| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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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 | 10028982 |
| E.1.2 | Term | Neoplasm biliary tract |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10074879 |
| E.1.2 | Term | Extrahepatic cholangiocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017614 |
| E.1.2 | Term | Gallbladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate clinical efficacy of M7824 based on ORR |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate clinical efficacy of M7824 based on duration of response (DOR)
•To evaluate clinical efficacy of M7824 based on durable response rate (DRR)
•To evaluate clinical safety of M7824
•To evaluate clinical efficacy based on progression free survival (PFS)
•To evaluate ORR, DOR, DRR and PFS by Investigator read
•To evaluate clinical efficacy based on overall survival (OS)
•To characterize the pharmacokinetic (PK) profile of M7824
•To characterize the immunogenicity of M7824
•To evaluate clinical efficacy of M7824 based on ORR, DOR and DRR according to programmed death ligand 1 (PD-L1) expression and microsatellite instability (MSI) status retrospectively |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are ≥ 18 years of age at the time of signing the informed consent. In Japan, if a participant is at least 18 but < 20 years of age, written informed consent from his/her parent or guardian will be required in addition to the participant’s written consent.
2. Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC.
3. Availability of tumor (primary or metastatic) archival material or fresh biopsies is mandatory. Fine needle aspirates, transductal aspirates, or cell blocks are not acceptable. Endoscopic retrograde cholangiography or intraductal ultrasounds assisted biopsy is acceptable, needle or excisional biopsies, or resected tissue, are preferable. Tumor biopsies and tumor archival material must be suitable for biomarker assessment as described in the Laboratory Manual.
4. Participants with BTC must have failed or be intolerant to 1L systemic platinum-based chemotherapy administered for locally advanced or metastatic disease. Only one prior treatment line is allowed. Participants who received adjuvant platinum-based chemotherapy and had evidence of disease recurrence within 6 months of completion of the adjuvant treatment are also eligible. If recurrence occurs during or within 6 months after the adjuvant chemotherapy, adjuvant platinum-based chemotherapy is counted as 1L chemotherapy.
5. Disease must be measurable with at least 1 unidimensionally measurable lesion by RECIST 1.1 and verified independently by IRC.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1 at study entry and Day 1 of treatment with M7824.
7. Life expectancy ≥ 12 weeks as judged by the Investigator.
8. Adequate hematological function defined by white blood cell (WBC) count ≥ 3 × 109/L with absolute neutrophil count ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 75 × 109/L, and hemoglobin (Hgb) ≥ 9 g/dL.
9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase (AST) level ≤ 2.5 × ULN, and an alanine aminotransferase (ALT) level ≤ 2.5 × ULN. For participants with liver involvement in their tumor, AST ≤ 5.0 × ULN and ALT ≤ 5.0 × ULN is acceptable. Participants with biliary obstruction should have an adequate biliary drainage with no evidence of ongoing infection. Biliary duct obstruction should be relieved by internal endoscopic drainage/stenting at least 2 weeks prior to dosing or by palliative bypass surgery or percutaneous drainage prior to study entry, and the participant should have no active or suspected infection. Participants fitted with a biliary stent should be clinically stable and free of signs of infection for ≥ 2 weeks prior to dosing.
10. Adequate coagulation function defined as prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy.
11. Albumin ≥ 3.0 g/dL.
12. Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals (e.g., entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at study entry and with planned monitoring and management including baseline HBV DNA quantity according to appropriate labeling guidance. Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at study entry and with planned monitoring and management according to appropriate labeling guidance of an approved antiviral.
13. Adequate renal function defined by either creatinine ≤ 1.5 × ULN or an estimated creatinine clearance (CCr) > 40 mL/min according to the Cockcroft-Gault formula or by measure of CCr from 24-hour urine collection.
• CCr (mL/min) = (140 age) × weight (kg)/(72 × serum Cr jaffe)
• If female, × 0.85
• If Cr is measured by enzymatic method, add 0.2 and use as Crjaffe = 0.2 + Crenzume.
14. Male participants are eligible to participate if they agree to the appropriate contraception requirements, as described in the protocol, during the intervention period and for at least 4 months after the last dose of study intervention.
15. A female is eligible if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP
OR
• If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, as described in the protocol, before the first dose of the study intervention, during the intervention period and after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 2 months after the last dose of study intervention.
Other criteria may apply (refer to Clinical Trial Protocol) |
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| E.4 | Principal exclusion criteria |
1.Ampullary cancer is excluded
2.Rapid clinical deterioration other than malignancy which,in the opinion of the Investigator, may predispose to inability to tolerate treatment or study procedures
3.Participants with active central nervous system(CNS) metastases causing clinical symptoms or metastases that require therapeutic intervention are excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months and do not require continued steroid therapy
5.Other previous and/or intercurrent malignancy except for curatively treated cancers with no recurrence in >3 years since treatment completion, or early cancers treated with curative intent, including cervical carcinoma in situ, superficial, noninvasive bladder cancer, or basal cell or squamous cell carcinoma in situ. Endoscopically resected early gastrointestinal cancers limited in mucosal layer (esophageal, gastric, and colorectal) that are without recurrence in >1 year are allowed
6.Significant acute or chronic infections, including:
•Uncontrolled biliary infection. Biliary tract obstruction should be released by stenting or percutaneous transhepatic biliary drainage
•Known history of positive test for HIV or known acquired immunodeficiency syndrome
•Active tuberculosis infection (clinical symptoms, physical or radiographic, and laboratory findings)
•Active bacterial or fungal infection requiring IV systemic therapy
7.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
•Participants with diabetes type 1, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
•Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤10 mg of prednisone or equivalent per day
•Administration of steroids for other conditions through a route known to result in a minimal systemic exposure(topical, intranasal, intro-ocular, or inhalation) is acceptable
8.History of non-infectious ILD requiring systemic steroid treatment, or current pneumonitis
9.Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before enrollment
10.Known severe hypersensitivity (Grade ≥3 NCI CTCAE 5.0) to investigational product (M7824) or any components in their formulations, any history of anaphylaxis, or recent, within 5 months, history of uncontrolled asthma
11.Persisting Grade >1 NCI CTCAE 5.0 toxicity (except alopecia and vitiligo) related to prior therapy;however, sensory neuropathy Grade ≤2 is acceptable
12.Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke(<6 months prior to enrollment), myocardial infarction(<6 months prior to enrollment), unstable angina, congestive heart failure (≥NYHA class II), or serious cardiac arrhythmia
13.Clinically relevant diseases (eg.inflammatory bowel disease) and/or uncontrolled medical conditions. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for study intervention are also excluded.
14.Any psychiatric condition that would prohibit the understanding or rendering of informed consent
15.Participants who are not eligible for or have not been treated with 1L systemic chemotherapy will be excluded
16.Systemic anticancer treatment after failing 1L platinum-based chemotherapy
17.Concurrent treatment with nonpermitted drugs
18.Prior participation in a M7824 clinical trial
19.Prior therapy with other immunotherapy or checkpoint inhibitors, such as anti-PD 1,anti PD L1, anti-CTLA-4 antibodies
20.Prior therapy with any antibody or inhibitors targeting the TGF-β/TGF-β receptor pathway
21.Anticancer treatment within 21 days before the start of study intervention, eg, cytoreductive therapy, radiotherapy involving >30% of the bone marrow (with the exception of palliative bone-directed radiotherapy),immune therapy, or cytokine therapy
22.Anticancer treatment with antibody within 28 days before the start of study intervention
23.Systemic therapy with immunosuppressive agents within 7 days before the start of intervention; or use of any investigational drug within 28 days before the start of intervention
24.Vaccine administration within 4 weeks of M7824 administration. Vaccination with live vaccines while on study is prohibited. Administration of inactivated vaccines is allowed
27.Major surgery within 28 days before the start of study intervention
28.Pregnancy or breast feeding.
30.Legal incapacity or limited legal capacity
Other criteria may apply-See Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by an Independent Review Committee (IRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from first administration of study intervention to up to month 24 |
|
| E.5.2 | Secondary end point(s) |
1.DOR assessed from complete response (CR) or partial response (PR) until progression of disease (PD), death, or last tumor assessment assessed by an IRC
2.Durable response of at least 6 months according to RECIST 1.1 assessed by an IRC
3.Occurrence of treatment-emergent adverse events (TEAEs) and treatment related adverse events (AEs), including adverse events of special interest (AESIs)
4.PFS according to RECIST 1.1 assessed by an IRC
5.OR, DOR, DRR, and PFS according to RECIST 1.1 assessed by Investigator read
6.OS
7.The concentration observed immediately at the end of infusion (CEOI) of M7824
8.The concentration observed immediately before next dosing (corresponding to pre-dose or trough concentration [Ctrough] for multiple dosing) of M7824
9.Immunogenicity of M7824 as measured by antidrug antibody (ADA) assay
10.Confirmed OR according to RECIST 1.1 assessed by an IRC according to PD-L1 expression and MSI status
11.DOR and durable response of at least 6 months according to RECIST 1.1 assessed by IRC according to PD-L1 expression and MSI status |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2.from first documentation of objective response (CR or PR) to the date of first documentation of objective PD or death due to any cause
3.from first dose to 30 days after last treatment
4-5.from first documentation of objective response (CR or PR) to the date of first documentation of objective PD or death due to any cause
6.from first administration of study intervention to the date of death due to any cause
7-8.Q6W up to/including W25, then Q12W from first administration of study intervention to last dose of treatment
9.Q6W up to/including W25, then Q12W from screening through 12 weeks (± 2 weeks) after last treatment
10-11.from first administration of study intervention to to the date of first documentation of objective progression of disease (PD) or death due to any cause |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| China |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study is defined as the date when each participant was followed up for at least 3 years after the End of Treatment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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