Pancreatic ductal adenocarcinoma (PDAC) is estimated to become the second leading cause of cancer-related death by 2030. Effective management of PDAC is challenged by a combination of late diagnosis, lack of effective screening methods and high risk of early metastasis. Although systemic chemotherapy improves survival, 5-year survival is only 6%. Chemotherapy efficacy is attenuated by innate and acquired drug resistance of tumor cells, a strong desmoplastic reaction that limits local accessibility of drugs and a "cold" tumor microenvironment (TME) with high infiltrating levels of immunosuppressive cells. In PDAC, increased T cell exhaustion defined by increased PD-1/PD-L1 activity in both peripheral blood and tumor microenvironment, is associated with poor prognosis. Hence the rationale for targeting the PD-1/PD-L1 axis with the aim to release the "brake" and exert an anti-tumor response. In PDAC successful results with Immune Checkpoint Inhibition (ICI) monotherapy are limited and combination therapy with other agents is encouraged; specifically agents that induce dendritic cell priming. We hypothesize that combination therapy of ICI therapy with a toll like receptor 3 (TLR-3) agonist is a potential effective strategy. TLR-3 agonists are hypothesized to increase dendritic cell maturation and cross-priming naïve cytotoxic CD8 T cells while eliminating regulatory T-cell attraction, thereby acting as an immune-boosting agent. We propose that rintatolimod/durvalumab-combination therapy is feasible and may induce synergistic anti-tumor immune responses in PDAC.
Histologically or cytologically (Bethesda 5 or 6) confirmed metastatic pancreatic cancer, as indicated by a definite cytology/histology report.
Stable disease according to RECIST criteria version 1.1 after at least 8 cycles of chemotherapy (FOLFIRINOX).
Inclusion ≤ 6 weeks after stopping FOLFIRINOX.
An accessible metastatic lesion for histological tissue collection.
Child-Pugh Classification grade B/C.
Current treatment with immunotherapeutic drugs.
Previous malignancy (excluding non-melanoma skin cancer, pancreatic neuroendocrine tumor (pNET) <2cm, and gastrointestinal stromal tumor (GIST) <2cm), unless no evidence of disease and diagnosed more than 3 years before diagnosis of pancreatic cancer, or with a life expectancy of more than 5 years from date of inclusion.
Malignant ascites or pleural effusion.
Sequential
Durvalumab
Biological/VaccineHuman anti-PD-L1 antibody
Rintatolimod
DrugTLR-3 agonist, synthetic double-stranded ribonucleic acid (poly I:C12U)
Phase Ib: Determine safety of combination therapy with durvalumab and rintatolimod
The primary endpoint of the safety run-in (phase Ib) is the recommended phase II dose (RP2D) defined by the highest dose per protocol without dose-limiting toxicity (DLT) according to a 3+3 design related to the intervention. A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to the investigational product (IP) or investigational regimen (IR), with two exceptions: any grade of vitiligo or alopecia will not qualify as a DLT. The DLT assessment period is from the time of first dose of IP/IR and ends upon administration of the first dose of IP/IR on Cycle 2, Day 1 (28 day cycle). Toxicities will be scored according to CTC criteria version 5.0 (Published November 27th, 2017). All participants that cannot complete the combination therapy as planned due to directly related toxicity will be discussed in the Study Steering Committee and they will determine whether the patient is classified as having a DLT.
Phase II: Determine the clinical benefit rate of combination therapy with durvalumab and rintatolimod.
Response is defined as stable disease, partial or complete response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), determined 6 months after start of combination therapy. If the number of responses is ≥ 4 out of 25 patients further research of this treatment regime is justified. Furthermore, the lower boundary of the 90% CI should be higher than 5% to justify further research of this treatment regime.
Determine the clinical effect of combination therapy with durvalumab and rintatolimod on survival rate
Overall survival (OS) of participants will be defined as the time between start combination therapy with durvalumab and rintatolimod to date of death
Determine the clinical effect of combination therapy with durvalumab and rintatolimod on progression free survival (PFS)
Progression free survival (PFS), defined as the time between start of combination therapy with durvalumab and rintatolimod to date of progression (according to RECIST criteria version 1.1) or death, whichever occurs first
Explore the immunogenic effect of combination therapy with durvalumab and rintatolimod on the circulating immune profile
During the study period peripheral blood samples will be collected. The immune profile will be explored in treatment naïve blood samples and compared in paired blood samples after combination therapy. Also, immuno-oncology gene expression signatures will be determined using multiplex gene expression analysis. Immunogenic efficacy, defined as \>50% increase in circulating Ki67+ CD 8+ T cell in the peripheral blood, will be evaluated 12 weeks after combination therapy
Explore the immunogenic effect of combination therapy with durvalumab and rintatolimod on the infiltrating immune profile
During the study period tumor site biopsies will be taken from an accessible metastasis site. One before and one after 3 study treatments. The immune profile will be explored in treatment naïve tissue samples and compared in paired tissue samples after combination therapy. Also, immuno-oncology gene expression signatures will be determined using multiplex gene expression analysis.
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Joachim Aerts, MD PhD
Lead sponsor
Erasmus Medical Center
Sponsor institution
AIM ImmunoTech Inc.
Collaborator
AstraZeneca
Collaborator
