| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced and/or Unresectable Biliary Tract Carcinoma (Intrahepatic, Extrahepatic, or Gallbladder) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced (metastatic) and/or unresectable (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or gallbladder cancer). This study is treatment naïve participants |
|
| 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 | 10004655 |
| E.1.2 | Term | Biliary carcinoma |
| 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 |
1. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by Blinded Independent Central Review (BICR), between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
2. To compare overall survival (OS) between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
|
|
| E.2.2 | Secondary objectives of the trial |
1. To compare objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by Blinded Independent Central Review (BICR), between pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin
2. To evaluate duration of response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
3. To evaluate the safety and tolerability profile of pembrolizumab plus gemcitabine/cisplatin
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Sponsor will conduct Future Biomedical Research on DNA (blood, tumor material) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time |
|
| E.3 | Principal inclusion criteria |
1. Has histologically confirmed diagnosis of advanced (metastatic) and/or unresectable (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or gallbladder cancer).
2. Have measurable disease based on RECIST 1.1, as determined by the site investigator. Lesions situated in a previously treated area by either radiotherapy, photodynamic therapy, or arterial embolization are considered measurable if progression has been demonstrated in such lesions and they meet criteria for measurable disease.
3. Participants with past or ongoing HCV infection are eligible for the study. Treated participants must have completed their treatment at least 1 month prior to starting study intervention. Untreated or incompletely treated HCV participants may initiate anti-viral therapy for HCV if liver function remains stable for at least 3 months on study intervention.
4. Participants with controlled hepatitis B are eligible for the study , as long as they meet the following criteria:
- Participants with chronic HBV infection, defined as HBsAg positive and/or detectable HBV DNA, must be given antiviral therapy for HBV for at least 4 weeks prior to the first dose of study intervention and HBV viral load must be less than 100 IU/mL prior to first dose of study treatment. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention. Antiviral therapy after completion of study intervention should follow local guidelines.
- Participants with clinically resolved HBV infection, defined as HBsAg negative and anti-HBc positive, and who have an undetectable HBV viral load at screening should be checked every 6 weeks for HBV viral load and treated for HBV if viral load is over 100 IU/mL. Antiviral therapy after completion of study intervention should follow local guidelines.
5. Is male or female, from at least 18 years of age inclusive, at the time of signing the informed consent.
6. Male participants are eligible to participate if they agree to the following during the intervention period and for at least and through 120 days after the last dose of chemotherapy:
• Refrain from donating sperm, PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
• Must agree to use contraception unless confirmed to be azoospermic.
• Male participants must also agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP) OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in the Protocol
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
8. The participant (or legally acceptable representative, if applicable) provides written informed consent for the study.
9. Have a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior to the first dose of study intervention.
10. Provide archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated (ie, obtained for histological confirmation) for biomarker analysis. The tumor tissue must be received by the central vendor and be deemed adequate for biomarker analysis evaluation prior to participant randomization. Formalin fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
11. Have a life expectancy of greater than 3 months.
12. Have adequate organ function. Specimens must be collected within 14 days prior to the first dose of study intervention. |
|
| E.4 | Principal exclusion criteria |
1. Has had previous systemic therapy for advanced (metastatic) or unresectable (locallyadvanced) biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), with the exception of adjuvant therapy which is allowed. Adjuvant therapy should have been completed at least 6 months prior to diagnosis of advanced and/or unresectable disease.
2. Has ampullary cancer.
3. Has small cell cancer, neuroendocrine tumors, lymphoma, sarcoma and/or Mucinous cystic neoplasms.
4. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
5. Has undergone major surgery and has not recovered adequately from the toxicity to ≤Grade 1 and/or complications from the intervention prior to starting study intervention.
6. A WOCBP who has a positive urine pregnancy test within 24 hours prior to administration of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX- 40, CD137).
8. Has received prior anti-cancer therapy for advanced unresectable biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), including investigational agents within 4 weeks prior to randomization.
9. Has not recovered (ie, AE ≤Grade 1 or baseline) from AEs due to previously administered chemotherapy. Participants with ≤Grade 2 neuropathy may be eligible based on investigator assessment.
10. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
11. Has received a live vaccine within 30 days prior to the first dose of study intervention.
12. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
14. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, gemcitabine, or cisplatin and/or any of their excipients.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
17. Has an active infection requiring systemic therapy, with the exception of HBV, and HCV.
18. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
19. Has a known history of human immunodeficiency virus (HIV) infection.
20. Has known active tuberculosis.
21. Has a known history of, or any evidence of, CNS metastases and/or carcinomatous meningitis, as assessed by local site investigator.
22. Has a history or current evidence of any condition, (eg, hearing impairment, etc.), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 210 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab or placebo, whichever is greater.
25. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR)
2. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 48 months
2. Up to 48 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
2. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
3. Number of Participants Who Experienced One or More Adverse Events (AEs)
4. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 48 months
2. Up to 48 months
3. Up to 48 months
4. Up to 48 months |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health Utility Scores; anti-MK3475 antibody levels |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| France |
| Germany |
| Hong Kong |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Netherlands |
| New Zealand |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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