Trial Title:
Combining Anti-PD-L1 Immune Checkpoint Inhibitor Durvalumab With TLR-3 Agonist Rintatolimod in Patients With Metastatic Pancreatic Ductal Adenocarcinoma for Therapy Efficacy
NCT ID:
NCT05927142
Condition:
Metastatic Pancreatic Cancer
Conditions: Official terms:
Adenocarcinoma
Pancreatic Neoplasms
poly(I).poly(c12,U)
Durvalumab
Conditions: Keywords:
Immunotherapy
Pancreatic cancer
anti PD-L1
TLR-3 agonist
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Sequential Assignment
Intervention model description:
Exploratory, non-randomized, open-label, single center, phase I-II study
Primary purpose:
Other
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Durvalumab
Description:
Human anti-PD-L1 antibody
Arm group label:
Durvalumab and rintatolimod combination therapy
Other name:
Imfinzi
Other name:
MEDI4736
Intervention type:
Drug
Intervention name:
Rintatolimod
Description:
TLR-3 agonist, synthetic double-stranded ribonucleic acid (poly I:C12U)
Arm group label:
Durvalumab and rintatolimod combination therapy
Other name:
Ampligen
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.
Criteria for eligibility:
Criteria:
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 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.
- 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.
- 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.
- 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
calculated 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), 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Erasmus MC
Address:
City:
Rotterdam
Zip:
3000 CA
Country:
Netherlands
Status:
Recruiting
Contact:
Last name:
Songul Kucukcelebi, MD
Phone:
+31614300617
Email:
s.kucukcelebi@erasmusmc.nl
Contact backup:
Last name:
Judith Verhagen, PhD
Phone:
+31650032401
Email:
j.verhagen-oldenampsen@erasmusmc.nl
Investigator:
Last name:
Marjolein Homs, MD, PhD
Email:
Principal Investigator
Investigator:
Last name:
Casper van Eijck, Prof, MD, PhD
Email:
Sub-Investigator
Investigator:
Last name:
H Verheul, Prof, MD, PhD
Email:
Sub-Investigator
Start date:
January 9, 2024
Completion date:
April 2027
Lead sponsor:
Agency:
Joachim Aerts, MD PhD
Agency class:
Other
Collaborator:
Agency:
AIM ImmunoTech Inc.
Agency class:
Industry
Collaborator:
Agency:
AstraZeneca BV
Agency class:
Other
Source:
Erasmus Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05927142
