A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma.

BACKGROUND: There is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. METHODS: CBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. RESULTS: Among 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1-2. CONCLUSIONS: The combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT04953962.

Influence of human lipoproteins on the progesterone synthesis of human term placenta in organ culture.

In the presence of LDL (200 micrograms/ml) and HDL (400 micrograms/ml), the uptake of radioactive cholesterol by a human term placenta in organ culture was enhanced by about 1.5 and 2.5, respectively, after 24-h incubation. Using cholesterol linoleate, the ratio was 1.0 and 1.5, and the tissue concentration of progesterone was 5-fold higher in the presence of LDL (600 micrograms/ml) than in the presence of HDL (4.4 mg/ml). A dose-dependent increase in medium progesterone was found using either LDL or HDL in combination with cholesterol or cholesterol linoleate, respectively. In human term placenta in organ culture, the human lipoproteins LDL and HDL both have a carrier function for cholesterol and cholesteryl linoleate, stimulate the uptake of these steroids in the placental tissue, and enhance placental progesterone formation. Furthermore, the lipoproteins facilitate progesterone release from the placental tissue.