Two sets of study data will be evaluated: the primary RXDX-101 objective will be

evaluated in the full analysis set (FAS). The FAS is defined as the set of data generated from the included patients who received at least the safety dose. The secondary objectives will be evaluated in both FAS and per-protocol set (PPS). The PPS is defined as the set of data generated from the included patients who complied with the protocol. Monitoring The IDMC will perform a safety review after each series of treatments of three consecutive patients. The IDMC members have no conflict of interest with the sponsor because they are not involved in the study, nor are they receiving funds. The IDMC will work according to standard operating procedures and will receive reports on a regular RG7420 basis on all toxicity CTCAE ≥ grade 3 reported for this trial. Recruitment will not be interrupted unless otherwise requested by the chairman of the IDMC. The responsibilities of the IDMC include:

minimize the exposure of patients to an unsafe therapy or dose make recommendations for changes in study processes where appropriate endorse continuation of the study inform the institutional IEC in the case of toxicity CTCAE ≥ grade 3 and/or when the well-being of the subjects is jeopardized Ethical considerations The study will be conducted according to the principles of the Declaration of Helsinki (version 9.10.2004) and in accordance with the Medical Research Involving Human Patients Act (WMO), the requirements of International Conference on Harmonization Tau-protein kinase – Good Clinical Practice. The study protocol has been approved by the IEC and by the institutional Radiation Protection Committee. Discussion The HEPAR trial is a phase I study to evaluate the safety and toxicity profile of 166Ho radioembolization. Secondary endpoints are tumour response, biodistribution assessment, performance status,

quality of life and comparison of the biodistributions of the 99mTc-MAA scout dose and the 166Ho-PLLA-MS safety dose. With regard to the method of administration, viz. through a catheter placed in the hepatic artery, the in-vivo characteristics (no significant release of radionuclide), and the mechanism of action (local irradiation of the tumour), 166Ho-PLLA-MS constitute a device analogous to the 90Y microspheres, which are currently applied clinically. 166Ho-PLLA-MS only differ in the radioisotope and the device matrix that are used. In a toxicity study in pigs on 166Ho-RE, it has been demonstrated that (healthy) pigs can withstand extremely high liver absorbed doses, at least up to 160 Gy [23]. During these animal experiments, only very mild side effects were seen: slight and transitory inappetence and somnolence, which may well have been associated with the anaesthetic and analgesic agents that had been given and not necessarily with the microsphere administration.