Spots Global Cancer Trial Database for Combining Anti-PD-L1 Immune Checkpoint Inhibitor Durvalumab With TLR-3 Agonist Rintatolimod in Patients With Metastatic Pancreatic Ductal Adenocarcinoma for Therapy Efficacy

Study Description

Brief Summary: 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.

Detailed Description: Rationale: 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. Objective: The primary objective of the safety run-in (phase Ib) is to determine the safety of combination therapy with durvalumab and rintatolimod. The primary objective of the phase II trial is to determine the clinical benefit rate of combination therapy with durvalumab and rintatolimod. The secondary objective is to explore the immunogenic effect and survival rates after combination therapy. Study design: Exploratory, open-label, single center, phase I-II study. In phase 1 between 9 and max. 18 patients will be included. In the phase II study between 13 and 25 patients will be included. Study population: Adult patients with metastatic PDAC who completed standard of care (chemotherapy FOLFIRINOX) and have radiologically confirmed stable disease according to RECIST version 1.1 criteria. Intervention: All included patients will receive combination therapy with rintatolimod and durvalumab. Patients will start with rintatolimod 200mg via IV infusion twice per week for a total of 6 weeks (12 doses). Rintatolimod dose will be escalated to 400mg according to a 3+3 DLT design. The first dose of rintatolimod will be administered preferably 4-6 weeks after the last chemotherapy FOLFIRINOX dose. After two doses of rintatolimod, the first dose of durvalumab 1500mg via IV infusion will be introduced in week 2. Patients will continue to receive 1500 mg durvalumab via IV infusion every 4 weeks for up to a maximum of 48 weeks (up to 12 doses/cycles) with the last administration on week 48 or until confirmed disease progression according to Response Evaluation Criteria in solid Tumors (RECIST 1.1), unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Main study parameters/endpoints: The primary objective of the safety run-in (phase Ib) is to determine safety of combination therapy with durvalumab and rintatolimod. The primary objective of the phase II trial is to determine the clinical benefit rate of combination therapy with durvalumab and rintatolimod. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will receive 12 doses of rintatolimod via IV infusion and a max. of 12 doses durvalumab via IV infusion. In addition, they will undergo additional blood sampling in order to determine tumor-specific immune and tumor marker responses. Intravenous administration of medication and blood sampling can cause bruising or slight short-term discomfort. In previously performed trials, monotherapy with rintatolimod and monotherapy with durvalumab proved to be safe showing a low toxicity profile. Therefore we do not expect any major side-effects of this treatment in our patient population. However, combination treatment with rintatolimod and durvalumab has not been investigated yet, and a synergistic effect can induce unwanted side effects. To determine the safety of combination therapy, a limited number of patients will be included in the safety run-in to determine the RP2D. In addition, to explore the local anti-tumor effect of combination therapy, biopsies will be performed before start and after 12 weeks of treatment in a subset of the included patients.

Keywords

Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: ALL

Healthy Volunteers: No

Locations

Contact Details

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