E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced, unresectable and/or metastatic cholangio- and gallbladder carcinoma |
fortgeschrittenes, nicht resezierbares und / oder metastasiertes Cholangio- und Gallenblasen-Karzinom |
|
E.1.1.1 | Medical condition in easily understood language |
advanced, inoperable and/or metastatic bile duct and gallbladder cancer |
fortgeschrittener, inoperabler und / oder metastasierter Gallengangs- und Gallenblasenkrebs |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017617 |
E.1.2 | Term | Gallbladder cancer non-resectable |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017620 |
E.1.2 | Term | Gallbladder carcinoma |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025941 |
E.1.2 | Term | Malignant neoplasm of gallbladder and extrahepatic bile ducts |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025940 |
E.1.2 | Term | Malignant neoplasm of gallbladder |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007426 |
E.1.2 | Term | Carcinoma of gallbladder |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017622 |
E.1.2 | Term | Gallbladder carcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025943 |
E.1.2 | Term | Malignant neoplasm of gallbladder and extrahepatic bile ducts non-resectable |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077744 |
E.1.2 | Term | Adenocarcinoma of gallbladder metastatic |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077847 |
E.1.2 | Term | Gallbladder adenocarcinoma metastatic |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008594 |
E.1.2 | Term | Cholangiocarcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077846 |
E.1.2 | Term | Cholangiocarcinoma metastatic |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
Untersuchung der Wirksamkeit der Kombination von Durvalumab und Tremelimumab mit Gemcitabin oder mit Gemcitabin und Cisplatin bei nicht-vorbehandelten Patienten mit fortgeschrittenem, nicht resezierbarem und / oder metastasiertem Cholangio- und Gallenblasen-Karzinom in Bezug auf die objektive Ansprechrate (ORR). |
|
E.2.2 | Secondary objectives of the trial |
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). |
1.) Untersuchung der Wirksamkeit der Kombination von Durvalumab und Tremelimumab mit Gemcitabin oder mit Gemcitabin und Cisplatin bei nicht-vorbehandelten Patienten mit fortgeschrittenem, nicht resezierbarem und / oder metastasiertem Cholangio- und Gallenblasen-Karzinom in Bezug auf das mediane Gesamtüberleben (OS), auf das mediane progressionsfreie Überleben (PFS) und auf die Dauer des Ansprechens 2.) Untersuchung der Sicherheit/Toxizität innerhalb einer ersten Sicherheitsstufe und während der gesamten Studie 3.) Erfassung der Lebensqualität (QoL)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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 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 tremelimumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy. 21. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product. 22. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment. 23. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR according to RECIST 1.1 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• PFS • OS • Duration of response • AEs / SAEs and Treatment Emergent Adverse Events according to CTC 4.03 • Health related Quality of Life (HR-QoL; EORTC QLQ-C30)
|
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of Study (EoS) is either defined as the time-point when the last subject randomized has completed a 12 months treatment and follow-up period OR the last subject on experimental treatment has received his/her last dose of IMP and completed an EoT visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 40 |
E.8.9.1 | In the Member State concerned days | |