In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. PR005-PR005
Abstract:
In preclinical work, the inflammatory cytokine IL-1β was shown to be upregulated in pancreatic cancer tumors and to contribute to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We conducted an open-label multicenter Phase Ib study evaluating gemcitabine, nab-paclitaxel, canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a PD-1 mAb. Eligible subjects had previously untreated metastatic PDA and RECIST measurable disease. The primary objective was to confirm recommended phase II dose by evaluating the incidence of dose limiting toxicities (DLTs) in the first 56 days of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. Subjects underwent baseline and on-study tissue and blood collection for correlative translational research. Results: 10 subjects were enrolled between Nov 2020 and Mar 2021. At the primary data cut off of May 23, 2021, 6 subjects were evaluable for DLT. There were no DLTs, the recommended Phase II dose was established as: gemcitabine (1000mg/m2 IV) day 1,8,15; nab-paclitaxel (125mg/m2 IV) day 1,8,15; canakinumab (250mg SC) day 1, spartalizumab (400mg IV) day 1; of each 28 day cycle. At the time of an updated database extraction on June 1, 2022, 2 subjects remain on study. Adverse events were consistent with those typically seen with chemotherapy. The most common Grade 3/4 AEs were neutropenia (60%) and anemia (50%), with no fatal AEs. One patient discontinued spartalizumab due to grade 3 pneumonitis. In preliminary efficacy analysis (n=10), there are 3 confirmed PRs, 5 subjects with stable disease, 2 subjects with progression as best response. Individual site data estimates that the 12 month OS rate is 60%; updated RR, PFS and OS data will be reported. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in both responder and non-responder patients. Using an in vitro suppression assay, we showed that baseline serum from responders could induce myeloid derived suppressor cells, an effect that was abrogated with treatment. Single cell transcriptional profiling, multiplex immunofluorescence and spatial transcriptomics also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical response. Conclusions: PanCAN-SR1 established the Phase II dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA, based upon favorable benefit-risk assessment. Based on our comprehensive analysis of 10 patients treated with combination therapy including IL-1b blockade, we hypothesize that the definitive role of anti-IL-1b in human patients with pancreatic cancer is to reduce systemic immune suppression and to reduce immunosuppressive myeloid cell activation in the tumor. The clinical utility of targeting IL-1β in pancreatic cancer is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. NCT04581343. Citation Format: Paul E. Oberstein, Osama Rahma, Nina Beri, Amy Stoll-D'Astice, Emily A. Kawaler, Igor Dolgalev, Gregor Werba, Victoire Cardo-Ruffino, Naïma Böllenrücher, Andressa Dias Costa, Saloney Nazeer, Matthew Squires, Jonathan Nowak, Dafna Bar-Sagi, Brian Wolpin, Diane M Simeone, Stephanie K Dougan. Primary results of PanCAN-SR1, a phase 1b study evaluating Gemcitabine, nab-Paclitaxel, Canakinumab, and Spartalizumab to target IL-1β and PD-1 in metastatic pancreatic cancer with correlative tissue and blood biomarker analysis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR005.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.PANCA22-PR005
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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