Phase 2 Study of Preoperative Gemcitabine Plus Cisplatin with Durvalumab (MEDI4736) and Tremelimumab in intrahepatic cholangiocarcinoma (NeoTreme)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Schleswig-Holstein AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Jun 2023 → 12 Jan 2026

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

AstraZeneca GmbH

External identifiers

EU CT number

2024-515660-31-00

EudraCT number

2021-004411-11

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

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 objectives 6

1. pathological response rates
2. impact on radiological resectability
3. radiological response
4. safety and toxicity
5. 90-day perioperative morbidity and mortality
6. quality of life

Conditions and MedDRA coding

intrahepatic cholangiocarcinoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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 in the protocol
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

Exclusion criteria 27

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, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen4 (anti-CTLA- 4) antibody, therapeutic cancer vaccines
4. Any other concurrent antineoplastic treatment including chemotherapy, biologic or hormonal therapy or irradiation
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
6. Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start (minor procedures within 1 week)
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 (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.]). Few exceptions to this criterion are defined in the protocol
11. Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive heart failure (New York Heart Association Class III or IV), 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 (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") 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 (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg) result], hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
20. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. Few expeptions to this rule are described in the protocol
21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IMP and up to 30 days after the last dose of IMP
22. Female patients who are pregnant or breastfeeding
23. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
24. Distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Infiltration of any adjacent organs or structures by CT or MRI, indicating an unresectable situation
25. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry
26. Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study
27. Preexisting hearing impairment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. R0/R1-resection rates

Secondary endpoints 1

1. Pathological response rates, radiological resectability and response, safety and toxicity, 90-day perioperative morbidity, mortality and QoL

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Schleswig-Holstein AöR

Sponsor organisation

Universitaetsklinikum Schleswig-Holstein AöR

Address

Ratzeburger Allee 160

City

Luebeck

Postcode

23538

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Schleswig-Holstein AöR

Contact name

Prof. Jens Marquardt

Public contact point

Organisation

Universitaetsklinikum Schleswig-Holstein AöR

Contact name

Prof. Jens Marquardt

Locations

1 EU/EEA country · 6 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 9 files

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

Application history

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