Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib

BMC Cancer. 2019 Sep 10;19(1):901. doi: 10.1186/s12885-019-6121-3.


Background: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited.

Methods: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses.

Discussion: We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity.

Trial registration: Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).

Keywords: Dose escalation; Dose limiting toxicity; Olaparib; PARP inhibitor; Phase 1; Radiosensitisation; Radiotherapy; TITE-CRM.

Publication types

  • Clinical Trial Protocol
  • Clinical Trial, Phase I

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / radiotherapy
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / radiotherapy
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / radiotherapy
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / radiotherapy
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / radiotherapy
  • Maximum Tolerated Dose
  • Neoplasms / drug therapy*
  • Neoplasms / radiotherapy*
  • Phthalazines / therapeutic use*
  • Piperazines / therapeutic use*
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Radiotherapy, Adjuvant


  • Antineoplastic Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • olaparib

Associated data