A study to investigate whether treatment of bile duct or gallbladder cancer with Durvalumab and Tremelimumab in combination with gemcitabine alone or with gemcitabine and cisplatin is more effective in comparison to standard chemotherapy with gemcitabine and cisplatin.

Phase 1

• Conditions: advanced, unresectable and/or metastatic cholangio- and gallbladder carcinoma; MedDRA version: 20.0Level: LLTClassification code 10017617Term: Gallbladder cancer non-resectableSystem Organ Class: 100000004864; MedDRA version: 20.0Level: LLTClassification code 10017620Term: Gallbladder carcinomaSystem Organ Class: 100000004864; MedDRA version: 20.0Level: LLTClassification code 10025941Term: Malignant neoplasm of gallbladder and extrahepatic bile ductsSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10025940Term: Malignant neoplasm of gallbladderSystem Organ Class: 100000004864; MedDRA version: 20.0Level: LLTClassification code 10007426Term: Carcinoma of gallbladderSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10017622Term: Gallbladder carcinoma non-resectableSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10025943Term: Malignant neoplasm of gallbladder and extrahepatic bile ducts non-resectableSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10077744Term: Adenocarcinoma of gallbladder metastaticSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10077847Term: Gallbladder adenocarcinoma metastaticSystem Organ Class: 100000004864

• Registration Number: EUCTR2017-001538-25-DE
• Lead Sponsor: AIO-Studien-gGmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-11-14
• Last Update Posted: 2 March 2022

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 128

Inclusion Criteria

1. Fully-informed written consent and locally required authorization (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. Age = 18 years.
3. Histologically documented diagnosis of cholangiocarcinoma or gall bladder carcinoma and available tumor tissue (block or at least 4 slides) for translational research.
4. Performance status (PS) = 1(ECOG scale).
5. At least one measurable site of disease as defined by RECISTv1.1 criteria.
6. Adequate bone marrow and renal function including the following: Hemoglobin = 9.0 g/dL; absolute neutrophil count = 1.5 x 10^9/L; platelets =100x 10^9 /L; Creatinine = 1.5 x upper normal limit.
7. Calculated creatinine clearance =40 mL/min as determined by the Cockcroft-Gault equation (using actual body weight)
Males: Creatinine CL (mL/min) = (Weight (kg) × (140 - Age)) / (72 × serum creatinine (mg/dL))
Females: Creatinine CL (mL/min) = (Weight (kg) × (140 - Age) × 0.85) / (72 × serum creatinine (mg/dL))
8. Adequate hepatic function (with stenting for any obstruction, if required) including the following: Total bilirubin = 2x upper normal limit; AST (SGOT), ALT (SGPT) = 5 x upper normal limit; prothrombin time = 60%; albumin = 30 g/L.
9. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women =50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
11. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
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 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 28

Exclusion Criteria

1. 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
2. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
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 antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines.
4. Prior chemotherapy with gemcitabine, cisplatin and/or capecitabine (exception: gemcitabine, cisplatin and/or capecitabine in the adjuvant setting, last infusion has to be = 6 months prior randomization).
5. 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
6. Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions for palliative intent is acceptable (eg, local radiotherapy).
7. 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 drugs.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to the first dose of the investigational product (IMP) of starting the study and patients must have recovered from effects of major surgery. Note: Local non-major surgery for palliative intent (eg, surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.
9. History of allogenic organ transplantation.
10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
13. History of leptomeningeal carcinomatosis
14. 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.
15. History of active primary immunodeficiency
16. 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.
17. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.
18. 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.
19. Body weight =30 kg.
20. Female patients who

Study & Design

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

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the efficacy in terms of objective response rate (ORR) of the combination of durvalumab and tremelimumab in addition with gemcitabine or in addition with gemcitabine and cisplatin in treatment-naïve patients with advanced, unresectable and/or metastatic cholangio- and gallbladder carcinoma.;Secondary Objective: To determine 1.) the efficacy of the combination of durvalumab and tremelimumab in addition with gemcitabine or in addition with gemcitabine and cisplatin in treatment-naïve patients with advanced, unresectable and/or metastatic cholangio- and gallbladder carcinoma in terms of median overall survival (OS), median progression-free survival (PFS) and duration of response, 2.) to determine the safety/toxicity within a first safety stage and during the whole study, and 3.) quality of life (QOL).;Primary end point(s): ORR according to RECIST 1.1;Timepoint(s) of evaluation of this end point: End of Study (EoS)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • PFS<br>• OS<br>• Duration of response<br>• AEs / SAEs and Treatment Emergent Adverse Events according to CTC 4.03<br>• Health related Quality of Life (HR-QoL; EORTC QLQ-C30)<br>;Timepoint(s) of evaluation of this end point: End of Study (EoS)