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Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

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اقرأ على الانترنت اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • المصدر:
      Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: London : BioMed Central, [2001-
    • الموضوع:
      Chemoradiotherapy*/methods ; Uterine Cervical Neoplasms*/therapy ; Uterine Cervical Neoplasms*/drug therapy ; Uterine Cervical Neoplasms*/pathology; Adult ; Female ; Humans ; Cisplatin/administration & dosage ; Cisplatin/therapeutic use ; United Kingdom ; Clinical Trials, Phase I as Topic ; Multicenter Studies as Topic
    • نبذة مختصرة :
      Background: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT).
      Methods: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m 2 . This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee.
      Discussion: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome.
      Trial Registrations: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).
      (© 2024. The Author(s).)
    • References:
      Mol Cancer Ther. 2018 Jul;17(7):1381-1391. (PMID: 29695633)
      J Clin Oncol. 2008 Dec 10;26(35):5802-12. (PMID: 19001332)
      Cell. 2011 Mar 4;144(5):646-74. (PMID: 21376230)
      Br J Radiol. 2018 Dec;91(1092):20180005. (PMID: 30179056)
      Clin Cancer Res. 2019 Nov 1;25(21):6463-6474. (PMID: 31266830)
      Nat Rev Drug Discov. 2012 Feb 01;11(2):109-24. (PMID: 22293567)
    • Grant Information:
      CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance; CRCPJT\100019 Cancer Research UK Combinations Alliance
    • Contributed Indexing:
      Keywords: Cervical cancer; Chemoradiotherapy; Cisplatin; Phase I; Tolinapant
    • الرقم المعرف:
      Q20Q21Q62J (Cisplatin)
    • الموضوع:
      Date Created: 20240607 Date Completed: 20240607 Latest Revision: 20240723
    • الموضوع:
      20240725
    • الرقم المعرف:
      PMC11162013
    • الرقم المعرف:
      10.1186/s12885-024-12310-w
    • الرقم المعرف:
      38849715