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Systemic cytotoxic chemotherapy has benefited manypatients with haematological and solid tumours. However,the success of cytotoxic drugs is hampered by their tox-icity to non-tumour tissue. The relative non-selectivity ofconventional chemotherapy limits the dose that can bedelivered to tumours and can cause significant morbid-ity (and occasionally mortality) in patients. Therapy withsmall, targeted molecules, for example sunitinib, aims tosuppress pathways that promote tumour survival, but speci-ficity can be limited by the inhibition of multiple targets.The exquisite specificity of antibodies potentially over-comes this challenge and provides an ideal mechanism fortargeted cancer therapy. The ability to produce antibod-ies with a single specificity, that is, monoclonal antibod-ies (mAbs), has produced a revolution in cancer therapy.Using hybridoma technology, antibody libraries, or trans-genic mice, high-affinity antibodies can be generated againstan extensive range of targets. mAb therapy can disruptcancer cells using a variety of mechanisms. An mAb cantarget a growth factor or its receptor, initiate an immuno-logical assault, activate apoptosis, or deliver a cytotoxicpayload such as a radioisotope. Furthermore, the physicalcharacteristics of mAb-based molecules can be extensivelymodified so that therapeutics can be designed to meet spe-cific clinical requirements. Several antibody-based therapiesare now licensed to treat haematological or solid tumours(Table 1).

Background: HDACi have demonstrated activity as anticancer agents and are licensed for use in cutaneous and peripheral T cell lymphoma. Cardiac effects including arrhythmias and QTc prolongation have previously been associated with HDACi administration in humans. This report summarizes the cardiac adverse event (AE) profile observed during the recently completed FIH Phase I trial of JNJ26481585. Methods: Continuous oral daily dosing (QD) of JNJ26481585 in 21-day (D) cycles (C) was investigated initially in 20 patients (pts) demonstrating activity (including 1 partial response, 1 minor response, 1 prolonged stable disease in melanoma) but ventricular arrhythmia (2 pt) and fatigue (1 pt) were dose-limiting. To improve tolerability, 3 intermittent schedules (QD Mon/Wed/Fri (MWF); QD Mon/Tue/Wed/Thu (MTWT); QD Mon/Thu (MT)) also in 21-D C were subsequently explored in 38 (including expansion cohort), 19 and 15 pts respectively. All pts had triplicate 12-lead ECG (tECG), 24 hour ECG (Holter) and echocardiography or MUGA scan for assessment of left ventricular ejection fraction (LVEF) at baseline and during treatment. Analysis of mean QTcF, categorical QTcF and preliminary assessment of cardiac rhythm/morphology was performed. Results: 12mg QD MWF was identified as the recommended Phase II dose (RP2D) based on safety, tolerability, PK predictions and PD activity. Maximum average increase in mean QTcF from baseline ranged from 0 to 8 milliseconds (ms) during cycles 1 and 2 across the 4 schedules. At RP2D, the maximum average increase in mean QTcF observed was 6ms. 1 out of 38 pts (2.6%) treated on the MWF schedule experienced a Grade (G) 3 QTcF prolongation, possibly related to ST-T segment changes identified as a class effect of HDACi. QTcF prolongation G1–2 was rarely observed across schedules and mostly occurred as an isolated reversible observation whilst on study drug. Reversible, non-sustained ventricular tachycardia (NSVT) was observed as a dose limiting toxicity (DLT) in 3 out of 39 pts (7.7%) receiving QD or MTWT dosing but was not observed on the MWF or MT schedules. Other reversible, but dose-limiting, cardiac effects were T-wave inversion (2 pts on MT and MTWT), supraventricular tachycardia (1 pt on MT) and hypertension with raised troponin (1 pt on MWF). Non-specific, reversible, asymptomatic ST-T segment changes were frequently observed. LVEF was unaffected during treatment with JNJ26481585. Conclusion: The RP2D of JNJ26481585 was determined as 12 mg on the MWF schedule and demonstrated an acceptable cardiac safety profile. One pt had QTcF>500 ms but no clinically significant effect on the QTcF interval was observed across schedules. Reversible NSVT was identified as a DLT in some patients on the QD and MTWT dosing schedules but not on the MWF and MT schedules. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A164.

Background: Antibody Directed Enzyme Prodrug Therapy (ADEPT) uses an antibody linked to an enzyme to deliver enzyme selectively to tumor deposits. When enzyme has localized to the tumor and cleared from the circulation, a low-toxicity prodrug is given. The prodrug is converted into an active cytotoxic drug by the enzyme in tumor deposits. Each targeted enzyme can convert many molecules of the prodrug and a bystander effect is generated. We have previously reported on dose-finding, immunogenicity, and toxicity in a Phase I clinical trial and that the components of ADEPT function as designed in patients (Mayer A, et al. Clin Cancer Res 2006;12:6509-16). Evidence of efficacy is now reported in relation to total prodrug dose (TPD), toxicity, and repeated treatment. Methods: A fixed dose of recombinant fusion protein (MFECP1) was administered intravenously (iv). It consisted of single chain Fv targeting carcinoembryonic antigen (CEA) and carboxypeptidase G2 (Tolner B, et al. Nature Protocols 2006;1:1006-21; Tolner B, et al. Nature Protocols 2006;1:1213-22). Bis-iodo phenol mustard prodrug was given iv when carboxypeptidase activity had cleared from the blood. Patients had measurable, previously treated, advanced malignancy. Either 1, 2, or 3 ADEPT treatments were given over 2 to 10 days. Results: 43 patients with CEA expressing tumors were treated (colorectal, gastro-esophageal, breast, unknown primary, gallbladder, peritoneal, appendix, pancreas). TPD per patient was escalated from 37 mg/m2 to 3226 mg/m2. Thrombocytopenia and neutropenia were the principal side effects, resulting in a maximum tolerated TPD dose of 1200 mg/m2 divided into 2 complete ADEPT treatments. Human anti-enzyme antibody developed in 40% of patients having a single treatment, in 75% of patients after 2 treatments, and in 100% of patients after 3 treatments; it is not yet known whether this will compromise repeated therapy. Efficacy was assessed by 18F FDG-PET using the criteria for partial response defined by Green et al. and shown to predict significant survival prolongation (Eur J Nucl Med Mol Imaging 2008;35:393-406). Four of 9 patients had partial response at TPD ≥ 900 mg/m2. There was a significant correlation between TPD and reduction of tumor FDG uptake (P=0.031). Response was corroborated by falls in serum CA19-9 ≥ 25% in the 3 patients with partial response who had raised levels before treatment. Stable disease by RECIST criteria was seen in 69% of patients having TPD ≥ 900 mg/m2. Conclusions: Evidence of efficacy was shown at a TPD ≥ 900 mg/m2 with clinically significant responses in 44% of patients. These results support the case for conducting a randomized Phase II clinical trial.