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

NCT05927142 | Recruiting Phase 1

• 2 other identifiers: NL83224.078.222022-003780-23
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Pancreatic Cancer

Keywords

Immunotherapy; Pancreatic cancer; anti PD-L1; TLR-3 agonist

Outcome Measures

Primary Outcomes (2)

• 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.

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

• 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.

  Determined 6 months after start of combination therapy

Secondary Outcomes (5)

• Determine the clinical effect of combination therapy with durvalumab and rintatolimod on survival rate

  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.

• Determine the clinical effect of combination therapy with durvalumab and rintatolimod on progression free survival (PFS)

  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.

• Explore the immunogenic effect of combination therapy with durvalumab and rintatolimod on the circulating immune profile

  From baseline till end of study (week 49)

• Explore the immunogenic effect of combination therapy with durvalumab and rintatolimod on the infiltrating immune profile

  From start of the study phase till week 12

• Determine the clinical effect of combination therapy on quality of life using questionnaires

  At baseline, 6 weeks, 3 months, 9 months, and 1 year after start immunotherapy

Study Arms (1)

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).

Biological: Durvalumab; Drug: Rintatolimod

Interventions

Durvalumab BIOLOGICAL

Human anti-PD-L1 antibody

Also known as: Imfinzi, MEDI4736

Durvalumab and rintatolimod combination therapy

Rintatolimod DRUG

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

Also known as: Ampligen

Durvalumab and rintatolimod combination therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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.

You may not qualify if:

• Child-Pugh Classification grade B/C.
• Current treatment with immunotherapeutic drugs.
• 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 randomization 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 (noninterventional) 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.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.

Sponsors & Collaborators

• Joachim Aerts, MD PhD: lead
• AIM ImmunoTech Inc.: collaborator
• AstraZeneca: collaborator

Study Sites (1)

Erasmus MC

Rotterdam, South Holland, 3000 CA, Netherlands

RECRUITING

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

durvalumab; poly(I).poly(c12,U)

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Marjolein Homs, PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

• Casper van Eijck, Prof, MD, PhD

  Erasmus Medical Center

  STUDY CHAIR

• Songul Kucukcelebi, MD

  Erasmus Medical Center

  STUDY DIRECTOR

Central Study Contacts

Songul Kucukcelebi, MD

CONTACT

+310614300617; s.kucukcelebi@erasmusmc.nl

Judith Verhagen, PhD

CONTACT

+31650032401; j.verhagen-oldenampsen@erasmusmc.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. dr.

Model Details: Exploratory, non-randomized, open-label, single center, phase I-II study

Study Record Dates

• First Submitted: June 5, 2023
• First Posted: July 3, 2023
• Study Start: January 9, 2024
• Primary Completion: April 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: February 25, 2025

Record last verified: 2025-02

Locations

NL (1)