Pemigatinib After Curative Local Therapy in Advanced iCCA With FGFR2 Fusion/Rearrangements

Inclusion Criteria: Patients who meet all of the following criteria are eligible for trial participation:

• Signed informed consent form (ICF).
• Patients*, age ≥ 18 years at the time of signing the informed consent form.
• Histologically proven and curatively treatable localized intrahepatic biliary tractcancer (iCCA only) with a previous maximum of 5 cm in diameter, without signs ofmetastatic disease, and proven FGRF2- fusions/ rearrangements, identified by routineFISH or by NGS testing. Note: Only CE-IVD marked NGS-tests are applicable which cover FGFR2 fusions andrearrangements
• Patients previously received SBRT or another minimally invasive technique (e.g.,laparoscopic liver resection) up to 12 weeks prior to enrolment
• Female patients who are considered as woman of childbearing potential (WOCBP) as wellas male patients who are sexually active with WOCBP must use any contraceptive methodwith a failure rate of less than 1% per year during the treatment as well as up to 1week after the last dose of pemigatinib. Female patients who are not of childbearingpotential (i.e., who are postmenopausal or surgically sterile, see section 13.5) aswell as azoospermic male patients do not require contraception. Female patientsconsidered as WOCBP must have a negative pregnancy test within the last 7 days priorto the start of study therapy.
• ECOG performance status 0-1.
• Appropriate hematological, hepatic and renal function:

1. Absolute number of neutrophils ≥ 1.5 x 109/L
2. Platelets ≥ 100 x 109/L
3. Hemoglobin ≥ 9 g/dL (5.58 mmol/L)
4. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
5. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN without existing liver metastases, or ≤ 5 xULN in the presence of liver metastases; AP ≤ 5 x ULN.

• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (measured by 24h urine) ≥ 40mL/min (i.e., if the serum creatinine level is > 1.5 x ULN, then a 24-h urine testmust be performed to check the creatinine clearance to be determined).

• Adequate coagulability, as determined by the International Normalized Ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 5 s above the ULN (unless anti-coagulationtherapy has been given). Patients receiving warfarin / Phenoprocoumon must be switchedto low molecular weight heparin before starting any study-specific procedures.

• Patients must be able to take oral medications.

• For patients with active hepatitis B virus (HBV): HBV DNA ≤ 500 IU/mL obtained within 28 days prior to initiation of study treatment, ANDAnti-HBV treatment (per local standard of care e.g. entecavir) prior to study entry andwillingness to continue treatment for the length of the study.

• For patients with active hepatitis C virus (HCV): Patients positive for HCV antibody areeligible, also if polymerase chain reaction testing is positive for HCV RNA However,anti-viral therapy against HCV is only allowed prior to trial but not during the trial.

• Patients infected with human immunodeficiency virus (HIV) are eligible if they meetall the following criteria:

1. CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibitedcytochrome (CYP)-interacting medications
2. Probable long-term survival with HIV if cancer were not present
3. Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks andwilling to adhere to their HAART regimen with minimal overlapping toxicity anddrug-drug interactions with the experimental agents in this study
4. HIV is not multi-drug resistant
5. Taking medication and/or receiving antiretroviral therapy that does not interactor have overlapping toxicities with the study medication

• Subject is willing and able to comply with the protocol (including contraceptivemeasures) for the duration of the study including undergoing treatment, and scheduledvisits and examinations including follow up.

Exclusion Criteria: Patients who meet at least one of the following criteria are not eligible for trialparticipation:

• Presence of tumors other than biliary tract cancer or a secondary tumor other thansquamous or basal cell carcinomas of the skin or in situ carcinomas of the cervixwhich have been effectively treated. The Sponsor decides to include patients who havereceived curative treatment and have been disease-free for at least 3 years.
• Metastatic biliary tract cancer (intrahepatic, hilar, or distal CCA as well asgallbladder carcinoma) disease.
• Pretreatment with any systemic anti-cancer therapy.
• Simultaneous, ongoing systemic immunotherapy, chemotherapy, or hormone therapy notdescribed in the study protocol.
• Simultaneous treatment with a different anti-cancer therapy other than that providedin the study (excluding palliative radiotherapy only for symptom control).
• Previous therapy with an FGFR- inhibitor.
• Stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of anygrade) with a history of hepatic encephalopathy or clinically significant ascitesresulting from cirrhosis. Clinically significant ascites is defined as ascitesresulting from cirrhosis requiring diuretics or paracentesis.
• Known allergic / hypersensitive reactions to at least one of the treatment components.
• Other serious illnesses or medical ailments within the last 12 months prior to thestart of the study.
• Current evidence of clinically significant corneal (including but not limited tobullous/band keratopathy, corneal abrasion, inflammation/ulceration, andkeratoconjunctivitis) or retinal disorder (including but not limited to central serousretinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment)as confirmed by ophthalmologic examination.
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalancewith ectopic calcification of soft tissues (exception: commonly observedcalcifications in soft tissues, such as the skin, kidney, tendons or vessels due toinjury, disease, and aging, in the absence of systemic mineral imbalance).
• History of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000 UI/weekly)to replenish the deficiency. NOTE: Participants receiving vitamin D supplements areeligible .
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14days or 5 half-lives (whichever is longer) before the first dose of study treatment.NOTE: Moderate CYP3A4 inhibitors are not prohibited (refer to section Fehler!Verweisquelle konnte nicht gefunden werden. Appendix 3 for a list of CYP3A4 inhibitorsand inducers).
• Presence of an active, uncontrollable infection.
• Has active infection with SARS-CoV-2 (positive antigen test in routine testing atsite).
• Chronic inflammatory bowel disease.
• Active disseminated intravascular coagulation.
• Any other serious concomitant or medical condition that, in the opinion of theinvestigator, presents a high risk of complications to the patient or reduces thelikelihood of clinical effect.
• On-treatment participation in another interventional clinical study in the period 30days prior to inclusion and during the study.
• Patient pregnant or breast feeding, or planning to become pregnant
• Patient in a closed institution according to an authority or court decision (AMG § 40,Abs. 1 No. 4).
• Subjects that are depending on the Sponsor/CRO or investigational site as well as onthe investigator.