Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.

INTRODUCTION: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors. MATERIALS AND METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B. RESULTS: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional. CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited. GOV IDENTIFIER: NCT03724890.

Lymphoma development in Bax transgenic mice is inhibited by Bcl-2 and associated with chromosomal instability.

Bax is a Bcl-2 family member that promotes apoptosis but has paradoxical effects on lymphoma development in p53-deficient mice. To better understand the mechanism of Bax-induced lymphoma development, the effect of Bax levels, p53 status and Bcl-2 coexpression on lymphoma development were determined. In addition, DNA content and cytogenetics were performed on young (premalignant) Lck-Bax mice as measures of genetic instability. Bax promoted lymphoma development in p53-deficient mice in a dose-dependent manner. Bax expression also led to lymphoma development in both p53 +/- and +/+ animals. Ploidy analysis in mice prior to the onset of overt thymic lymphomas demonstrated that Lck-Bax transgenic mice were more likely to be aneuploid and demonstrate increased chromosome instability. With tumor progression, aneuploidy increased and Bax expression was maintained. Importantly, coexpression of Bcl-2 delayed lymphoma development in Lck-Bax transgenic mice. These data support a model in which increased sensitivity to apoptosis leads directly to chromosome instability in developing T cells and may explain a number of paradoxical observations regarding Bcl-2 family members and the regulation of cancer.

Neuromuscular block with doxacurium (BW A938U) in patients with normal or absent renal function.

The characteristics of neuromuscular block induced by doxacurium were compared in patients with and without renal function. Seventeen patients with end stage chronic renal failure and 18 patients with normal renal function were anaesthetized with 0.5% halothane and nitrous oxide in oxygen and received doxacurium in an initial dose of 25 micrograms kg-1 (estimated from available data as an ED95 dose), with incremental doses of 5 micrograms kg-1. At the end of surgery, residual neuromuscular block was antagonized with either edrophonium 1.0 mg kg-1 or neostigmine 0.08 mg kg-1. There was no significant difference between the mean maximum blocks achieved with doxacurium: 17.4% (renal failure group) and 11.6% (control group) of control twitch heights, or between the mean times to achieve maximum block (10.9 min and 10.8 min, respectively). The mean duration of action of doxacurium, indicated by the time for twitch height to recover to 25% of control, was longer in the renal failure group (120.8 min vs 66.7 min in the control group) (ns). Similarly, the mean duration of action of increments was longer in the renal failure group (27.4 min vs 20.5 min in the control group). The rate of spontaneous recovery from doxacurium as indicated by the time for twitch height to recover from 0 to 5%, 5 to 10% and 10 to 25%, was not significantly different in the two groups. Antagonism of doxacurium was achieved more reliably with neostigmine than with edrophonium in both groups. The administration of doxacurium was associated with minimal cardiovascular effects.