A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

Beatty, Gregory L.; Torigian, Drew A.; Chiorean, E. Gabriela; Saboury, Babak; Alavi, Abass; Troxel, Andrea B.; Sun, Weijing; Teitelbaum, Ursina R.; Vonderheide, Robert H.; O’Dwyer, Peter J.

doi:10.1158/1078-0432.ccr-13-1320

Cited by 396 publications

(300 citation statements)

References 27 publications

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“…Prior clinical trials of single-agent agonistic CD40 mAb, or CD40 mAb in combination with chemotherapy, have demonstrated clinical activity. 7,11–13,15,21 In a previous trial, 4 patients among 15 with advanced melanoma had a PR to a single dose of the CD40 mAb CP-870,893. 7 Potential synergy of CD40 activation and CTLA-4 blockade has been established in mouse tumor models, 6 but this study is the first to test this hypothesis in patients.…”

Section: Discussionmentioning

confidence: 99%

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

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Section: Discussionmentioning

confidence: 99%

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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“…7,8 A second strategy would be to formally explore the potential of immunologic approaches such as CD40 agonists and T-cell engineering strategies. 9,10 Such strategies fit nicely with the current emphasis on understanding the unique role of the local host response to pancreatic cancer, and preclinical studies suggesting that the prolific stroma associated with pancreatic cancer serve as a barrier to the distribution of cytotoxic chemotherapy into the pancreatic primary tumor. 3,11,12 The extent to which a stromal barrier function can be targeted in metastatic pancreatic cancer is currently being addressed in trials using stromal disrupting agents in combination with chemotherapy.…”

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confidence: 90%

New Option for the Initial Management of Metastatic Pancreatic Cancer?

Abbruzzese

Hess

2014

JCO

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In the October 31, 2013, issue of the New England Journal of Medicine, Von Hoff et al 1 published an important article describing the results of a randomized clinical trial conducted in patients with metastatic pancreatic cancer that compared gemcitabine with a combination of gemcitabine and nab-paclitaxel. In this trial, 861 patients were randomly assigned: 431 to gemcitabine plus nab-paclitaxel and 430 to gemcitabine alone. The high-level results demonstrated a median overall survival of 8.5 months in the nab-paclitaxel group compared with 6.7 months in the gemcitabine group. The hazard ratio for death was 0.72 (95% CI, 0.62 to 0.83; P Ͻ .001). Other end points, including progression-free survival and response rate, were superior with the combination. Grade Ն 3 neutropenia occurred in 38% of the patients treated with gemcitabine plus nab-paclitaxel, with 3% of these instances resulting in febrile neutropenia. Twenty-six percent of the patients received growth factors. Cumulative peripheral neuropathy occurred in 17% of the patients treated with nab-paclitaxel, and it was managed with temporary discontinuation of nab-paclitaxel followed by a reduction in dose. Overall, however, 71% of the nab-paclitaxel doses were delivered at the intended starting dose. 1On the basis of these results, there are now two combination cytotoxic chemotherapy regimens with activity in patients with untreated metastatic pancreatic cancer: gemcitabine plus nab-paclitaxel and the combination of fluorouracil, irinotecan, and oxaliplatin known as FOLFIRINOX. The pivotal FOLFIRINOX trial (Partenariat de Recherche en Oncologie Digestive 4/Action Clinique Coordonnées en Cancérologie Digestive 11 [PRODIGE4/ACCORD 11]) also targeted patients with metastatic pancreatic cancer, randomly assigning 342 patients to receive FOLFIRINOX or gemcitabine. In that trial, the median overall survival was 11.2 months for patients treated with FOLFIRINOX and 6.8 months for patients treated with gemcitabine. However, despite the encouraging efficacy of FOLFIRINOX, the challenge with this regimen is its toxicity, with 46% of the FOLFIRINOXtreated patients developing grade 3 or 4 neutropenia, 5% febrile neutropenia, and 42% requiring growth factor support with filgrastim. The incidence of grade 3 or 4 diarrhea and sensory neuropathy were also significantly higher in the FOLFIRINOX group.2 However, despite the higher rates of adverse events with FOLFIRINOX relative to gemcitabine, FOLFIRINOX conferred a benefit by slowing deterioration in quality of life, presumably because of the anticancer activity of the regimen.Recognizing the limitations of cross-trial comparisons, practicing oncologists are now faced with the question of which of these two regimens should be considered for the first-line management of patients with metastatic pancreatic cancer. Both regimens are clearly active. As described in the reports, there are differences in the patient populations being treated. For example, patients treated with gemcitabine plus nab-paclitaxel compared with patient...

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“…They further showed that the tumor regression was mediated by macrophage that facilitated the depletion of tumor stroma. CP-870, 893, a monoclonal antibody, is a CD40 agonist that was evaluated in combination with gemcitabine in a phase I trial in patients with advanced PDA (33). Four of twentytwo patients (18%) achieved partial response.…”

Section: Immune Cellsmentioning

confidence: 99%

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

Mei¹,

Du²,

Wee³

2016

J. Gastrointest. Oncol.

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Pancreatic cancer is a highly lethal disease. Conventional therapeutics targeting pancreas cancer cell compartment using cytotoxics improved patient survival but at the expense of significant toxicity.Microscopically, the tumor is characterized by thick desmoplastic stroma that surrounds islands of pancreatic cancer cells. The tumor microenvironment has been found to play important roles in carcinogenesis, the development of drug resistance, and mediating immunosuppression. The understanding the tumor-stromal interaction has led to the development of novel therapeutic approaches. Here, we review the strategies that are currently in (or, near to) clinical evaluation and the underlying preclinical rationales.

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A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

Cited by 396 publications

References 27 publications

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

New Option for the Initial Management of Metastatic Pancreatic Cancer?

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

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