors and contributes to estrogen-mediated growth and survival of breast cancer cells in vitro by modulating estrogen receptor (ER) activity. Aromatase inhibitors have been reported to enhance antibody-dependent cell-mediated cytotoxicity elicited by antibodies in vitro. We compared the outcomes of patients with breast cancer treated with letrozole with or without AS1402. Experimental Design: The study population included 110 patients with locally advanced or metastatic hormone receptor-positive breast cancer randomized to receive 2.5 mg letrozole only once daily or with a weekly 9 mg/kg AS1402 infusion. The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, time to progression, and safety. AS1402 exposure and influence of allotypes of FcgRIIIa, FcgRIIa, and MUC1 were evaluated. Results: The study was stopped early because of a trend toward worse response rates and a higher rate of early disease progression in the AS1402 + letrozole arm. Final analysis revealed no significant difference in efficacy between the study arms. Evaluated gene polymorphisms did not define patient subgroups with improved outcomes. Addition of AS1402 to letrozole was associated with manageable toxicity. Conclusions: Because adding AS1402 to letrozole did not improve outcomes compared with letrozole only, blocking ER maybe a better strategy for harnessingMUC1modulation of the ER to a clinical advantage. FcgRIIIa, FcgRIIa, and MUC1 allotype did not predict outcome for patients treated with letrozole with or without AS1402. ©2011 AACR.


Rudman S.M.,King's College London | Rudman S.M.,Guys And St Thomas Nhs Foundation Trust | Jameson M.B.,Waikato Hospital | McKeage M.J.,Auckland City Hospital | And 7 more authors.
Clinical Cancer Research | Year: 2011

Purpose: AS1409 is a fusion protein comprising a humanized antibody BC1 linked to interleukin-12 (IL-12). It is designed to deliver IL-12 to tumor-associated vasculature using an antibody targeting the ED-B variant of fibronectin. Experimental Design: We conducted a phase 1 trial of weekly infusional AS1409 in renal carcinoma and malignant melanoma patients. Safety, efficacy, markers of IL-12-mediated immune response, and pharmacokinetics were evaluated. Results: A total of 11 melanoma and 2 renal cell carcinoma patients were treated. Doses of 15 and 25 μg/ kg were studied. Most drug-related adverse events were grade 2 or less, and included pyrexia, fatigue, chills, headache, vomiting, and transient liver function abnormalities. Three dose limiting toxicities of grade 3 fatigue and transaminase elevation were seen at 25 μg/kg. IFN-γ and interferon-inducible protein-10 (IP-10) were elevated in all patients, indicating activation of cell-mediated immune response; this was attenuated at subsequent cycles. Antidrug antibody responses were seen in all patients, although bioassays indicate these do not neutralize AS1409 activity. Plasma half-life was 22 hours and not dose-dependent. Five patients received 6 cycles or more and a best response of at least stable disease was seen in 6 (46%) patients. Partial response was seen in a melanoma patient, and disease shrinkage associated with metabolic response was maintained beyond 12 months in another melanoma patient despite previous rapid progression. Conclusions: The maximum tolerated dose was established at 15 μg/kg weekly. AS1409 is well tolerated at this dose. Evidence of efficacy assessed by RECIST, functional imaging, and biomarker response warrants the planned further investigation using this dose and schedule in malignant melanoma. ©2011 AACR.


Yin W.,Antisoma Research Ltd | Karyagina E.V.,Saint Petersburg National Health Care Institution City Hospital and 15 | Lundberg A.S.,Antisoma Research Ltd | Greenblatt D.J.,Tufts University | Lister-James J.,Antisoma Research Ltd
Biopharmaceutics and Drug Disposition | Year: 2010

The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25mg/m2, n = 14) or oral (40mg/m 2, n = 42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23 h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (±SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3±4.0 vs 9.772.0 h, p = 0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean oral bioavailability of 2F-ara-A was 58%. Compared to the time-matched drug-free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F-ara-AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F-ara-AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F-ara-AMP treatment. Thus the 25mg/m2 IV and 40mg/m 2 oral doses of 2F-ara-AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes. Copyright © 2009 John Wiley & Sons, Ltd.


Royer B.,Besancon University Hospital Center | Royer B.,French Institute of Health and Medical Research | Royer B.,University of Franche Comte | Yin W.,Antisoma Research Ltd | And 7 more authors.
British Journal of Cancer | Year: 2010

Background:HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model.Method:Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg -1. Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set.Results:A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion.Conclusion:A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody. © 2010 Cancer Research UK All rights reserved.

Loading Antisoma Research Ltd collaborators
Loading Antisoma Research Ltd collaborators