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Project

CRUKD/16/004 SPIRE: A Phase Ib/IIa clinical trial combining DNA Methyltransferase inhibitor SGI110 with cisplatin and gemcitabine chemotherapy in patients with advanced solid tumours including bladder cancer

Funder: Cancer Research UK

Funding period
0
Funding amount
Abstract
Background: Bladder cancer accounts for 10,000 new diagnoses and 5,000 deaths annually in the UK. Cisplatin based chemotherapy, most commonly combined in the UK with gemcitabine (GC), is the standard of care in both the first line metastatic and neoadjuvant settings. Subsequent progression or relapse following cisplatin carries a poor prognosis. Pre-clinical data from various sources support investigation of DNA demethylating agents in combination with platinum based chemotherapy in bladder cancer. These indicate that, in addition to single agent activity, demethylating agents synergise with cisplatin and are able to circumvent cisplatin resistance. SGI-110 is a DNA methyltransferase inhibitor from which decitabine is the active metabolite. It possesses favourable pharmacokinetic properties compared with decitabine or other currently available agents raising the potential to enhance pharmacodynamic, efficacy and safety properties. Aims: To establish safe maximum tolerated (MTD) and biologically effective (BED) doses for SGI-110 in combination with GC for bladder cancer and to provide preliminary evidence of pharmacodynamic effect and efficacy. Methods: This proposal is for a phase Ib/IIa trial of SGI-110 and GC in combination. The study incorporates an initial dose escalation phase in advanced solid tumours with a conventional 3+3 phase I design. This will test SGI-110 at four dose levels combined with full dose GC. Assessment of pre-defined dose limiting toxicity (DLT, by CTCAE version 4.03) will be utilised to make dose level and escalation decisions and to define MTD. BED will be based on plasma DNA LINE-1 demethylation and haemoglobin F re-expression. Other exploratory translational endpoints for the impact on methylation status and pharmacodynamic effects will also be addressed. The trial will then proceed to a randomised dose expansion phase. This will assess GC, with or without SGI-110 at the recommended dose for phase II evaluation, in bladder cancer patients receiving neoadjuvant chemotherapy prior to planned radical cystectomy. We will randomise 10 patients per arm. This proposal has been developed by the Southampton and Sheffield ECMC’s in collaboration with the ECMC Combinations Alliance and Astex Pharmaceuticals. How the results of this research will be used: Success of this trial would allow progression to a phase II/III randomised comparison of this combination to determine efficacy compared to chemotherapy alone. This combination might also be relevant for testing in other tumour sites (e.g., lung, biliary tract, ovary).
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Clinical Trials and Supportive Activities

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    6.1 Pharmaceuticals

  • Health Research Areas

    Clinical

  • Broad Research Areas

    Clinical Medicine and Science