Efficacy and Safety of GemCis Plus Trastuzumab Plus Pembrolizumab in Previously Untreated HER2-positive Biliary Tract Cancer

Inclusion Criteria:

1. Participant provides written informed consent.

2. Male/female Participants who are at least 18 years of age on the day of signinginformed consent.

3. Participant is, in the investigator's judgement, willing and able to comply with thestudy protocol.

4. Participant has histologically confirmed diagnosis of cholangiocarcinoma orgallbladder cancer.

5. Participant is not eligible for surgery.

6. Participants must have HER2-positive disease defined as either IHC 3+ or IHC 2+, thelatter in combination with FISH+, as assessed locally on primary tumor OR positivelyconfirmed by NGS-analysis OR positively confirmed by mRNA

7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose ofstudy intervention.

8. Male Participants must agree to use a contraception as detailed in Appendix 3 ofthis protocol during the treatment period and for at least 7 months after the lastdose of study treatment and refrain from donating sperm during this period. Female Participants are eligible to participate if they are not pregnant (seeAppendix 3), not breastfeeding, and at least one of the following conditionsapplies:

• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR

• A WOCBP who agrees to follow the contraceptive guidance as given in Appendix 3during the treatment period and for at least 7 months after the last dose ofstudy intervention

9. Participant has measurable disease based on RECIST v1.1. Lesions situated in apreviously irradiated area are considered measurable if progression has beendemonstrated in such lesions.

10. Have adequate organ function as defined in the following table (Table 2).

11. Criteria for known Hepatitis B and C positive subjects Hepatitis B and C screeningtests are not required unless there is a known history of HBV or HCV infectionand/or as mandated by local health authority

12. Hepatitis B positive subjects

• Participants who are HBsAg positive are eligible if they have received HBVantiviral therapy for at least 4 weeks and have undetectable HBV viralload (< 100 IU/mL) prior to enrollment
• Participants should remain on anti-viral therapy throughout studyintervention and follow local guidelines for HBV anti-viral therapy postcompletion of study intervention.

2. Participants with history of HCV infection are eligible if HCV viral load isundetectable at screening.

• Participants must have completed curative anti-viral therapy at least 4weeks prior to enrollment.

Exclusion Criteria:

1. Participant has received prior systemic anti-cancer therapy NOTE: Participants whohave received up to 2 cycles of prior GemCis treatment prior to initiation of studytreatment and would begin therapy according to protocol with cycle 3, are eligiblefor the study

2. Participant has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2agent or with an agent directed to another stimulatory or co-inhibitory T-cellreceptor (e.g., CTLA-4, OX 40, CD137).

3. Participant has received prior radiotherapy within 2 weeks of start of studyintervention. Participants must have recovered from all radiation-relatedtoxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) tonon-CNS disease.

4. Participant has received a live vaccine or live-attenuated vaccine within 30 daysbefore the first dose of study intervention. Administration of killed vaccines isallowed.

5. Participant is currently participating in or has participated in a study of aninvestigational agent or has used an investigational device within 4 weeks prior tothe first dose of study intervention. NOTE: Participants who have entered the follow-up phase of an investigational studymay participate as long as it has been 4 weeks after the last dose of the previousinvestigational agent.

6. Participant has a diagnosis of immunodeficiency or is receiving chronic systemicsteroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or anyother form of immunosuppressive therapy within 7 days prior to the first dose ofstudy drug.

7. Participant has known additional malignancy that is progressing or has requiredactive treatment within the past 3 years. Note: Participants with basal cellcarcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ,excluding carcinoma in situ of the bladder, that have undergone potentially curativetherapy are not excluded.

8. Participant has known active CNS metastases and/or carcinomatous meningitis.Participants with previously treated brain metastases may participate provided theyare radiologically stable, i.e. without evidence of progression for at least 4 weeksby repeat imaging (note that the repeat imaging should be performed during studyscreening), clinically stable and without requirement of steroid treatment for atleast 14 days prior to first dose of study intervention.

9. Participant has severe hypersensitivity (≥grade 3) to pembrolizumab, trastuzumab,gemcitabine, cisplatin and/or any of their excipients.

10. Participant has active autoimmune disease that has required systemic treatment inthe past 2 years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

11. Patient has inadequate cardiac function (LVEF value < 55%) as determined byechocardiography.

12. Participant has a history of (non-infectious) pneumonitis/interstitial lung diseasethat required steroids or has current pneumonitis/interstitial lung disease.

13. Participant has an active infection requiring systemic therapy.

14. Participant has a known history of Human Immunodeficiency Virus (HIV) infection.

15. Participant has a history or current evidence of any condition, therapy, orlaboratory abnormality or other circumstance that might confound the results of thestudy, interfere with the participant's participation for the full duration of thestudy, such that it is not in the best interest of the participant to participate,in the opinion of the treating investigator.

16. Participant has had an allogenic tissue/solid organ transplant.

17. Participant has known psychiatric or substance abuse disorders that would interferewith cooperation with the requirements of the trial.

18. Participants who are pregnant or breastfeeding or expecting to conceive or fatherchildren within the projected duration of the study, starting with the screeningvisit through 7 months after the last dose of trial treatment.

19. Participant is considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection. Examplesinclude, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstablespinal cord compression, superior vena cava syndrome, extensive interstitialbilateral lung disease on High Resolution Computed Tomography (HRCT) scan, previousallogenic bone marrow/blood transplantation or any psychiatric disorder or substanceabuse that prohibits obtaining informed consent

20. Patient who has been incarcerated or involuntarily institutionalized by court orderor by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.

21. Patients who are unable to consent because they do not understand the nature,significance and implications of the clinical trial and therefore cannot form arational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

22. Patients who are dependent on the sponsor, the investigator or the trial site.