A randomized phase II study of gemcitabine plus Z-360, a CCK2 receptor-selective antagonist, in patients with metastatic pancreatic cancer as compared with gemcitabine plus placebo

Abstract

Background We investigated the efficacy and safety of 60, 120, or 240 mg of Z-360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer.Methods Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m2 gemcitabine for each cycle and Z-360 tablets of 60 mg (GZ 60 mg group), 120, 240 mg or placebo tablets (Gem group) orally twice daily. The primary endpoint was overall survival (OS).ResultsThe median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated.ConclusionsIn this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-017-3351-4) contains supplementary material, which is available to authorized users.

[99mTc]Tc-DGA1, a Promising CCK2R-Antagonist-Based Tracer for Tumor Diagnosis with Single-Photon Emission Computed Tomography

“…A wide range of CCK 2 R antagonists reported in the literature could serve as motifs for the development of the respective radioligands, with only very few being peptides. In most cases, diverse classes of small-size organic peptidomimetics with the antagonistic profile at the CCK 2 R have been proposed for a number of clinical indications. − The two most prominent candidates, currently undergoing clinical testing, were the benzodiazepine derivatives netazepide (YF476) − and nastorazepide (Z-360). − Our interest was particularly triggered by Z-360, allowing the successful conjugation of (i) a [ 99m Tc]­Tc-chelate for molecular imaging of CCK 2 R-expressing tumors with single-photon emission computed tomography (SPECT)/CT, (ii) a fluorescent near-infrared dye for guided biopsy and surgery of CCK 2 R-positive lesions, and (iii) delivery of cytotoxic drugs to CCK 2 R-positive cancer cells with high specificity . These findings have verified that the Z-360 motif could be indeed structurally modified to accommodate appropriate entities for a number of theranostic applications and have strongly motivated the present work.…”

Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12/13–RhoA–ROCK signaling pathway

“…CCKBR, a GPCR member, has been regarded as a promising target in the therapy of pancreatic adenocarcinoma 10 . The CCKBR antagonists JB95008 and Z-360 have been tested in clinical trial, but the results have been unsatisfactory 52 , 53 . Our research elucidated a key signaling pathway in pancreatic cancer progression mediated by gastrin and/or CCKBR.…”

Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals

“…The rapid development of radiolabeled SSTR antagonists led to the development of other radiolabeled antagonistic vectors with reduced physiologic activity [ 33 , 34 , 35 ]. Nastorazepide (Z-360), a CCK2R antagonist with antiproliferative effects in gastrointestinal cancer models, has been recently evaluated in combination with gemcitabine in patients with metastatic pancreatic cancer [ 36 ]. This benzodiazepine derivative has been used for the design of the first CCK2R antagonist-based radiolabeled ligands.…”

“… Recent developments aiming towards optimizing CCK2R targeting (as described in references: [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]). …”