To investigate the efficacy and safety of neoadjuvant (preceding surgical removal) treatment with two cytostatic agents (gemcitabine, cisplatin) in combination with two monoclonal antibodies (durvalumab, tremelimumab) in patients with a specific type of malignant liver cancer.

Phase 1

• Conditions: Intrahepatic cholangiocarcinoma; MedDRA version: 27.0Level: LLTClassification code 10073077Term: Intrahepatic cholangiocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-004411-11-DE
• Lead Sponsor: niversity Hospital Schleswig-Holstein, Campus Lübeck

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2022-11-28
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 31

Inclusion Criteria

For inclusion in the study, patients should fulfill the following criteria:
1.Must have a life expectancy of at least 12 weeks.
2.Ability of patient to understand nature, importance and individual consequences of clinical trial.
3.Sufficient language skills to comprehend verbal and written information and 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.
4.Age >18 years.
5.Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
6.At least 1 lesion, not previously treated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to treatment start
7.Histologically confirmed diagnosis of iCCA and available tumor tissue for translational research.
8.Technical resectability of the primary tumor.
9.No prior systemic or local therapy and no prior partial or complete tumor resection for iCCA.
10.Body weight >30 kg
11.Adequate normal organ and marrow function as defined below:
a.Absolute neutrophil count (ANC =1.5 × 109 /L)
b.Hemoglobin =9 g/dL (transfusion permitted within 30 days of study entry).
c.Platelet count =100 × 109/L
d.Serum bilirubin =2.0 x institutional upper limit of normal (ULN).
e.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3x ULN
f.Creatinine normal for age: if serum creatinine is abnormal for age the patient must have a calculated creatinine clearance =50 mL/min using the CKD-EPI formula.
g.Quick =70% or International normalized ratio (INR) = 1.2 x ULN
12.Women post-menopausal for more than two years can participate in the trial. Women with childbearing potential can only participate, if they are surgically sterile or a negative pregnancy test (serum) is available within 7 days before trial and they are willing to either be totally sexually abstinent OR practice at least one highly effective and medically accepted contraception method during trial (see chapter 7.1). They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue to use it throughout the total duration of the drug treatment and the drug washout period (180 days after the last dose of durvalumab + tremelimumab and Gemcitabine/Cisplatin combination therapy).
13.Men must agree to remain abstinent or use contraceptive measures, and agree to refrain from donating sperm, as defined: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 180 days after the last dose of study treatment to avoid exposing the embryo. Vasectomised males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 21

Exclusion Criteria

1.Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study prior to inclusion and during the study.
2.Medical or psychological conditions that would jeopardize an adequate and orderly completion of the trial.
3.Prior immunotherapy or use of other investigational agents
4.Any other concurrent antineoplastic treatment including chemotherapy, biologic or hormonal therapy or irradiation
a.Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to study entry. Concurrent use of hormonal therapy for non-cancer related conditions is acceptable.
5.Any unresolved toxicity NCI CTCAE (V5.0) Grade =2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
a.Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after consultation with the medical monitor.
b.Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the medical monitor.
6.Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start
7.Prior radiation therapy within 14 days prior to study entry.
8.History of allogenic organ transplantation.
9.History of autologous/allogenic bone marrow transplant.
10.Active or prior documented autoimmune or inflammatory disorders (for exceptions see Protocol)
11.Uncontrolled intercurrent illness, including but not limited to, 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 or could compromise protocol objectives in the opinion of the Investigator and/or Sponsor.
12.Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to enrollment. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism within 3 months of enrollment.
13.Have Fridericia-corrected QT interval (QTcF) >470 msec (female) or >450 msec (male), or history of congenital long QT syndrome. Any ECG abnormality that in the opinion of the Investigator would preclude safe participation in the study; patients with pacemakers where QTc is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study.
14.Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.
15.History of another primary malignancy (for exceptions see protocol)
16.History of leptomeningeal carcinomatosis
17.History of active primary immunodeficiency
18.Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy.
19.Active infection including tuberculosis. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain rea

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To demonstrate safety and feasibility of neoadjuvant Gemcitabine plus Cisplatin with Durvalumab and Tremelimumab in intrahepatic Cholangiocarcinoma by a R0/R1 resection rate > 65%.;Secondary Objective: Secondary objectives include:<br>the pathological response rates<br>impact on radiological resectability<br>radiological response<br>safety and toxicity<br>90-day perioperative morbidity and mortality<br>quality of life;Primary end point(s): R0/R1-resection rates ;Timepoint(s) of evaluation of this end point: Pathological response will be evaluated after surgery by pathological assessment

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Pathological response rates, radiological resectability and response, safety and toxicity, 90-day perioperative morbidity, mortality and QoL;Timepoint(s) of evaluation of this end point: See protocol SCHEDULE OF STUDY ASSESSMENTS