| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intrahepatic Biliary Tract Carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
| Intrahepatic Biliary Tract Cancer |
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| 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 | 10008594 |
| E.1.2 | Term | Cholangiocarcinoma non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 | 10073077 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
Hypothesis of the trial: the addition of durvalumab +/- tremelimumab to SIRT improves tumor response rate (ORR) in intrahepatic BTC compared to a historical control of SIRT alone.
Primary objective
To assess the efficacy of durvalumab or durvalumab and tremelimumab administered after standard-of-care SIRT in treatment-naïve patients with unresectable intrahepatic biliary tract cancer as measured by the objective response rate (ORR). |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives
To assess safety of the combined treatment in the two treatment arms.
To assess the efficacy of durvalumab or durvalumab and tremelimumab administered after standard-of-care SIRT in treatment-naïve patients with unresectable intrahepatic biliary tract cancer as measured by duration of response (DoR), progression free survival (PFS) and overall survival (OS).
Exploratory objectives
To assess predictive biomarkers for ORR, DoR, PFS and OS in tumor tissue and blood samples.
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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]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
2. Age ≥ 18 years.
3. Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic, BTC not amenable to curative treatment (tumor resection or ablation), specified as
• Tumor being confined to the liver or
• In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent* AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation.
*Limited extent is defined in this protocol as presence of
o EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm)
o OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm).
o Presence of peritoneal or brain metastatsis excludes patients from study participation
4. Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator decision and after prior consultation with the tumor board if available at site and does not display contraindications against SIRT.
Contraindications against SIRT would be
o hepatic tumor load > 50%
o Any Gastrointestinal deposition that cannot be corrected via angiographic techniques
o irreversibly elevated serum bilirubin
o renal insufficiency
o increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs
o gastrointestinal ulceration
o hepatic dysfunction
o biliary complications
o portal hypertension
o vascular injury and lymphopenia.
5. Performance status (PS) ≤ 1 (ECOG scale).
6. Body weight >30 kg
7. At least one measurable site of disease as defined by RECIST 1.1 criteria.
8. Adequate bone marrow and renal function including the following:
o Hemoglobin ≥ 9.0 g/dL;
o absolute neutrophil count ≥ 1.5 x 103/L;
o platelets ≥100x 109 /L;
o Creatinine ≤ 1.5 x upper normal limit.
o Calculated creatinine clearance ≥40 mL/min as determined by the Cockcroft-Gault equation
9. Adequate hepatic function (with stenting for any obstruction, if required) including the following:
o Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN);
o AST (SGOT) / ALT (SGPT) ≤ 2.5x institutional ULN
(NOTE: if liver metastases are present AST / ALT must be ≤ 5x institutional ULN;
o prothrombin time 60%;
o albumin 30 g/L.
10. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
11. 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:
o 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).
o 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).
12. 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.
13. Must have a life expectancy of at least 12 weeks.
14. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria:
- Patients with HBV or HCV infection should be monitored for viral levels during study participation.
- Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines.
Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment.
- HCV patients with advanced BTC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug.
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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. Presence of peritoneal carcinomatosis or brain metastases.
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
o Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab and tremelimumab may be included only after consultation with the Coordinating Investigator.
6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
7. Prior radiotherapy treatment before the first dose of any study drug.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.
9. 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], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis]. The following are exceptions to this criterion:
o Patients with vitiligo or alopecia
o Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
o Any chronic skin condition that does not require systemic therapy
o Patients without active disease in the last 5 years may be included but only after consultation with the study physician
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, 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.
11. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2 pneumonitis.
12. History of another primary malignancy except for:
o 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
o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
o Adequately treated carcinoma in situ without evidence of disease
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. History of allogenic organ transplantation.
17. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or active hepatitis B/hepatitis C co-infection.
18. 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:
o Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
o Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
o Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
24. Receipt of live attenuated vaccine within 30 days prior to the first administration of any of the IMPs and without need to receive any live attenuated vaccines during study conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end of Tremelimumab treatment respectively.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint
• Objective response rate (ORR) [according to RECIST 1.1]
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After LPLV, approx. December 2023 |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
• Safety (rate of adverse events)
• Duration of response (DoR)
• Progression free survival (PFS)
• Overall survival (OS)
• Exploratory: Predictive biomarkers for ORR, DoR, PFS, OS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After LPLV, approx. December 2023 |
|
| 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 | No |
| 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 | No |
| 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 | 2 |
| 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 | 20 |
| 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
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| LVLS as defined as End of Safety Follow-Up of last treated subject in the trial (last patient last treatment +90 days) |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
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