Combining anti-PD-L1 immune checkpoint inhibitor durvalumab with TLR-3 agonist rintatolimod in patients with metastatic pancreatic ductal adenocarcinoma for therapy efficacy. DURIPANC study.

• 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.

• 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 past 2
years (i.e. with use of disease modifying agents, corticosteroids or other
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment. Active or
prior documented autoimmune or inflammatory disorders (including inflammatory
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis
syndrome, or Wegener syndrome [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
other form of immunosuppressive therapy within 14 days prior to the planned
first dose of the 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 prednisone or 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 and up to 30 days after the last dose of IP.
• Prior randomisation or treatment in a previous durvalumab clinical study
regardless of treatment arm assignment.
• Participation in another clinical study with an investigational product
during the last 3 months.
• Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional 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
sufficient wash-out time has not occurred due to the schedule or PK properties
of an agent, a longer wash-out period will be required, as agreed by
AstraZeneca and the investigator.
• Any unresolved toxicity NCI CTCAE Grade >=2 from previous anticancer therapy
with the exception of alopecia, vitiligo, and the laboratory values defined in
the inclusion criteria.
o Patients with Grade >=2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician.
o Patients with irreversible toxicity not reasonably expected to be exacerbated
by treatment with durvalumab may be included only after consultation with the
Study Physician.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(e.g., hormone replacement therapy) is acceptable.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide
field of radiation within 4 weeks of the first dose of study drug.
• Major surgical procedure (as defined by the Investigator) within 28 days
prior to the first dose of IP. Note: Local surgery of isolated lesions for
palliative intent is acceptable.
• History of allogenic organ transplantation.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or
active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung
disease, serious chronic gastrointestinal conditions associated with diarrhea,
or psychiatric illness/social situations that would limit compliance with study
requirement, substantially increase risk of incurring AEs or compromise the
ability of the patient to give written informed consent.
• History of leptomeningeal carcinomatosis.
• Brain metastases or spinal cord compression. Patients with suspected brain
metastases at screening should have an MRI (preferred) or CT each preferably
with IV contrast of the brain prior to study entry to rule out the presence of
brain metastasis.
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF)
>=470 ms.
• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,
hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody
(anti-HBc), at screening. Participants with a past or resolved HBV infection
(defined as the presence of anti HBc and absence of HBsAg) are eligible.
Participants positive for HCV antibody are eligible only if polymerase chain
reaction is negative for HCV RNA. Adjust wording as necessary and consider
evaluating at screening for studies with known 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 may include clinical history, physical examination and
radiographic findings, or tuberculosis testing in line with local practice).
• Serious concomitant systemic disorders that would compromise the safety of
the patient or his/her ability to complete the study, at the discretion of the
investigator.