Interim results of an open-label, single-arm trial of ultratrace I-131-iobenguane in patients with metastatic pheochromocytoma/paraganglioma (Pheo)

e13592 Background: To evaluate the therapeutic efficacy of no carrier added (nca) I-131-MIBG in pheo as measured by > 50% reduction of all antihypertensive medication for ≥ 6 months. Secondarily, to evaluate safety (including radiation absorbed dose to normal organs) and the proportion of subjects with objective response per modified RECIST and biomarker response by change in Chromogranin A (CgA). Methods: Pts with metastatic pheo causing secondary hypertension were treated with up to two 500 mCi doses of 131 I-nca-MIBG 3-6 months apart. The administered dose was limited by pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). Response and toxicity were evaluated for a minimum of 1 year. Results: To date, 41 pts (17-72 years) received at least one treatment (full analysis; FA); 34 pts received 2 treatments (per protocol; PP); All patients have been followed at least 1 year or until death. The primary endpoint of sustained reduction in HTN meds was achieved in 32% and 29% of PP and FA, respectively. In total, 25/41 subjects who received at least 1 treatment had ≥ 50% reduction in their HTN meds. Mean duration of the reduction was 7.7 ± 6.6 months (range 0.1 – 22.1 months). Objective PR was seen in 41% (PP) and 34% (FA). 56% of PP had at least objective MR. All subjects in PP had at least stable disease and 90% in FA had at least stable disease. At 8 months there was a 60±33% reduction in CgA from baseline in PP. Primary toxicity was myelosupression: grade 3 (17%), grade 4 (20%). Grade 3 GI disorders were 15%. There were 3 deaths during follow up, all due to disease. Biomarker response correlated well to objective response and HTN improvement. Thrombocytopenia was the most common treatment-emergent SAE (n=9) considered related to study drug. No other treatment-emergent SAE was considered related to study drug in > 2 subjects. Conclusions: 11 of 34 pts in PP in this ongoing study met the primary endpoint of a positive clinical benefit (decreased HTN meds), which correlated with objective tumor response and biomarker levels in this disease with no approved, efficacious therapies. Toxicity for all patients (n=41) was tolerable and predominantly limited to myelosupression

Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions