| Eligibility |
Inclusion Criteria:
1. Participant provides written informed consent.
2. Male/female Participants who are at least 18 years of age on the day of signing
informed consent.
3. Participant is, in the investigator's judgement, willing and able to comply with the
study protocol.
4. Participant has histologically confirmed diagnosis of cholangiocarcinoma or
gallbladder cancer.
5. Participant is not eligible for surgery.
6. Participants must have HER2-positive disease defined as either IHC 3+ or IHC 2+, the
latter in combination with FISH+, as assessed locally on primary tumor OR positively
confirmed by NGS-analysis OR positively confirmed by mRNA
7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of
study intervention.
8. Male Participants must agree to use a contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least 7 months after the last dose of
study treatment and refrain from donating sperm during this period.
Female Participants are eligible to participate if they are not pregnant (see Appendix
3), not breastfeeding, and at least one of the following conditions applies:
- 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 3
during the treatment period and for at least 7 months after the last dose of
study intervention
9. Participant has measurable disease based on RECIST v1.1. Lesions situated in a
previously irradiated area are considered measurable if progression has been
demonstrated 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 screening
tests are not required unless there is a known history of HBV or HCV infection and/or
as mandated by local health authority
1. Hepatitis B positive subjects
- Participants who are HBsAg positive are eligible if they have received HBV
antiviral therapy for at least 4 weeks and have undetectable HBV viral load
(< 100 IU/mL) prior to enrollment
- Participants should remain on anti-viral therapy throughout study
intervention and follow local guidelines for HBV anti-viral therapy post
completion of study intervention.
2. Participants with history of HCV infection are eligible if HCV viral load is
undetectable at screening.
- Participants must have completed curative anti-viral therapy at least 4
weeks prior to enrollment.
Exclusion Criteria:
1. Participant has received prior systemic anti-cancer therapy NOTE: Participants who
have received up to 2 cycles of prior GemCis treatment prior to initiation of study
treatment and would begin therapy according to protocol with cycle 3, are eligible for
the study
2. Participant 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 (e.g., CTLA-4, OX 40, CD137).
3. Participant 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 not have had radiation pneumonitis. A 1-week washout
is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.
4. Participant has received a live vaccine or live-attenuated vaccine within 30 days
before the first dose of study intervention. Administration of killed vaccines is
allowed.
5. Participant 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.
NOTE: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
6. Participant 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
drug.
7. Participant has known additional malignancy that is progressing or has required active
treatment within the past 3 years. Note: Participants with basal cell carcinoma of the
skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in
situ of the bladder, that have undergone potentially curative therapy are not
excluded.
8. Participant has known active CNS metastases and/or carcinomatous meningitis.
Participants with previously treated brain metastases may participate provided they
are radiologically stable, i.e. without evidence of progression for at least 4 weeks
by repeat imaging (note that the repeat imaging should be performed during study
screening), clinically stable and without requirement of steroid treatment for at
least 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 in the
past 2 years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment and is allowed.
11. Patient has inadequate cardiac function (LVEF value < 55%) as determined by
echocardiography.
12. Participant has a history of (non-infectious) pneumonitis/interstitial lung disease
that 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, or laboratory
abnormality or other circumstance that might confound the results of the study,
interfere with the participant's participation for the full duration of the study,
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 interfere
with cooperation with the requirements of the trial.
18. Participants who are pregnant or breastfeeding or expecting to conceive or father
children within the projected duration of the study, starting with the screening visit
through 7 months after the last dose of trial treatment.
19. Participant is considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on High Resolution Computed Tomography (HRCT) scan, previous allogenic bone
marrow/blood transplantation or any psychiatric disorder or substance abuse that
prohibits obtaining informed consent
20. Patient who has been incarcerated or involuntarily institutionalized by court order or
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 a
rational 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.
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