A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Authors

Andrew L Coveler
Matthew J Reilley
Mark Zalupski
Teresa Macarulla
Christos Fountzilas
Mariano Ponz-Sarvisé
Adnan Nagrial
Nataliya V Uboha
Sophia Frentzas
Michael Overman
Anne Noonan
Wells A Messersmith
Nick Pavlakis
Niharika B Mettu
Ina Bisha
Ying Wang
Paul Smith
Elina Murtomaki
Agata A Bielska
Veronique Bragulat
Zachary A Cooper
Rakesh Kumar
David R Spigel

Publication Date

10-15-2024

Journal

Clinical Cancer Research

Abstract

Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option.

Patients and methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm A1), oleclumab [recommended phase II dose (RP2D)] with GnP (arm A2), or oleclumab (RP2D) with durvalumab plus GnP (arm A3). Primary objectives were safety (escalation) and objective response rate (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS).

Results: During escalation, 1/11 patients from cohort B (oleclumab 3,000 mg) experienced two dose-limiting toxicities. Oleclumab's RP2D was 3,000 mg. During expansion, grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. The objective response rate was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs. A3; P = 0.650). PFS [HR = 0.72; 95% confidence interval (CI), 0.47, 1.11] and OS (HR = 0.75; 95% CI, 0.50-1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution.

Conclusions: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

Keywords

Humans, Female, Male, Antineoplastic Combined Chemotherapy Protocols, Middle Aged, Carcinoma, Pancreatic Ductal, Aged, Antibodies, Monoclonal, Adult, Pancreatic Neoplasms, Aged, 80 and over, Paclitaxel, Neoplasm Metastasis, Antibodies, Monoclonal, Humanized, Progression-Free Survival

DOI

10.1158/1078-0432.CCR-24-0499

PMID

39106081

PMCID

PMC11474165

PubMedCentral® Posted Date

8-6-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes