Neo-adjuvant Chemo and immunotherapy with durvalumab (MEDI4736) and tremelimumab (MEDI1123) In The pre-operAtive Treatment of locally advanced cholangIOcarciNoma: an exploratory and translational study.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Sep 2023 → ongoing

Decision date (initial)

2024-11-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-518656-23-00

EudraCT number

2023-000138-13

ClinicalTrials.gov

NCT06341764

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The primary objective of this study is to determine whether neoadjuvant therapy decrease the recurrence rate of CCA at 12 months after surgery

Secondary objectives 1

1. The secondary objective of this study is to describe:  Rate of R0 resections (number of resections with surgical margins free from cancer/total number of resections) as assessed by pathologic examination (R1: microscopic disease; R2 macroscopic residual tumour, at gross examination);  Radiologic responses evaluated through the RECIST v1.1 criteria;  Pathologic responses (number of surgically removed tumour specimens with absence of any residual viable neoplastic cells);  Toxicity assessed by the NCI CTCAE v5.0;  Progression free survival (PFS) measured from study enrolment to death;  Overall survival (OS) measured from study enrolment to death. Analysis of secondary end-points will be descriptive because of pragmatic and exploratory approach of this trial.

Conditions and MedDRA coding

locally advanced cholangiocarcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
2. Histologically or pathologically confirmed CCA.
3. Age >18 years at time of study entry.
4. Eastern Cooperative Oncology Group (ECOG) 0 or 1.
5. Initially unresectable CCA (as assessed in multidisciplinary sessions). Patients, in the absence of extrahepatic disease or hilar cholangiocarcinoma, are defined as "initially unresectable" for one or more of the following conditions at CT-based radiologic staging: - Tumor adjacent to the remaining liver; - Tumor adjacent or infiltrating the portal vein; - Tumor with up to three contralateral metastases in the remaining liver; - Loco-regional lymphnodes involvement.
6. Life expectancy of at least 16 weeks.
7. Body weight >30 kg
8. Adequate normal organ and marrow function as defined below: - Haemoglobin ≥9.0 g/dL; - Absolute neutrophil count (ANC ≥1.5 × 109 /L); - Platelet count ≥100 × 109/L; - Serum 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; - AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN; - Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance; - At least 1 lesion 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 randomization; - No previous systemic or local treatments including radiation therapy, radiofrequency ablations, electro-chemotherapy.

Exclusion criteria 15

1. Any previous participation in another clinical interventional study.
2. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
3. History of allogenic organ transplantation.
4. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Local surgery of isolated lesions for palliative intent is acceptable.
5. 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, interstitial lung disease, 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
6. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, history of myocardial infarction within 12 months, 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.
7. History of bowel obstruction, refractory ascites, or bowel perforation due to advanced disease within the past 3 months from start of study treatment.
8. Significant bleeding diathesis or coagulopathy. Serious, nonhealing wound, ulcer, or current healing fracture.
9. History of another primary malignancy except for: a. 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; b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; c. Adequately treated carcinoma in situ without evidence of disease
10. History of leptomeningeal carcinomatosis
11. 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.
12. History of active primary immunodeficiency.
13. 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.
14. 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).
15. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. 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 (e.g., CT scan premedication); - Receipt of live attenuated vaccine within 30 days prior to the first dose of IP; - 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 or180 days after the last dose of durvalumab and tremelimumab combination therapy; - Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients; - Known allergy or hypersensitivity to IP or any excipient.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. For the primary endpoint the proportion of CCA at 12 months after surgery will be computed along with an exact 90% confidence interval (CI). A one-sided exact test with a significance level of 0.05 will be performed assuming a H0 of the proportion of CCA at 12 months equal to 0.512. The safety analyses will be carried out on the SP. All the information necessary to identify the appearance of adverse events will be used in the analysis and summarized through descriptive statistics.

Secondary endpoints 1

1. For secondary endpoints summary statistics will be calculated and reported along with 95% CI. Time-to event variables (PFS and OS) will be analyzed using the Kaplan-Meier product limit method (KM) and survival curves will be reported along with 95% CI.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Alessandro Ottaiano

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Alessandro Ottaiano

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications