Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors.

INTRODUCTION: This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. METHODS: APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed. RESULTS: Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months. CONCLUSION: APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.

Simultaneous inhibition of caudal medullary raphe and retrotrapezoid nucleus decreases breathing and the CO2 response in conscious rats.

The medullary raphe (MR) and the retrotrapezoid nucleus (RTN) in the ventral medulla are two of many central chemoreceptor sites. We examine their combined function in conscious rats by focal inhibition using microdialysis. Inhibition of RTN neurons with the GABA(A) receptor agonist muscimol, with simultaneous dialysis of artificial cerebrospinal fluid (ACSF) in or near to the caudal MR, causes hypoventilation (decrease in the ratio of minute ventilation to oxygen consumption, V(E)/V(O2)) and reduces the ventilatory response to 7% CO(2) by 24%. Inhibition of caudal MR serotonergic neurons with the 5-HT(1A) receptor agonist (R)-(+)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), with simultaneous dialysis of ACSF in or near to the RTN, causes hypoventilation but has no significant effect on the CO(2) response. Inhibition of both the RTN and the caudal MR simultaneously produces enhanced hypoventilation and a 51% decrease in the CO(2) response. The effects of treatment on the CO(2) response are similar in wakefulness and in non-rapid eye movement sleep. Comparison of the effect of 8-OH-DPAT microdialysed into a more rostral portion of the MR, where the CO(2) response is reduced by 22%, demonstrates heterogeneity within the MR of the function of serotonergic neurons in breathing. We conclude that serotonergic neurons within the caudal MR provide a non-CO(2)-dependent tonic drive to breathe and potentiate the effects of RTN neurons that contribute to a resting chemical 'drive to breathe' as well as the response to added CO(2). These effects of caudal MR serotonergic neurons could be at a chemoreceptor site, e.g. the RTN, or at 'downstream' sites involved in rhythm and pattern generation.