A Phase I/II trial to determine the Safety, Toxicity and Efficacy of Iodine-131-Rituximab and the Histone Deacetylase Inhibitor Panobinostat in Relapsed and Refractory Indolent B-cell Lymphoma

All patients will receive oral panobinostat (20 or 30 or 40mg in 5, 15 and 20mg tablets) which will commence on day one on a Monday and will continue to be given on Monday, Wednesday and Friday weekly for four weeks. A tracer activity of 200 MBq131I-rituximab will be administered intravenously after an intravenous dose of 375 mg/m2 rituximab unlabeled antibody, with both given on day four. Whole-body imaging and background scans will be performed within one hour in the administering department, and be repeated four and seven days later under the same imaging conditions. The residence time of 131I-rituximab is calculated from whole-body gamma camera counts at these time points. The radio-immunotherapeutic dose will be administered intravenously on day 11 (+/- one day dependant on availability of single isolation room) after an additional 375 mg/m2 loading dose of intravenous unlabeled rituximab on the same day. The administered activity is estimated to deliver a whole-body radiation absorbed dose of 0.75 Gy. During rituximab infusions cardiac monitoring in the form of regular blood pressure and pulse monitoring will take according to institutional practice. After administration of therapeutic 131I-rituximab patients will be treated according to institutional and state practice, and will either require isolation until radiation levels fall below mandated thresholds (approximately five days), or will be allowed home. Prophylactic Lugols iodine 10 drops per day will commence on day three and continue until day 21 in order to block thyroid uptake of radio-iodine. There are two phases for this study; The aim of the study is to evaluate the safety and exclude a clinically unacceptable rate of hematological and non-hematological toxicity of the combination of 131I-rituximab and panobinostat in patients with relapsed and refractory indolent B-cell NHL. Three dose levels of panobinostat will be considered in phase I of the study, which is the dose finding phase. This will be followed by phase II, which consists of an expanded cohort at the phase I determined dose of panobinostat. For the first 3 patients in the pilot phase, a dose of 30mg panobinostat will be used with a standard dose of 131I-rituximab (dose level 1). If 0/3 patients have a DLT then a second cohort will be opened at dose level 2 starting immediately. If 1/3 patients has a DLT then a further 3 patients will be enrolled at dose level 1. If there are no further DLTs then the current dose will be declared to be the final dose, and the phase II part of the study will begin. If there are >2/6 DLT’s in total then the panobinostat dose will be reduced to 20mg monday/wednesday/friday for ongoing patients and a new pilot cohort of three patients will be enrolled at dose level -1. If > 2/3 patients or the first two patients accrued have a DLT then the panobinostat dose will be reduced to 20mg monday/wednesday/friday for ongoing patients and a new pilot cohort of three patients will be enrolled at dose level -1. For patients enrolled at dose level -1 (20mg panobinostat) If 0/3 patients have a DLT then the current dose will be declared to be the final dose and expansion to phase II study at dose level -1 will start immediately If 1/3 patients have a DLT then a further 3 patients will be enrolled at the current dose level. If there are no further DLTs then the current dose will be declared to be the final dose and the phase II study will begin at dose level -1. If >2/6 or > 2/3patients have a DLT then the study will be terminated. For patients enrolled at dose level 2 (40mg panobinostat) If 0/3 patients have DLTs then the current dose will be declared to be the final dose and expansion to phase II will start at 40mg. If 1/3 patients has DLT then a further 3 patients will be enrolled to the current cohort. If there are no further DLTs then the current dose will be declared to be the final dose and the phase II study will begin at 40mg. If there are >2/6 patients in total with DLTs then dose level 1 will be declared to be the final dose and the phase II part of the study will begin at 30mg of panobinostat. Prior to initiation of phase II, the safety monitoring committee will review data to ensure safety. If committee approved, patients will be accrued following the completion of the phase I cohort(s). The schedule of treatment will be identical to the pilot group, whilst the dose of panobinostat will be 20mg (dose level -1), 30mg (dose level 1) or 40 mg (dose level 2) dependent on the outcome of the pilot phase.