A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies.

Purpose Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and methods Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL

Commissioning of the BRIKEN beta-delayed neutron detector for the study of exotic neutron-rich nuclei

published_or_final_versio

Observation of a mu s isomer in In-134(49)85: Proton-neutron coupling "southeast" of Sn-132(50)82

We report on the observation of a microsecond isomeric state in the single-proton-hole, three-neutron-particle nucleus ¹³⁴In. The nuclei of interest were produced by in-flight fission of a ²³⁸U beam at the Radioactive Isotope Beam Factory at RIKEN. The isomer depopulates through a γ ray of energy 56.7(1) keV and with a half-life of T1/2=3.5(4)μs. Based on the comparison with shell-model calculations, we interpret the isomer as the Iπ=5− member of the π0g−19/2⊗ν1f37/2 multiplet, decaying to the Iπ=7− ground state with a reduced-transition probability of B(E2;5−→7−)=0.53(6)W.u.Observation of this isomer, and lack of evidence in the current work for a Iπ=5− isomer decay in ¹³²In, provides a benchmark of the proton-neutron interaction in the region of the nuclear chart “southeast” of ¹³²Sn, where experimental information on excited states is sparse

β-Delayed One and Two Neutron Emission Probabilities Southeast of ^{132}Sn and the Odd-Even Systematics in r-Process Nuclide Abundances.

The β-delayed one- and two-neutron emission probabilities (P_{1n} and P_{2n}) of 20 neutron-rich nuclei with N≥82 have been measured at the RIBF facility of the RIKEN Nishina Center. P_{1n} of ^{130,131}Ag, ^{133,134}Cd, ^{135,136}In, and ^{138,139}Sn were determined for the first time, and stringent upper limits were placed on P_{2n} for nearly all cases. β-delayed two-neutron emission (β2n) was unambiguously identified in ^{133}Cd and ^{135,136}In, and their P_{2n} were measured. Weak β2n was also detected from ^{137,138}Sn. Our results highlight the effect of the N=82 and Z=50 shell closures on β-delayed neutron emission probability and provide stringent benchmarks for newly developed macroscopic-microscopic and self-consistent global models with the inclusion of a statistical treatment of neutron and γ emission. The impact of our measurements on r-process nucleosynthesis was studied in a neutron star merger scenario. Our P_{1n} and P_{2n} have a direct impact on the odd-even staggering of the final abundance, improving the agreement between calculated and observed Solar System abundances. The odd isotope fraction of Ba in r-process-enhanced (r-II) stars is also better reproduced using our new data

THE BRIKEN PROJECT: EXTENSIVE MEASUREMENTS OF beta-DELAYED NEUTRON EMITTERS FOR THE ASTROPHYSICAL r PROCESS

An ambitious program to measure decay properties, primarily β-delayed neutron emission probabilities and half-lives, for a significant number of nuclei near or on the path of the rapid neutron capture process, has been launched at the RIKEN Nishina Center. We give here an overview of the status of the project

<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math> -delayed neutron emissions from <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>N</mml:mi><mml:mo>&gt;</mml:mo><mml:mn>50</mml:mn></mml:mrow></mml:math> gallium isotopes

β-delayed γ-neutron spectroscopy has been performed on the decay of A=84 to 87 gallium isotopes at the RI-beam Factory at the RIKEN Nishina Center using a high-efficiency array of He3 neutron counters (BRIKEN). β-2n-γ events were measured in the decays of all of the four isotopes for the first time, which is direct evidence for populating the excited states of two-neutron daughter nuclei. Detailed decay schemes with the γ branching ratios were obtained for these isotopes, and the neutron emission probabilities (Pxn) were updated from the previous study. Hauser-Feshbach statistical model calculations were performed to understand the experimental branching ratios. We found that the P1n and P2n values are sensitive to the nuclear level densities of 1n daughter nuclei and showed that the statistical model reproduced the P2n/P1n ratio better when experimental levels plus shell-model level densities fit by the Gilbert-Cameron formula were used as the level-density input. We also showed the neutron and γ branching ratios are sensitive to the ground-state spin of the parent nucleus. Our statistical model analysis suggested J≤3 for the unknown ground-state spin of the odd-odd nucleus Ga86, from the Iγ(4+→2+)/Iγ(2+→0+) ratio of Ga84 and the P2n/P1n ratio. These results show the necessity of detailed understanding of the decay scheme, including data from neutron spectroscopy, in addition to γ measurements of the multineutron emitters