• 383P A phase I dose-escalation study of the novel peptide ALM201 in patients (pts) with advanced solid tumours.

      El-Helali, A; Plummer, R; Jayson, Gordon C; Coyle, V; Drew, Y; Mescallado, Nerissa; Harris, N; Clamp, Andrew R; McCann, J; Kennedy, R; et al. (2017-09)
    • A biomarker-guided first-in-human trial of subcutaneous ALM201 in patients with solid tumours.

      El-Helali, A; Plummer, R; Jayson, Gordon C; Coyle, V.; Rogers, C; D'arcangelo, M; Graham, D; Drew, Y; Clamp, Andrew R; McCann, J; et al. (2016-10-01)
    • Aspirin as an adjuvant treatment for cancer: feasibility results from the Add-Aspirin randomised trial

      Joharatnam-Hogan, N; Cafferty, F; Hubner, Richard A; Swinson, D; Sothi, S; Gupta, K; Falk, S; Patel, K; Warner, N; Kunene, V; et al. (2019)
      BACKGROUND: Preclinical, epidemiological, and randomised data indicate that aspirin might prevent tumour development and metastasis, leading to reduced cancer mortality, particularly for gastro-oesophageal and colorectal cancer. Randomised trials evaluating aspirin use after primary radical therapy are ongoing. We present the pre-planned feasibility analysis of the run-in phase of the Add-Aspirin trial to address concerns about toxicity, particularly bleeding after radical treatment for gastro-oesophageal cancer. METHODS: The Add-Aspirin protocol includes four phase 3 randomised controlled trials evaluating the effect of daily aspirin on recurrence and survival after radical cancer therapy in four tumour cohorts: gastro-oesophageal, colorectal, breast, and prostate cancer. An open-label run-in phase (aspirin 100 mg daily for 8 weeks) precedes double-blind randomisation (for participants aged under 75 years, aspirin 300 mg, aspirin 100 mg, or matched placebo in a 1:1:1 ratio; for patients aged 75 years or older, aspirin 100 mg or matched placebo in a 2:1 ratio). A preplanned analysis of feasibility, including recruitment rate, adherence, and toxicity was performed. The trial is registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN74358648) and remains open to recruitment. FINDINGS: After 2 years of recruitment (October, 2015, to October, 2017), 3494 participants were registered (115 in the gastro-oesophageal cancer cohort, 950 in the colorectal cancer cohort, 1675 in the breast cancer cohort, and 754 in the prostate cancer cohort); 2719 (85%) of 3194 participants who had finished the run-in period proceeded to randomisation, with rates consistent across tumour cohorts. End of run-in data were available for 2253 patients; 2148 (95%) of the participants took six or seven tablets per week. 11 (0á5%) of the 2253 participants reported grade 3 toxicity during the run-in period, with no upper gastrointestinal bleeding (any grade) in the gastro-oesophageal cancer cohort. The most frequent grade 1-2 toxicity overall was dyspepsia (246 [11%] of 2253 participants). INTERPRETATION: Aspirin is well-tolerated after radical cancer therapy. Toxicity has been low and there is no evidence of a difference in adherence, acceptance of randomisation, or toxicity between the different cancer cohorts. Trial recruitment continues to determine whether aspirin could offer a potential low cost and well tolerated therapy to improve cancer outcomes. FUNDING: Cancer Research UK, The National Institute for Health Research Health Technology Assessment Programme, The MRC Clinical Trials Unit at UCL.
    • Aspirin use after radical cancer therapy - feasibility and toxicity data from the Add-Aspirin trial

      Joharatnam, N; Cafferty, F; Ring, A; Kynaston, H; Wilson, R; Gilbert, D; Cameron, D; Din, F; Hubner, Richard A; Thomas, A; et al. (2018)
    • Magnetic resonance imaging of anal cancer.

      Roach, S C; Hulse, Paul; Moulding, F J; Wilson, R; Carrington, Bernadette M; Department of Diagnostic Radiology, Christie Hospital, Manchester, UK. (2005-10)
      AIM: The purpose of this study was to evaluate the magnetic resonance imaging (MRI) appearances of primary and recurrent anal carcinoma, and to demonstrate the commonest patterns of local and distant disease spread. METHODS: A retrospective review was performed of 27 cases of biopsy-proven anal carcinoma, where MRI was used for primary staging (9 patients) or suspected recurrence (18 patients). Two oncological radiologists reviewed the MR images, following a standardized approach. The size, extent and signal characteristics of the anal tumour were documented. Metastatic disease spread to lymph nodes, viscera and bone was recorded. In all, 7 patients with recurrent disease underwent surgery and subsequent histological correlation was performed. RESULTS: Primary and recurrent tumours were of high signal intensity relative to skeletal muscle on T2-weighted images (T2WI), and of low to intermediate signal intensity on T1-weighted images (T1WI). Lymph node metastases were of similar signal intensity to the anal cancer. Recurrent tumours were more locally advanced than primary tumours and extended into adjacent organs and the pelvic skeleton. Recurrent lymph node disease involved perirectal, presacral and internal iliac nodes more commonly than did primary lymph node disease. CONCLUSION: MRI can be useful in the primary staging of bulky tumours or of those with a long craniocaudal extent. MR has a role in the preoperative evaluation and surgical planning of cases of recurrent disease following radiotherapy.
    • P3.02c-003 TAX-TORC: The novel combination of weekly paclitaxel and the dual mTORC1/2 inhibitor AZD2014 for the treatment of squamous NSCLC.

      Krebs, Matthew G; Spicer, J; Steele, N; Talbot, D; Brada, M; Wilson, R; Jones, R; Basu, B; Dawes, J; Parmar, M; et al. (2017-01)
    • A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer.

      Clamp, Andrew R; Schöffski, Patrick; Valle, Juan W; Wilson, R; Marreaud, Sandrine; Govaerts, A-S; Debois, M; Lacombe, D; Twelves, C; Chick, J; et al. (2008-04)
      PURPOSE: OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. METHOD: A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. RESULTS: Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. CONCLUSIONS: The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).
    • A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.

      Jamieson, D; Griffin, M; Sludden, J; Drew, Y; Cresti, N; Swales, K; Merriman, M; Allen, R; Bevan, P; Buerkle, M; et al. (2016-09-28)
      We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.
    • A phase II study of the potent PARP inhibitor, rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.

      Plummer, R; Lorigan, Paul C; Steven, N; Scott, L; Middleton, M; Wilson, R; Mulligan, E; Curtin, N; Wang, D; Dewji, R; et al. (2013-05)
      poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma.
    • Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre Phase I study.

      Saunders, Mark P; Wilson, R; Peeters, M; Smith, R; Godwood, A; Oliver, S; Van Cutsem, E; Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK, Mark.Saunders@christie.nhs.uk. (2009-01-29)
      PURPOSE: The safety and tolerability of vandetanib (ZACTIMAtrade mark; ZD6474) plus FOLFIRI was investigated in patients with advanced colorectal cancer (CRC). METHODS: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of FOLFIRI. RESULTS: A total of 21 patients received vandetanib 100 mg (n = 11) or 300 mg (n = 10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort and one DLT of hypertension (CTCAE grade 3) in the 300 mg cohort. The most common adverse events were diarrhoea (n = 20), nausea (n = 12) and fatigue (n = 10). Two patients (one in each cohort) discontinued vandetanib due to adverse events (rash, 100 mg cohort; hypertension, 300 mg cohort). There was no apparent pharmacokinetic interaction between vandetanib and FOLFIRI. Preliminary efficacy results included two confirmed partial responses in the 100 mg cohort and 9 patients with stable disease >/=8 weeks (100 mg, n = 7; 300 mg, n = 2). CONCLUSIONS: Once-daily vandetanib (100 or 300 mg) in combination with a standard FOLFIRI regimen was generally well tolerated in patients with advanced CRC.
    • Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high grade serous ovarian and squamous non-small cell lung cancer.

      Basu, B; Krebs, Matthew G; Sundar, R; Wilson, R; Spicer, J; Jones, R; Brada, M; Talbot, D; Steele, N; Ingles Garces, A; et al. (2018-07-17)
      We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.