Clinical Trials and Experimental Medicine Project Portfolio

Project “Dashboard”

An interactive “Dashboard”, using MS PowerPoint, has been created to allow easy access to summary information on the portfolio, and the projects within. This is based on “1-pager” summaries of all trials and experimental medicine projects in the portfolio, which can be accessed via a series of hyperlinks. Using this system, the user can search the portfolio for projects in particular disease areas, involving certain drugs, using particular biomarkers etc. The first version of the Dashboard was used to assist reviewers at the CRUK Quinquennial Review in December 2013.

MCT-1: A Cancer Research UK Phase I trial of AZD3965, a monocarboxylate transporter 1 inhibitor (MCT1) in patients with advanced cancer

This is a phase-1 study with the primary objective of establishing the maximum tolerated dose and establishing a safety profile in patients with advanced cancer. The Clinical and Experimental pharmacology group are involved in the translation aspect of the study where we aim to explore the ability of AZD3965 to cause tumour apoptosis (measured by M30 and M65 ELISA). In Phase II of the study we also aim to investigate the number of Circulating Tumour Cells (CTCs) in an expansion cohort of Small Cell Lung Cancer (SCLC) and also expression of the monocarboxylate transporter inhibitors 1 (a sensitivity marker) and 4 (a resistance marker) on the CTCs in order to relate this to the potential anti-tumour activity of AZD3965.

STOMP: Small cell lung cancer Trial of Olaparib (AZD2281) as Maintenance Programme: a randomised double blind multicentre phase II trial

The aim of this study is primarily to assess the safety of the PARP inhibitor Olaparib in chemoresponsive Small Cell Lung Cancer (SCLC). Patients will be treated with platinum therapy (to induce DNA damage) followed by a maintenance therapy of Olaparib (to prevent DNA damage repair). Clinical and Experiment Pharmacology aim use translational blood samples from the study to investigate the effect of Olaparib maintenance on the inhibition of DNA damage repair in circulating tumour cells. This will be done using a validated assay to detect γH2AX as a biomarker of DNA damage repair. The assay involves first isolating CTCs from participating patient blood samples at Baseline, Day 28 and End of Treatment using the CellSearch system then examining them for the presence of γH2AX foci.  It is hypothesised that the absence of γH2AX foci (therefore lack of DNA repair) may be used to predict the efficacy of Olaparib maintenance therapy in SCLC.

SERD: A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ascending Doses of AZD9496 in Women with Estrogen Receptor Positive HER-2 Negative Advanced Breast Cancer

Breast cancer is the most common malignancy in the UK and Estrogen receptors are overexpressed in 70% of breast cancer cases. Acquired resistance to first line therapies such as aromatase, tamoxifen and fulvestrant have led to the development of selective estrogen receptor downregulator (SERD) AZD9496. AZD9496 is an orally administered AstraZeneca trial drug with significant anti-proliferative and anti-tumour activity in estrogen receptor +ve/HER-2 -ve advanced breast cancer.

CEP is currently assessing the performance of AZD9496 by evaluating the ER and Ki67 biomarker profile in response to treatment. By using the Veridex CellSearch® for enumeration of ER and Ki67 positive CTCs together with the CTC-Endocrine Therapy Index (ETI) calculation developed by collaborators Daniel Hayes lab University of Michigan, we hope to predict patients’ resistance or rapid progression in response to treatment with AZD9496.

AZD0156 / ATMi

Ataxia Telangiectasia Mutated (ATM) kinase is required to repair double strand DNA breaks caused by common anti-cancer treatments. Inhibiting ATM could potentiate the activity of ionising radiation (IR), topoisomerase I and topoisomerase II inhibitors. AZD0156 is an AstraZeneca trial drug which is an inhibitor of ATM activity. The Phase I Trial designed to study PK PD and tolerability of AZD0156, and has incorporated into it an exploratory biomarker research component to assess correlations with biological activities and clinical efficacy. The GCP Team is contributing to this exploratory biomarker work by developing assays for activated ATM (pATM) and γH2AX in CTCs, and then measuring these in CTCs from bloods from patients on the AZD0156 trial.

CIRCCa: Phase II of carboplatin/paclitaxel/cediranib (AZD2171) v C/P plus placebo in cervical cancer

This study is the first trial to investigate the efficacy of the VEGFR inhibitor cediranib in cervical cancer. CEP performed initial multiplex ELISA analysis on patient plasma samples for VEGFA and VEGFR2, and when aligned to the clinical data this showed a mean plasma decrease in circulating VEGFR2 concentration from baseline after the first cycle of chemotherapy in the cediranib group, and an increase in the placebo group. The reductions in circulating VEGFR2 concentration support its use as a biomarker of the biological activity of cediranib, and was included in a 2015 publication in Lancet Oncology (Symonds et al., 2015, Lancet Oncol. 16(15):1515-24).

This initially interesting data will be followed up by further multiplex ELISA analysis on the same sample set, incorporating Ang-1 and Tie-2 assays.