Preliminary results from ASCENT-J02: a phase 1/2 study of sacituzumab govitecan in Japanese patients with advanced solid tumors.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved outside Japan for second-line and later metastatic triple-negative breast cancer (mTNBC), based on the ASCENT study (NCT02574455). We report SG safety and efficacy in an open-label, phase 1/2 bridging study in Japanese patients with advanced solid tumors (ASCENT-J02; NCT05101096; jRCT2031210346). METHODS: Phase 1 was a standard 3 + 3 design. Patients received intravenous SG 6 mg/kg, escalating to 10 mg/kg, on Days 1 and 8 per 21-day cycle; primary endpoints were safety, incidence of dose-limiting toxicity/toxicities (DLTs), and determination of the recommended phase 2 dose (RP2D). In the multicohort phase 2 study, patients in the mTNBC cohort with previously treated disease received SG at the RP2D; primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; RECIST v1.1). Safety was a secondary endpoint. RESULTS: In phase 1 (N = 15), one DLT (grade 3 elevated transaminases) occurred with SG 10 mg/kg; RP2D was SG 10 mg/kg regardless of UGT1A1 status. In phase 2, 36 patients with mTNBC received SG 10 mg/kg. At median follow-up of 6.1 months, IRC-assessed ORR was 25.0% (95% CI 12.1-42.2; P = 0.0077). Median progression-free survival was 5.6 months (95% CI 3.9-not reached [NR]); median overall survival was NR. No treatment-emergent adverse events led to discontinuation or death. CONCLUSIONS: SG RP2D was established as 10 mg/kg in Japanese patients. SG showed efficacy in Japanese patients with previously treated mTNBC, a manageable safety profile, and no new safety signals, consistent with the previous ASCENT study.

Regulation of spontaneous Ca(2+) spikes by metabotropic glutamate receptors in primary cultures of rat cortical neurons.

Periodic and spontaneous Ca(2+) spikes are observed in neurons during development of the central nervous system, and spontaneous changes in intracellular Ca(2+) concentration in neurons play important roles in the development of neural circuits. To clarify the roles of metabotropic glutamate receptors (mGluRs) in the regulation of spontaneous Ca(2+) spikes, we investigated the effects of selective and nonselective mGluRs ligands on primary cultures of rat cortical neurons. Cultured cortical neurons expressed all eight mGluR subtypes on reverse transcription-PCR. The mGluR2 and mGluR3 agonists LY379268, LY354740, and (2R,4R)-APDC increased the amplitude but decreased the frequency of spontaneous Ca(2+) spikes in cultured cortical neurons. The effects of these mGluR2 and mGluR3 agonists were completely inhibited by the presence of a potent mGluR2 and mGluR3 antagonist, LY341495, and by pretreatment with pertussis toxin. No significant effect was observed with either activation or inhibition of mGluR1, mGluR4, mGluR5, mGluR6, mGluR7, and mGluR8 on the spontaneous Ca(2+) spikes in cultured cortical neurons. These findings indicate that, among mGluRs, the group II mGluR subtypes mGluR2 and mGluR3 play principal roles in modulation of spontaneous Ca(2+) spikes.

Face-washing behavior induced by the group I metabotropic glutamate receptor agonist (S)-3,5-DHPG in mice is mediated by mGlu1 receptor.

It is known for the non-selective group I metabotropic glutamate (mGlu) receptors agonist (S)-3,5-dihydroxyphenylglycine (S-3,5-DHPG) to cause convulsions, which are mediated by mGlu1 receptor. However, the behavioral changes other than convulsions caused by (S)-3,5-DHPG have not been well studied. The purpose of the present study was to explore the behavioral changes elicited by activation of group I mGlu receptors with (S)-3,5-DHPG and to clarify which, mGlu1 receptor or mGlu5 receptor, is responsible for such behavior. (S)-3,5-DHPG at doses of 3-30 nmol caused characteristic face-washing behavior. This behavioral change was inhibited by both the competitive mGlu1 receptor antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) and (S)-4-carboxyphenylglycine (S-4CPG) and the non-competitive mGlu1 receptor antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), but not by the mGlu5 receptor antagonist 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the N-methyl-d-asparate (NMDA) receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), or the competitive non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). These findings indicate that face-washing behavior is due to selective activation of mGlu1 receptor by (S)-3,5-DHPG, and that the face-washing behavior induced by (S)-3,5-DHPG in mice can be used for in vivo testing of the antagonistic potency of both competitive and non-competitive mGlu1 receptor antagonists.

Hyperpolarization-activated current I(h) in nucleus of solitary tract neurons: regional difference in serotonergic modulation.

The nucleus of solitary tract (NTS) contains diverse neural circuits responsible for basic vital functions. We examined the effect of serotonin (5-HT) on hyperpolarization-activated current (I(h)) in neurons acutely isolated from caudal, medial and rostral parts of the NTS. Caudal and medial NTS neurons showed a large amplitude of I(h) compared with rostral neurons. In these neurons, perfusion with 5-HT potentiated Ih amplitude in a concentration-dependent manner. The effect of 5-HT was blocked by NAN-190, a 5-HT1A receptor antagonist. Thus, 5-HT1A receptors may regulate I(h) channel activity in caudal and medial NTS neurons.