A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma

Abstract

Purpose: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA).

Experimental design: Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle.

Results: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007).

Conclusions: CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.

©2013 AACR.

Figures

Figure 1

Treatment schema. Gemcitabine (1000 mg/m2) was infused on days 1, 8, and 15 of each 28 day cycle with CP-870,893 administered once during each treatment cycle on day 3.

Figure 2

FDG-PET/CT imaging of (A-B) primary pancreatic tumors and (C-D) metastatic hepatic lesions. (A, C) Change relative to baseline in MVPmean as a measure of metabolic activity. (B, D) CT, FDG-PET and fused PET/CT images (baseline vs. end of cycle 4) showing (B) a responding primary pancreatic lesion (green arrow) and (D) a mixed response in liver with representative new or progressive lesions (red arrowheads), stable lesions (yellow arrowheads), and responding lesions (green arrows). Also seen is normal FDG excretion in kidneys and ureters.

Figure 3

The response of individual lesions measured by changes in lesional MVPmean from baseline to end of cycle 2, shown for (A) each patient and (B) for each metastatic site (all patient lesions pooled) including liver, lung, lymph node (LN), and peritoneal cavity. Changes in MVPmean were classified as complete metabolic response (CMR) indicating disappearance of lesion; partial metabolic response (PMR) indicating >25% reduction in MVPmean; progressive metabolic disease (PMD) indicating >25% increase in MVPmean or new lesion; and stable metabolic disease (SMD) indicating insufficient decrease to qualify for PMR and insufficient increase to qualify for PMD.

Figure 4

Biological correlatives for overall survival after treatment with CP-870,893 in combination with gemcitabine. (A) Median overall survival and progression free survival for patients (n=21) receiving at least one dose of CP-870,893. Relationship between (B) percent change in CA19-9 at end of one cycle of therapy compared to baseline (R = −0.579; p = 0.049), (C) overall survival and tumor response determined by RECIST 1.0 at completion of two cycles of therapy (R = −0.652; p = 0.002), and (D) percent change in total MVPmean for all lesions, primary pancreatic lesion, and all hepatic lesions after two weeks of therapy compared to baseline (R = −0.929; p = 0.007). Best overall tumor response measured by RECIST 1.0 is indicated in (B), (C), and (D) using open circles (partial response), grey circles (stable disease), and black circles (progressive disease).