CEND-1 Offers Hope in Advanced Pancreatic Cancer

Chemotherapy combined with the CEND-1 cyclic peptide showed promising efficacy, and was well tolerated as a first-line treatment, for patients with metastatic pancreatic cancer, researchers reported.

In a phase I study of 29 patients evaluable for efficacy, 59% (95% CI 39-77) responded to the combination of CEND-1 -- a novel 9-amino acid cyclic peptide that targets αV integrins and neuropilin-1 -- plus gemcitabine and nab-paclitaxel (Abraxane), according to Andrew Dean, MBChB, of St. John of God Subiaco Hospital in Subiaco, Australia, and colleagues.

This overall response rate (ORR) was considerably higher than the 23% ORR reported for gemcitabine plus nab-paclitaxel alone in the IMPACT trial, which established that regimen as standard therapy, they noted in Lancet Gastroenterology & Hepatology.

Overall, 16 patients had partial responses, one had a complete response, and nine achieved stable disease following treatment.

With a follow-up of about 26 months, median progression-free survival (PFS) was 9.7 months (95% CI 6.2-11.6) and median overall survival (OS) was 13.2 months (95% CI 9.7-22.5). These results also compared favorably to the IMPACT trial, which reported a median PFS of 5.5 months and OS of 8.5 months with gemcitabine/nab-paclitaxel.

"CEND-1 (when co-administered with standard chemotherapies) has the potential to selectively target tumors and -- via neuropilin-1 modulation -- enhance the distribution of anticancer drugs throughout the tumor and avoid healthy tissues," Dean's group explained. "This ability is expected to improve the efficacy of anticancer therapy and reduce side-effects through increased specificity and sensitivity."

Common adverse events (AEs) experienced with the study combination were consistent with those seen with gemcitabine plus nab-paclitaxel alone.

"These results, if confirmed in larger studies, would represent an important step not only in the treatment of patients with pancreatic ductal adenocarcinoma, but also in the establishment of a new class of drugs with potential use in many other cancers and in combination with many other drugs," wrote John Neoptolemos, MD, PhD, and Christoph Springfeld, MD, PhD, both of Heidelberg University Hospital in Germany, in an accompanying comment.

Dean and colleagues decided to focus on pancreatic ductal adenocarcinoma because of an unmet need for life-extending treatments in this difficult-to-treat disease, and due to the fact that CEND-1 had previously shown activity in animal models.

The open-label, multicenter study was conducted at three hospitals in Australia. In total, 31 patients (mean age 64; 65% male; 87% white) with histologically confirmed metastatic pancreatic ductal adenocarcinoma were enrolled. Patients had to have one or more lesions measurable on MRI or CT; an ECOG performance status score of 0 or 1; and a life expectancy of at least 3 months.

An initial dose-escalation phase assessed the safety and activity of four different doses of CEND-1, while a subsequent expansion phase included doses of 1.6 mg/kg and 3.2 mg/kg. CEND-1 monotherapy was given as an IV fluid bolus on the first day of a 7-day run-in phase, followed by CEND-1 plus intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15 of 28-day treatment cycles until disease progression.

Dean and colleagues observed no CEND-1 dose-limiting toxicities in the full cohort of 31 patients. The most common grade 3/4 AEs were neutropenia (in 55%), anemia (26%), leukopenia (16%), and pulmonary embolism (13%). Serious AEs occurred in 71% of patients, mostly related to disease progression. Ten deaths occurred during the study, nine of which were due to progression of metastatic disease, and one due to a left middle cerebral artery stroke.

Neoptolemos and Springfeld suggested that substantial translational research will be necessary to determine which patients, and which cancers, will be suitable for CEND-1. They also noted that other agents -- such as pegvorhyaluronidase alfa -- showed promise in phase II studies, yet failed to demonstrate efficacy in randomized phase III trials.

"A novel drug that boosts efficacy of different therapies in various cancers sounds almost too good to be true," the duo wrote, noting that results from the randomized phase II ASCEND study comparing gemcitabine/nab-paclitaxel with or without CEND-1 in pancreatic cancer are "eagerly awaited."

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