Studies with Cancer Research UK

Clinical Pharmacology and Trials Team

Section: Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)

 

A Phase I Pharmacokinetic and Pharmacodynamic Study of 17AAG via Intravenous Administration of Patients with Advanced Malignancy

The Phase I trial of 17-allyl-amino,17-demethoxygeldanamycin (17AAG) was completed and closed in 2004. Evidence was produced in tumour tissue that the drug successfully inhibited the molecular chaperone HSP90 (heat shock protein 90), as judged by reproducible changes in Raf-1 and cyclin-dependent kinase 4 (CDK4) depletion along with HSP70 induction. Evidence of prolonged stable disease was seen in two patients with melanoma. Based on our experience with the weekly schedule, approval has been given by the National Cancer Institute for a Phase II study with 17AAG in melanoma together with a Phase I study with the 17AAG analogue 17DMAG which is due to commence shortly.

A Phase I Trial of SR-4554 via Intravenous Administration for the Non-Invasive Investigation of Tumour Hypoxia by Magnetic Resonance Spectroscopy (MRS) in Patients with Malignancy

The Phase I study of SR-4554, a new in-house hypoxia imaging agent developed in collaboration with SRI International, has demonstrated localisation of fluorine signal in tumours using MRS. Studies have shown satisfactory pharmacokinetics and identified a maximum tolerated dose in the absence of anti-emetics. Further dose escalation with prophylactic anti-emetics has been carried out and a maximum deliverable dose identified.  It remains to be determined whether signal localisation will prove to be feasible.

A Phase I Trial of the DNA Hypomethylating Agent 5-Aza-2'-deoxycytidine (Decitabine) in Combination with Carboplatin Both Given 4 Weekly by Intravenous Injection in Patients with Advanced Solid Tumours

Decitabine is an inhibitor of DNA methyltransferase. Gene transcription may be switched off by promoter hypermethylation. Inhibiting methyltransferase may result in re-expression of such genes. Of particular interest are mismatch repair genes, such as MLH1, since loss of expression can lead to cytotoxic drug resistance. In preclinical studies in cisplatin- and carboplatin-resistant tumour models, pre-treatment with decitabine can restore sensitivity to these agents. A Phase I trial combining decitabine with carboplatin has been conducted in collaboration with the Beatson Oncology Centre in Glasgow, which incorporates measurement of DNA methylation in peripheral blood lymphocytes, among other pharmacodynamic markers, as a surrogate marker of drug action.  This trial has identified a recommended dose of this combination and Phase II trials are planned.

A Cancer Research UK Phase I Trial Combining CB1954 and EP-0152R Administered Every 3 Weeks by Intravenous Infusion

CB1954 is a prodrug that is converted into an alkylating agent by reductive metabolism.  This does not occur efficiently in man but the administration of the artificial cofactor EP-1052R is designed to enhance the ability of the human enzyme NQO2 to carry out this activation step.  NQO2 is overexpressed in human malignancies offering the rationale that this combination could provide a degree of tumour targeting.