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

Inclusion Criteria:

• Histologically or cytologically (Bethesda 5 or 6) confirmed metastatic pancreaticcancer, as indicated by a definite cytology/histology report.

• Stable disease according to RECIST criteria version 1.1 after at least 8 cycles ofchemotherapy (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, absoluteneutrophil 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 thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

• Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and any locally required authorization (e.g.,European Union Data Privacy Directive) obtained from the patient/legalrepresentative prior to performing any protocol-related procedures, includingscreening evaluations.

Exclusion Criteria:

• Child-Pugh Classification grade B/C.

• Current treatment with immunotherapeutic drugs.

• Previous malignancy (excluding non-melanoma skin cancer, pancreatic neuroendocrinetumor (pNET) <2cm, and gastrointestinal stromal tumor (GIST) <2cm), unless noevidence of disease and diagnosed more than 3 years before diagnosis of pancreaticcancer, 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 ofreproductive potential who are not willing to employ effective birth control fromscreening 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 drugexcipients.

• An active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or otherimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment. Active or priordocumented autoimmune or inflammatory disorders (including inflammatory boweldisease [e.g., colitis or Crohn's disease], diverticulitis [with the exception ofdiverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegenersyndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

A. Patients with vitiligo or alopecia; B. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; C. Any chronic skin condition that does not require systemic therapy; D. Patients without active disease in the last 5 years may be included but only after consultation with the study physician; E. Patients with celiac disease controlled by diet alone.

• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any otherform of immunosuppressive therapy within 14 days prior to the planned first dose ofthe study. The following are exceptions to this criterion: 1) Intranasal, inhaled,topical steroids, or local steroid injections (e.g., intra articular injection), 2)Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisoneor its equivalent and 3) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP andup to 30 days after the last dose of IP.

• Prior randomization or treatment in a previous durvalumab clinical study regardlessof treatment arm assignment.

• Participation in another clinical study with an investigational product during thelast 3 months.

• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of aninterventional study.

• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy,endocrine therapy, targeted therapy, biologic therapy, tumor embolization,monoclonal antibodies) ≤28 days prior to the first dose of study drug If sufficientwash-out time has not occurred due to the schedule or PK properties of an agent, alonger wash-out period will be required, as agreed by AstraZeneca and theinvestigator.

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria.

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Study Physician.

• Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with theStudy Physician.

• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.

• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug.

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

• History of allogenic organ transplantation.

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent.

• History of leptomeningeal carcinomatosis.

• Brain metastases or spinal cord compression. Patients with suspected brainmetastases at screening should have an MRI (preferred) or CT each preferably with IVcontrast of the brain prior to study entry to rule out the presence of brainmetastasis.

• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated from 3 ECGs (within 15 minutes at 5 minutes apart).

• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti HBc and absence of HBsAg) are eligible. Participants positive forHCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.Adjust wording as necessary and consider evaluating at screening for studies withknown hepatotoxicity or other relevant requirements.

• Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that mayinclude clinical history, physical examination and radiographic findings, ortuberculosis testing in line with local practice).

• Serious concomitant systemic disorders that would compromise the safety of thepatient or his/her ability to complete the study, at the discretion of theinvestigator.