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

Brief summary public domain (ClinicalTrials.gov)

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 public domain (ClinicalTrials.gov)

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.

Detailed description public domain (ClinicalTrials.gov)

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.

Intervention public domain (ClinicalTrials.gov)

Biological: Durvalumab. Human anti-PD-L1 antibody

Intervention public domain (ClinicalTrials.gov)

Drug: Rintatolimod. TLR-3 agonist, synthetic double-stranded ribonucleic acid (poly I:C12U)

Arm public domain (ClinicalTrials.gov)

Durvalumab and rintatolimod combination therapy (experimental): 1500mg Durvalumab administered via IV infusion once every first day of a 28 day cycle for a total of maximum 12 cycles (12 infusions in total). 200-400mg Rintatolimod administered via IV infusion twice per week for a total of 6 weeks (12 infusions in total).

Primary outcome public domain (ClinicalTrials.gov)

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. Time frame: from the start of rintatolimod until 6 weeks after the first day of the first cycle of durvalumab (one cycle is 28 days).

Primary outcome public domain (ClinicalTrials.gov)

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. Time frame: Determined 6 months after start of combination therapy.

Secondary outcome public domain (ClinicalTrials.gov)

Determine the clinical effect of combination therapy with durvalumab and rintatolimod on survival rate. Time frame: from the date of first administration of the combination therapy durvalumab and rintatolimod to date of death from any cause, assessed up to 60 months..

Secondary outcome public domain (ClinicalTrials.gov)

Determine the clinical effect of combination therapy with durvalumab and rintatolimod on progression free survival (PFS). Time frame: From the date of first administration of the combination therapy durvalumab and rintatolimod to date of progression (according to RECIST criteria version 1.1) or death from any cause, whichever occurs first, assessed up to 60 months..

Secondary outcome public domain (ClinicalTrials.gov)

Explore the immunogenic effect of combination therapy with durvalumab and rintatolimod on the circulating immune profile. Time frame: From baseline till end of study (week 49).

Secondary outcome public domain (ClinicalTrials.gov)

Explore the immunogenic effect of combination therapy with durvalumab and rintatolimod on the infiltrating immune profile. Time frame: From start of the study phase till week 12.

Secondary outcome public domain (ClinicalTrials.gov)

Determine the clinical effect of combination therapy on quality of life using questionnaires. Time frame: At baseline, 6 weeks, 3 months, 9 months, and 1 year after start immunotherapy.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * 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. * SIII\<900 (Systemic Immune-Inflammation Index = ((absolute neutrophil count \* platelet count) / absolute lymphocyte count)). * CA 19.9 \<1000kU/L. * Age ≥ 18 years at time of study entry. * Body weight \>30 kg. * WHO performance status of 0-1. * Adequate renal function (eGFR \> 40 ml/min). * Adequate liver tests (bilirubin ≤ 1.5 times normal; ALAT/ASAT ≤ 5 times normal). * Adequate bone marrow function (WBC \> 3.0 x 109/L, platelets \> 75 x 109/L, absolute neutrophil count (ANC) ≥1.0 × 109 /L and hemoglobin \> 5.6 mmol/L. * Effective contraceptive methods. * Patient must have a life expectancy of at least 12 weeks. * Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., European Union Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. Exclusion Criteria: * 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. * Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. * Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. * An active autoimmune disease that has required systemic treatment in …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 43 participants (estimated).