Trial Title:
Precision Medicine in Patients With Unresectable CholAngiocarcinoma: RadioEmbolization and Combined Biological Therapy
NCT ID:
NCT06375915
Condition:
Intrahepatic Cholangiocarcinoma
Conditions: Official terms:
Cholangiocarcinoma
Gemcitabine
Durvalumab
Conditions: Keywords:
intrahepatic cholangiocarcinoma
precision medicine
combined treatment
radioembolization (TARE)
intrahepatic cholangiocarcinoma (iCC)
immunotherapy
immunogenicity
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
radioembolization with Y-90
Description:
Radioembolization with Y-90 will be performed in nominal day 0
Arm group label:
tretament arm
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
Following radioembolization, for 6 cycles -intravenous infusion on day 1 of each cycle
Arm group label:
tretament arm
Intervention type:
Drug
Intervention name:
Cisplatin
Description:
Following radioembolization, for 6 cycles -intravenous infusion on day 1 and 8 of each
cycle
Arm group label:
tretament arm
Intervention type:
Drug
Intervention name:
Gemcitabine
Description:
Following radioembolization, for 6 cycles -intravenous infusion on day 1 and 8 of each
cycle
Arm group label:
tretament arm
Summary:
Underlying disease mechanisms are fundamental for correct treatment selection and patient
management in highly invasive and debilitating non-transmissible diseases. Even though
overall disease burden of cancer may have decreased due to a higher degree of awareness,
the availability of high-quality healthcare and early diagnosis may become challenging in
certain neoplasms. Cholangiocarcinoma is usually diagnosed at advanced stages due to
non-specific presentation and is frequently refractory to chemotherapy, causing a massive
impact on patients and their families. Surgery is currently the only curative treatment
but is available to only approximately 30% of patients. The combination of
interventional- and immune-oncology to standard of care creates the perfect substrate for
synergistic mechanisms to fight tumor growth; in situ cell death following transarterial
embolization(TARE) elicits immune mediated response, inflammatory response and biomarkers
of oxidative stress and increases antigen presenting T-cells which an anti-anti progam
death ligand (PD-L)1 can bind to; standard of care can then add on with its known
effects.The rationale of a combined- locoregional and systemic - treatment lies in the
synergistic effects of each of the treatments.
Detailed description:
Tumors are highly selective and well defined abnormal cellular proliferations in which
microenvironment plays an important role in response to treatment. Intrahepatic
Cholangiocarcinoma (iCCA), a tumor derived from the epithelia cells of the bile duct, is
particularly invasive and malignant. Personalized treatment options with documented
efficacy in patients with iCCA are still not available due to the complex and
heterogenous molecular pathogenesis which has not been holistically described. Disease
models have limited reproducibility; underlying chronic cholestatic disease, chronic
inflammation and risk factors contribute to the complexity and diversity of tumor
microenvironment. Although novel systemic therapeutic agents show improvement compared to
standard of care chemotherapy, a significant percentage of patients still does not
respond to treatment, maybe due to molecular/immunologic features which confer
resistance. Local treatment prior to systemic therapy has shown to induce subtle changes
in the tumor microenvironment and a systemic immune response: engagement of the immune
system may therefore lead to enhanced and long term immunosurveillance and therefore,
lasting benefits for cancer patients.
Combined systemic treatment with an anti PD-L1, that binds to the programmed cell death
protein 1, and the standard of care (SOC) protein kinase inhibitor sorafenib and
gemcitabine (which inhibits DNA synthesis), have been used in clinical trials for other
primary liver indications and in patients with biliary tract cancers (TOPAZ trial).
Radioembolization (TARE) combines the embolization properties of microspheres with the
radiant effect of Yttrium-90 (Y-90). The locally treated tumor tissue is left in place
and releases tumor-associated antigens and danger-associated molecular peptides
originating from dead or dying cancer cells which promote the activation of antigen
presenting cells and anti-tumor CD8+T cells. The resulting development of a systemic
immune response following local treatment may lead to tumor regression at different sites
than the one treated locally, leading to the so-called abscopal effect.
Comprehensive evaluations in patients undergoing combined treatment may allow a better
understanding of tumor pathophysiology as well as the optimization of combined treatment
schemes.
This study will investigate the efficacy, primary endpoint overall response rate
according to mRECIST (modified Response Evaluation Criteria in Solid Tumors) , and safety
of the association of locoregional radioembolization followed by the combination of
standard of care (SOC) chemotherapy with Cisplatin and Gemcitabine and durvalumab in
patients with liver predominant unresectable intrahepatic cholangiocarcinoma. The
biological profile of patients prior to and following locoregional treatment and the
effect of systemic therapy will be characterized in terms of potential biomarkers such as
quantitative non-invasive radiological based parameters, tumor tissue profiling and
evaluation of biological substrates to help define and stratify patients with higher
response and better outcome.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- 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 (European
Union [EU] Data Privacy Directive) obtained from the patient/legal representative
prior to performing any protocol related procedures, including screening
evaluations.
- Patients with liver predominant intrahepatic cholangiocarcinoma with
intermediate/high rate of early recurrence calculated according to
https://k-sahara.shinyapps.io/Veryearlyrecurrence/.
- Patients aged > 18 to ≤ 80 at time of study entry;
- Body weight >30kg
- Suspicion or biopsy confirmed diagnosis of iCC, not previously treated with systemic
or surgical therapies, including not previously enrolled in another clinical study
with an investigational product;
- Preserved liver function as defined as: Child Pugh Class A; Model for End Stage
Liver Disease Score (MELD) <10; Future Liver Remnant (FLR) uptake function
≥2.7%/min/m2 on technetium- 99m mebrofenin hepatobiliary scintigraphy and FLR
volume> 30% of total functional liver volume for a normal liver, or > 40% of total
functional liver volume if the liver has been damaged by chronic liver disease,
cholestasis, steatohepatitis or diabetes;
- No technical contraindications to TARE as confirmed by pre-procedural angiographic
and scintigraphy;
- DNA tests for hepatitis B virus (HBV) and RNA tests for hepatitis C virus (HCV)
negative at Screening;
- Adequate heart and lung function;
- Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or 1;
- Adequate renal and hepatic function as indicated by: serum creatinine <2x upper
limit of normal and estimated glomerular filtration rate (eGFR) ≥30ml/min or 1.73m2;
measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL>40 mL/min
by the Cockcroft-Gault formula (Cockcroft and Gault 1976*) or by 24-hour urine
collection for determination of creatinine clearance; Alkaline phosphatase (ALP),
alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 5 times the
upper limit of normal (ULN) and total bilirubin ≤ 1.5 x institutional upper limit of
normal (ULN) (this will not apply to patients with confirmed Gilbert's syndrome
(persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in
the absence of hemolysis or hepatic pathology), who will be allowed only in
consultation with their physician);
- Hemoglobin ≥9 g/dL, platelet count ≥75,000/mm3, absolute neutrophil count (ANC) ≥
1.0 x 109 /L
- 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.
- Must have a life expectancy of at least 12 weeks
Exclusion Criteria:
- Cancer classified as a combined or mixed type (HCC hepatocelular carcinoma and ICC)
at screening -histopathological examination;
- Child-Pugh class B or more or evidence of severe portal hypertension at screening or
at any time up to and including baseline;
- History of major gastrointestinal bleeding that required medical intervention within
30 days prior to screening or baseline;
- Known hypersensitivity to tumor specific chemotherapy agents used during the study;
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients;
- Previous allogeneic bone marrow transplant, kidney or liver transplant, i.e. -
history of allogenic organ transplantation;
- Active viral, bacterial or fungal infection, clinically relevant for the assessment
of suitability;
- Current history or evidence of neuropsychiatric diseases, including depression,
schizophrenia,bipolar disorder, impaired cognitive function, dementia, or suicidal
tendency;
- 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: Patients with vitiligo or alopecia; Patients with hypothyroidism
(e.g., following Hashimoto syndrome) stable on hormone replacement; Any chronic skin
condition that does not require systemic therapy; Patients without active disease in
the last 5 years may be included but only after consultation with the study
physician; Patients with celiac disease controlled by diet alone;
- History of severe cardiovascular disease such as a previous stroke, coronary artery
disease requiring surgery, or unresolved arrhythmias within the past 6 months;
- 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);
- 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 adverse events (AEs) or compromise the ability of the
patient to give written informed consent
- History of another primary malignancy except for: malignancy treated with curative
intent and with no known active disease ≥5 years before the first dose of IP and of
low potential risk for recurrence; Adequately treated non-melanoma skin cancer or
lentigo maligna without evidence of disease; Adequately treated carcinoma in situ
without evidence of disease
- History of leptomeningeal carcinomatosis;
- Evidence of any hematological malignancy;
- History of active primary immunodeficiency - Positive for human immunodeficiency
virus type 1 or 2 (HIV-1, HIV-2) (serum or RNA) - and / or hepatitis B virus surface
antigen (HBsAg) positive and/or active Treponema pallidum infection or Mycoplasma
(active tuberculosis infection); 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;
- Alcohol abuse in the 2 months prior to study or other substance abuse in the 6
months prior to the study;
- Pregnant or breastfeeding women or women planning to become pregnant;
- Known bleeding diathesis or history of abnormal bleeding or any other known
coagulation abnormality that may contraindicate future surgery or biopsies;
- Use of systemic immunosuppressants or steroids (prednisone equivalent> 10 mg/day);
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion: Intranasal,
inhaled, topical steroids, or local steroid injections (e.g., intra articular
injection); Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent; Steroids as premedication for hypersensitivity
reactions;
- Active autoimmune conditions
- Patients weighing <30kg will be excluded from enrolment;
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients;
- Major surgical procedure (as defined by the Investigator) within 28 days prior to
the first dose of Investigational product (IP). Note: Local surgery of isolated
lesions for palliative intent is acceptable.
- 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 90 days after the last dose of IP and up to 90 days after the last dose;
- Presence of Hepatopulmonary shunt >20% at diagnostic angiography/99mTC-MAA.
- Prior randomisation or treatment in a previous durvalumab clinical study regardless
of treatment arm assignment;
- Presence of Hepatopulmonary shunt >20% at diagnostic angiography/99mTC-MAA;
- 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Department of Radiology, IRCCS Ospedale San Raffaele
Address:
City:
Milano
Zip:
20132
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Francesco De Cobelli, MD
Phone:
+39022643
Phone ext:
2529
Email:
decobelli.francesco@hsr.it
Contact backup:
Last name:
Stephanie Steidler, PhD
Phone:
+39022643
Phone ext:
6111
Email:
steidler.stephanie@hsr.it
Investigator:
Last name:
Francesco De Cobelli, MD
Email:
Principal Investigator
Investigator:
Last name:
Francesca Ratti, MD
Email:
Sub-Investigator
Start date:
May 1, 2024
Completion date:
January 2026
Lead sponsor:
Agency:
Francesco De Cobelli
Agency class:
Other
Collaborator:
Agency:
Cardarelli Hospital
Agency class:
Other
Collaborator:
Agency:
A.O. Ospedale Papa Giovanni XXIII
Agency class:
Other
Collaborator:
Agency:
AOU Pisana, Pisa, Italy
Agency class:
Other
Source:
IRCCS San Raffaele
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06375915
