A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK).

BACKGROUND: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS: Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS: Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS: Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV: NCT00942877.

A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach. MATERIALS AND METHODS: This study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed. RESULTS: Sixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break. CONCLUSIONS: Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.

Primary mediastinal B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBCL) is a sub-type of the heterogeneous diffuse large B-cell lymphoma category, and comprises approximately 5% of all non-Hodgkin's lymphomas (NHL). It was first recognized as a distinct clinico-pathologic entity 20 years ago, and recent work has further characterized specific molecular features. Gene expression profiling has suggested a partial overlap with nodular sclerosing Hodgkin lymphoma (HL), with which it shares some clinical features. The optimal management remains a matter of debate. There is uncertainty as to whether weekly alternating chemotherapy regimens may be more effective than CHOP, whether consolidation radiotherapy (RT) to the mediastinum is always required, whether PET scanning can be used to determine this, and whether the use of rituximab as part of initial therapy will change the answers to these questions. The International Extranodal Lymphoma Study Group (IELSG) 26 clinicopathologic study of PMBCL, which has recently opened, represents a first attempt to gather data prospectively on some of these issues.

ABVD for Hodgkin's lymphoma: full-dose chemotherapy without dose reductions or growth factors.

BACKGROUND: We investigated whether administration of full-dose ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy without growth factors, and irrespective of the granulocyte count, caused treatment delays or increased the number of infective episodes, in patients with Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Thirty-eight patients with confirmed predominantly early-stage HL were treated with ABVD outside clinical trial protocols over a 5-year period on an outpatient basis. RESULTS: Ninety-five per cent of patients completed their scheduled ABVD regimen without adverse effects despite the development of neutropenia. Anaemia and thrombocytopenia did not present problems. Febrile neutropenia complicated 0.57% of combination chemotherapy injections. No growth factors were used and no dose modifications were carried out apart from the omission of bleomycin in one patient for the last two cycles of treatment due to the development of lung toxicity. All patients are currently disease-free, although three (7.8%) required salvage high-dose therapy (one relapsed and two with refractory disease). CONCLUSIONS: ABVD administration irrespective of granulocyte counts allowed the treatment to be given at full dose without delays or significant number of infective episodes. There was no need for growth factor support, minimising treatment costs. The use of full-dose ABVD irrespective of granulocyte count should be evaluated in future protocols for HL.

Engineering antibody molecules.

Advances in PCR techniques and the increase of the antibody V region sequences in the database have boosted developments in the field of antibody engineering. The V region genes can be amplified from hybridomas (1), preimmunized donors (2), naive donors (3), or from the cells expressing antibodies.

Antibody engineering: comparison of bacterial, yeast, insect and mammalian expression systems.

Engineered antibody molecules, and their fragments, are being increasingly exploited as scientific and clinical tools. However, one factor that can limit the applicability of this technology is the ability to express large amounts of active protein. In this review we describe the relative advantages and disadvantages of bacterial, yeast, insect and mammalian expression systems, and discuss some of the problems that can be encountered when using them. There is no 'universal' expression system, that can guarantee high yields of recombinant product, as every antibody-based molecule will pose its own problems in terms of expression. As a result the choice of system will depend on many factors, including the molecular species being expressed, the precise sequence of the individual antibody and the preferences of the individual investigator. However, there are general rules with regards to the design of expression vectors and systems which will help the investigator to make informed choices as to which strategy might be appropriate for their application.

Construction, expression and characterisation of a single chain anti-tumour antibody (scFv)-IL-2 fusion protein.

We describe the production and preliminary characterisation of a fusion protein between interleukin-2 and a single-chain Fv version of the H17E2 anti-placental alkaline phosphatase (PLAP) antibody. This molecule could be used to target interleukin-2 to PLAP-expressing tumours.